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2022 Rare Neurological Disease Special Report
INTRODUCTION
Editor’s note
By Glenn S. Williams
Our 7th annual issue highlights several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing.
A note from NORD
By Peter L. Saltonstall
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
CLINICAL REVIEWS
Health care providers should have higher suspicion for rare diseases
By Jeff Craven
Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The paradox of Pompe disease
By Jennie Smith
For nearly 2 decades, patients with even the most severe genetic mutations have been surviving on therapy. But clinicians must now contend with previously unknown manifestations of this rare muscular disease.
Rett syndrome: Looking to the future and the promise of gene therapy
By Courtney S. Ambrose and Barbara J. Bailus, PhD
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and conviction, not just hopeful optimism.
Rare disease patient advocacy groups empowered by data
By Theodore Bosworth
On the IAMRARE platform, patient advocacy organizations are trained to conduct observational research and host natural history.
Myasthenia gravis: Finding strength in treatment options
By Peter van der Eb; Scarlet Toruno, MS; and Jason Laird, DMSc, MHS, MBA, PA-C
Although the treatment of myasthenia gravis might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies.
Spinal muscular atrophy: Patient care in the age of genetically targeted therapy
By Kelli Whitlock Burton
Newly available treatments have changed the natural history of SMA. Newborn screening, updated treatment guidelines, and treatment algorithms have likewise changed what can be clinically done for patients with SMA, but still questions remain.
The broad and challenging – but promising – landscape of peripheral neuropathy
By Yun Seo Lee; Jonathan Kosacki; Kanika Bhandari, PharmD; Amanda Tran, PharmD
This review of peripheral neuropathy summarizes the more common causative entities, diagnostic tools that can potentially be employed to identify the disorder, and treatments that are in use or being tested to prevent, slow, or reverse its effects.
NORD Rare Disease Centers of Excellence: A new network seeks to break down barriers in rare disease care
By Jennie Smith
“The goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.”
Staying alert for patients with narcolepsy
By Erik Greb
The chronic neurologic disorder entails not only excessive sleepiness but also social and professional challenges.
ONLINE-ONLY CONTENT
Novel gene-based therapies for neuromuscular diseases
By Nahomi Yewhalashet, MBS, and Larry J. Davis, PharmD
Novel gene-based therapies show significant potential for transforming the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Duchenne muscular dystrophy.
The urgent need to diagnose Sanfilippo syndrome at an early age
By Theodore Bosworth
The quest for effective treatments is dependent on enrolling more children at a very young age, before loss of milestones.
INTRODUCTION
Editor’s note
By Glenn S. Williams
Our 7th annual issue highlights several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing.
A note from NORD
By Peter L. Saltonstall
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
CLINICAL REVIEWS
Health care providers should have higher suspicion for rare diseases
By Jeff Craven
Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The paradox of Pompe disease
By Jennie Smith
For nearly 2 decades, patients with even the most severe genetic mutations have been surviving on therapy. But clinicians must now contend with previously unknown manifestations of this rare muscular disease.
Rett syndrome: Looking to the future and the promise of gene therapy
By Courtney S. Ambrose and Barbara J. Bailus, PhD
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and conviction, not just hopeful optimism.
Rare disease patient advocacy groups empowered by data
By Theodore Bosworth
On the IAMRARE platform, patient advocacy organizations are trained to conduct observational research and host natural history.
Myasthenia gravis: Finding strength in treatment options
By Peter van der Eb; Scarlet Toruno, MS; and Jason Laird, DMSc, MHS, MBA, PA-C
Although the treatment of myasthenia gravis might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies.
Spinal muscular atrophy: Patient care in the age of genetically targeted therapy
By Kelli Whitlock Burton
Newly available treatments have changed the natural history of SMA. Newborn screening, updated treatment guidelines, and treatment algorithms have likewise changed what can be clinically done for patients with SMA, but still questions remain.
The broad and challenging – but promising – landscape of peripheral neuropathy
By Yun Seo Lee; Jonathan Kosacki; Kanika Bhandari, PharmD; Amanda Tran, PharmD
This review of peripheral neuropathy summarizes the more common causative entities, diagnostic tools that can potentially be employed to identify the disorder, and treatments that are in use or being tested to prevent, slow, or reverse its effects.
NORD Rare Disease Centers of Excellence: A new network seeks to break down barriers in rare disease care
By Jennie Smith
“The goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.”
Staying alert for patients with narcolepsy
By Erik Greb
The chronic neurologic disorder entails not only excessive sleepiness but also social and professional challenges.
ONLINE-ONLY CONTENT
Novel gene-based therapies for neuromuscular diseases
By Nahomi Yewhalashet, MBS, and Larry J. Davis, PharmD
Novel gene-based therapies show significant potential for transforming the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Duchenne muscular dystrophy.
The urgent need to diagnose Sanfilippo syndrome at an early age
By Theodore Bosworth
The quest for effective treatments is dependent on enrolling more children at a very young age, before loss of milestones.
INTRODUCTION
Editor’s note
By Glenn S. Williams
Our 7th annual issue highlights several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing.
A note from NORD
By Peter L. Saltonstall
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
CLINICAL REVIEWS
Health care providers should have higher suspicion for rare diseases
By Jeff Craven
Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The paradox of Pompe disease
By Jennie Smith
For nearly 2 decades, patients with even the most severe genetic mutations have been surviving on therapy. But clinicians must now contend with previously unknown manifestations of this rare muscular disease.
Rett syndrome: Looking to the future and the promise of gene therapy
By Courtney S. Ambrose and Barbara J. Bailus, PhD
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and conviction, not just hopeful optimism.
Rare disease patient advocacy groups empowered by data
By Theodore Bosworth
On the IAMRARE platform, patient advocacy organizations are trained to conduct observational research and host natural history.
Myasthenia gravis: Finding strength in treatment options
By Peter van der Eb; Scarlet Toruno, MS; and Jason Laird, DMSc, MHS, MBA, PA-C
Although the treatment of myasthenia gravis might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies.
Spinal muscular atrophy: Patient care in the age of genetically targeted therapy
By Kelli Whitlock Burton
Newly available treatments have changed the natural history of SMA. Newborn screening, updated treatment guidelines, and treatment algorithms have likewise changed what can be clinically done for patients with SMA, but still questions remain.
The broad and challenging – but promising – landscape of peripheral neuropathy
By Yun Seo Lee; Jonathan Kosacki; Kanika Bhandari, PharmD; Amanda Tran, PharmD
This review of peripheral neuropathy summarizes the more common causative entities, diagnostic tools that can potentially be employed to identify the disorder, and treatments that are in use or being tested to prevent, slow, or reverse its effects.
NORD Rare Disease Centers of Excellence: A new network seeks to break down barriers in rare disease care
By Jennie Smith
“The goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.”
Staying alert for patients with narcolepsy
By Erik Greb
The chronic neurologic disorder entails not only excessive sleepiness but also social and professional challenges.
ONLINE-ONLY CONTENT
Novel gene-based therapies for neuromuscular diseases
By Nahomi Yewhalashet, MBS, and Larry J. Davis, PharmD
Novel gene-based therapies show significant potential for transforming the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Duchenne muscular dystrophy.
The urgent need to diagnose Sanfilippo syndrome at an early age
By Theodore Bosworth
The quest for effective treatments is dependent on enrolling more children at a very young age, before loss of milestones.
Rare disease patient advocacy groups empowered by data
With the goal of advancing treatment of rare neurological diseases – or rare diseases of any type – the National Organization for Rare Disorders (NORD) has launched innovative new research initiatives in recent years to help patient advocacy organizations develop a precious asset: data to support better understanding of diseases and research that might lead to life-altering diagnostics or treatments.
“Most rare diseases still don’t have approved therapies, and the problem is often a lack of the basic information needed to advance research,” explained Aliza Fink, DSc, the director of research programs at NORD. “Our goal is to help patient organizations play a key role in the collection, analysis, and sharing of data to support better understanding of how a disease presents, its natural history, the types and severity of symptoms, and other unanswered questions.”
Over the past 2 decades, the Internet, social media, and other communications resources have provided patient organizations with unprecedented reach. As a result, these organizations are in a unique position to connect patients and caregivers around the world – those dealing with even the rarest of rare diseases – and become a repository of information on the disease and the patient experience.
Since the late 1980s, NORD has had a research grants program, and the grants this program provides to academic researchers have led to numerous significant discoveries and publications, as well as to two products that ultimately were approved by FDA. More recently, however, NORD’s research programs have been expanded to include an initiative known as IAMRARE, in which patient advocacy organizations are trained to conduct observational research and host natural history studies and registries on a platform developed by NORD.
“We work with the patient groups to determine what types of data would be most important to drive research, help develop the methodology for data collection, and advise them on protocols for supporting the quality and integrity of the data,” Dr. Fink said. “By systematically collecting data from the patients and families they serve, these groups are in a position to contribute enormously to understanding the disease and advancing research.”
NORD also helps with the practical aspects of conducting research of sufficient quality to be publishable, such as providing groups with guidelines and best practices for developing medical advisory committees, creating templates and materials to streamline their project’s submission to institutional review boards, ensuring data security and privacy in accordance with Health Insurance Portability and Accountability Act criteria, and developing other expected standards for data collection and analysis.
Unlike even academic medical centers with an interest in a given rare disease, leading patient advocacy groups for these specific disorders have unmatched access to affected patients and families. This includes patients being managed in diverse settings or those not yet receiving care at all. By harnessing this patient population to record the signs, symptoms, disease course, and other information, the patient advocacy groups can contribute greatly to the pool of available data and ultimately what is known about the disease.
Data empowers research
While NORD helps groups through the IAMRARE program to become research-ready and guides them in developing research protocols and goals, the data are ultimately owned by the patient advocacy groups themselves. This helps to ensure that the patient voice is heard. By controlling data collection and dissemination, the advocacy groups can take a leading role in defining the goals of research, including what outcome measures are important to them and what they agree are the most promising avenues for research to achieve those goals.
“By collecting the data to understand the disease, it sets the stage for the next steps in research,” explained Debbie Drell, the director of membership for NORD. She noted that IAMRARE has grown steadily since its inception in 2014 and that there are now close to 40 advocacy groups participating.
The value of this initiative is not difficult to grasp. Even though direct participation in research was not generally part of the agenda for some advocacy groups when IAMRARE was conceived, Ms. Drell said that this initiative is a compelling perk of becoming involved with NORD. Groups that elect to become research-ready in order to participate in IAMRARE fall into a category of membership that requires specific organizational structures – such as a medical advisory board – and NORD provides templates and guidance to help them meet these qualifications to successfully become research-ready.
Collaboration leads to progress
NORD was founded by an ad hoc committee of patient organizations that played a key role in enactment of the Orphan Drug Act nearly 40 years ago. Shortly after the Orphan Drug Act was passed by Congress and signed into law by President Ronald Reagan in 1983, the ad hoc committee formally united to create NORD to continue the momentum of this initial collaboration and support the rare disease community. According to Mary Dunkle, a senior advisor at NORD, passage of the Orphan Drug Act, which is widely considered a major driver of progress in development of treatments for rare diseases, made the advantages of their cooperation clear.
“The groups had so many issues in common across the spectrum of diseases that they decided to continue their collaboration,” she explained. ”They realized that, while each disease is rare, the challenges they present to patients, families, clinicians, and researchers have many similarities.”
The definition of rare disease, according to the National Institutes of Health, is a disorder that affects fewer than 200,000 people in the United States. More than 7,000 such disorders have been identified. Approximately one-third of rare diseases are neurological. Whether neurological or affecting different or multiple organ systems, most – perhaps 75%-80% – involve a genetic component, according to Ms. Dunkle.
Research reaps rewards
Altogether, today there are more than 1,000 patient organizations that provide various types of support and services for patients and caregivers affected by rare diseases. Approximately one-third of these organizations are members of NORD. For organizations that don’t yet meet the membership criteria or for other reasons have not yet formally joined NORD, there are still many opportunities to get involved and to learn best practices to strengthen their governance, infrastructure, and capacity to support their members.
Of these, the IAMRARE program is one of the best examples of ways to get involved. Beyond the many other ways these groups help patients and families cope with challenging diseases, participation in research takes rare disorder advocacy to a different level. Objective data can attract the attention of those with the resources to further study the disease, while also giving advocacy groups a seat at the table when researchers or industry become interested.
“Why create a registry? It removes competition between academic centers or industry working on their own. It creates one central source for data-sharing, and the advantage is that advocacy groups have a trusted relationship with the patient community because they are not-for-profit, community-run, and patient-driven,” Ms. Drell explained.
The registry platforms developed for IAMRARE are customizable. With guidance from NORD, the advocacy groups themselves decide what data to collect and what questions they wish to answer, according to Dr. Fink. Once the registries are created, patients and caregivers participate by responding to survey questions on disease onset, progression over time, types and severity of symptoms, and other topics. The data can be de-identified for research purposes. The advocacy groups decide how and when to share the data, including whether to publish findings.
“Some of the groups have been very successful in getting the data published and leveraging their results to drive research forward, but there is variability in the extent of dissemination across the groups,” said Dr. Fink. She noted that many of the registries that NORD has helped set up involve groups whose officers have had little or no prior research experience.
“We have advocacy groups that have had biomedical researchers on staff and other groups that are coming to research completely new,” Dr. Fink said. In trying to get them up to speed on quality data collection, “We try to meet them where they are,” she added, indicating that leading groups to a research-ready status is not just about logistics but can sometimes involve an organizational reorientation.
The examples of peer-reviewed publications that can be directly traced to IAMRARE registries are growing. One example is a registry on Prader-Willi syndrome, which is a complex neurodevelopmental disorder characterized by failure to thrive and by multiple endocrine abnormalities. The registry was developed in NORD’s IAMRARE program by the Foundation for Prader-Willi Research, a nonprofit created in 2003 by parents of children with this disorder.
By 2019, when the first data from the Global Prader-Willi Syndrome Registry were published, they drew from 23,550 surveys completed for 1,696 separate cases of the disorder in 37 countries. The surveys provided some preliminary findings on demographics and on the genetic subtypes most commonly encountered, as well as simply proof that the registry was viable. From its inception in 2015, a significant proportion of the Prader-Willi population in the United States had been enrolled, according to the study authors. With time, the serial accumulation of more data on more cases will be invaluable for documenting disease characteristics. It will be a constantly maturing resource even after fundamental questions on disease impact and prognosis are addressed.
Data accumulation
Only about 10% of rare diseases currently have approved treatments, but there is widespread belief in the rare community that collecting and analyzing the data that can promote understanding of the biology of the disease and identify therapeutic targets could accelerate the development of treatments for diseases that currently have none.
Therefore, data accumulation has become central to the mission of NORD. In addition to IAMRARE, the organization has embarked on several other important initiatives in data accumulation for rare diseases. One is the Rare Disease Cures Accelerator – Data and Analytics Platform (RDCA-DAP), an initiative in which NORD is partnering with the Critical Path Institute. The goal of this program is to gather disparate pools of existing data in a standardized format to increase their power.
“With funding from the Food and Drug Administration, we have helped to support this platform, which is designed specifically to provide a centralized structure for combining and sharing of data,” according to Dr. Fink. In RDCA-DAP, patient-level data is being assembled from a variety of resources, including academic centers, industry, registries, observational studies, and clinical trials. The program was launched in September 2021. In some cases, gaining access to data includes resolving privacy issues or addressing the proprietary concerns of those who currently have the data, but the value of the combined data is a compelling argument for participation.
“What we are trying to do is pull together the data from their current silos into one platform, and then make it generally available,” said Dr. Fink. As with IAMRARE, RDCA-DAP offers enormous potential.
“The primary challenge for those studying rare diseases is the small numbers of patients. Randomized clinical trials for some of these diseases are simply not feasible because there are not enough subjects to power two study arms,” said Dr. Fink in explaining why NORD has turned to novel strategies for data generation. One strategy for maximizing the potential value of data from these small populations of patients is data-sharing. For RDCA-DAP, data access will be open to all stakeholders after scientific review and approval.
“Anyone can get an account and request data from the platform,” said Dr. Fink, who expects this to spur more and novel types of research in rare disorders.
Another example of recent NORD initiatives to advance research and understanding of rare diseases is a study of metachromatic leukodystrophy (MLD) that is now enrolling patients, which also represents a partnership with the FDA. For this study, which is known as the HOME study, NORD hosts a platform where patients and caregivers enter data to capture the natural history of this disease. All MLD patients, even if they are already participating in a clinical trial or another registry, are invited. As with the IAMRARE registries, surveys capture patient or caregiver responses entered from a computer or smart device.
“We have always believed that the fact that so many rare diseases don’t have treatments or are not even being studied by researchers doesn’t reflect a lack of interest among academic or industry researchers. Rather, it reflects a lack of data to support research and to provide a fundamental understanding of the disease,” Dr. Fink said. “If NORD’s expanded research programs can draw the patient community together to provide that crucially needed data, we will have provided an important and essential service to patients, patient organizations, and researchers alike.”
Theodore Bosworth is a freelance journalist and editor specializing in medicine and health.
With the goal of advancing treatment of rare neurological diseases – or rare diseases of any type – the National Organization for Rare Disorders (NORD) has launched innovative new research initiatives in recent years to help patient advocacy organizations develop a precious asset: data to support better understanding of diseases and research that might lead to life-altering diagnostics or treatments.
“Most rare diseases still don’t have approved therapies, and the problem is often a lack of the basic information needed to advance research,” explained Aliza Fink, DSc, the director of research programs at NORD. “Our goal is to help patient organizations play a key role in the collection, analysis, and sharing of data to support better understanding of how a disease presents, its natural history, the types and severity of symptoms, and other unanswered questions.”
Over the past 2 decades, the Internet, social media, and other communications resources have provided patient organizations with unprecedented reach. As a result, these organizations are in a unique position to connect patients and caregivers around the world – those dealing with even the rarest of rare diseases – and become a repository of information on the disease and the patient experience.
Since the late 1980s, NORD has had a research grants program, and the grants this program provides to academic researchers have led to numerous significant discoveries and publications, as well as to two products that ultimately were approved by FDA. More recently, however, NORD’s research programs have been expanded to include an initiative known as IAMRARE, in which patient advocacy organizations are trained to conduct observational research and host natural history studies and registries on a platform developed by NORD.
“We work with the patient groups to determine what types of data would be most important to drive research, help develop the methodology for data collection, and advise them on protocols for supporting the quality and integrity of the data,” Dr. Fink said. “By systematically collecting data from the patients and families they serve, these groups are in a position to contribute enormously to understanding the disease and advancing research.”
NORD also helps with the practical aspects of conducting research of sufficient quality to be publishable, such as providing groups with guidelines and best practices for developing medical advisory committees, creating templates and materials to streamline their project’s submission to institutional review boards, ensuring data security and privacy in accordance with Health Insurance Portability and Accountability Act criteria, and developing other expected standards for data collection and analysis.
Unlike even academic medical centers with an interest in a given rare disease, leading patient advocacy groups for these specific disorders have unmatched access to affected patients and families. This includes patients being managed in diverse settings or those not yet receiving care at all. By harnessing this patient population to record the signs, symptoms, disease course, and other information, the patient advocacy groups can contribute greatly to the pool of available data and ultimately what is known about the disease.
Data empowers research
While NORD helps groups through the IAMRARE program to become research-ready and guides them in developing research protocols and goals, the data are ultimately owned by the patient advocacy groups themselves. This helps to ensure that the patient voice is heard. By controlling data collection and dissemination, the advocacy groups can take a leading role in defining the goals of research, including what outcome measures are important to them and what they agree are the most promising avenues for research to achieve those goals.
“By collecting the data to understand the disease, it sets the stage for the next steps in research,” explained Debbie Drell, the director of membership for NORD. She noted that IAMRARE has grown steadily since its inception in 2014 and that there are now close to 40 advocacy groups participating.
The value of this initiative is not difficult to grasp. Even though direct participation in research was not generally part of the agenda for some advocacy groups when IAMRARE was conceived, Ms. Drell said that this initiative is a compelling perk of becoming involved with NORD. Groups that elect to become research-ready in order to participate in IAMRARE fall into a category of membership that requires specific organizational structures – such as a medical advisory board – and NORD provides templates and guidance to help them meet these qualifications to successfully become research-ready.
Collaboration leads to progress
NORD was founded by an ad hoc committee of patient organizations that played a key role in enactment of the Orphan Drug Act nearly 40 years ago. Shortly after the Orphan Drug Act was passed by Congress and signed into law by President Ronald Reagan in 1983, the ad hoc committee formally united to create NORD to continue the momentum of this initial collaboration and support the rare disease community. According to Mary Dunkle, a senior advisor at NORD, passage of the Orphan Drug Act, which is widely considered a major driver of progress in development of treatments for rare diseases, made the advantages of their cooperation clear.
“The groups had so many issues in common across the spectrum of diseases that they decided to continue their collaboration,” she explained. ”They realized that, while each disease is rare, the challenges they present to patients, families, clinicians, and researchers have many similarities.”
The definition of rare disease, according to the National Institutes of Health, is a disorder that affects fewer than 200,000 people in the United States. More than 7,000 such disorders have been identified. Approximately one-third of rare diseases are neurological. Whether neurological or affecting different or multiple organ systems, most – perhaps 75%-80% – involve a genetic component, according to Ms. Dunkle.
Research reaps rewards
Altogether, today there are more than 1,000 patient organizations that provide various types of support and services for patients and caregivers affected by rare diseases. Approximately one-third of these organizations are members of NORD. For organizations that don’t yet meet the membership criteria or for other reasons have not yet formally joined NORD, there are still many opportunities to get involved and to learn best practices to strengthen their governance, infrastructure, and capacity to support their members.
Of these, the IAMRARE program is one of the best examples of ways to get involved. Beyond the many other ways these groups help patients and families cope with challenging diseases, participation in research takes rare disorder advocacy to a different level. Objective data can attract the attention of those with the resources to further study the disease, while also giving advocacy groups a seat at the table when researchers or industry become interested.
“Why create a registry? It removes competition between academic centers or industry working on their own. It creates one central source for data-sharing, and the advantage is that advocacy groups have a trusted relationship with the patient community because they are not-for-profit, community-run, and patient-driven,” Ms. Drell explained.
The registry platforms developed for IAMRARE are customizable. With guidance from NORD, the advocacy groups themselves decide what data to collect and what questions they wish to answer, according to Dr. Fink. Once the registries are created, patients and caregivers participate by responding to survey questions on disease onset, progression over time, types and severity of symptoms, and other topics. The data can be de-identified for research purposes. The advocacy groups decide how and when to share the data, including whether to publish findings.
“Some of the groups have been very successful in getting the data published and leveraging their results to drive research forward, but there is variability in the extent of dissemination across the groups,” said Dr. Fink. She noted that many of the registries that NORD has helped set up involve groups whose officers have had little or no prior research experience.
“We have advocacy groups that have had biomedical researchers on staff and other groups that are coming to research completely new,” Dr. Fink said. In trying to get them up to speed on quality data collection, “We try to meet them where they are,” she added, indicating that leading groups to a research-ready status is not just about logistics but can sometimes involve an organizational reorientation.
The examples of peer-reviewed publications that can be directly traced to IAMRARE registries are growing. One example is a registry on Prader-Willi syndrome, which is a complex neurodevelopmental disorder characterized by failure to thrive and by multiple endocrine abnormalities. The registry was developed in NORD’s IAMRARE program by the Foundation for Prader-Willi Research, a nonprofit created in 2003 by parents of children with this disorder.
By 2019, when the first data from the Global Prader-Willi Syndrome Registry were published, they drew from 23,550 surveys completed for 1,696 separate cases of the disorder in 37 countries. The surveys provided some preliminary findings on demographics and on the genetic subtypes most commonly encountered, as well as simply proof that the registry was viable. From its inception in 2015, a significant proportion of the Prader-Willi population in the United States had been enrolled, according to the study authors. With time, the serial accumulation of more data on more cases will be invaluable for documenting disease characteristics. It will be a constantly maturing resource even after fundamental questions on disease impact and prognosis are addressed.
Data accumulation
Only about 10% of rare diseases currently have approved treatments, but there is widespread belief in the rare community that collecting and analyzing the data that can promote understanding of the biology of the disease and identify therapeutic targets could accelerate the development of treatments for diseases that currently have none.
Therefore, data accumulation has become central to the mission of NORD. In addition to IAMRARE, the organization has embarked on several other important initiatives in data accumulation for rare diseases. One is the Rare Disease Cures Accelerator – Data and Analytics Platform (RDCA-DAP), an initiative in which NORD is partnering with the Critical Path Institute. The goal of this program is to gather disparate pools of existing data in a standardized format to increase their power.
“With funding from the Food and Drug Administration, we have helped to support this platform, which is designed specifically to provide a centralized structure for combining and sharing of data,” according to Dr. Fink. In RDCA-DAP, patient-level data is being assembled from a variety of resources, including academic centers, industry, registries, observational studies, and clinical trials. The program was launched in September 2021. In some cases, gaining access to data includes resolving privacy issues or addressing the proprietary concerns of those who currently have the data, but the value of the combined data is a compelling argument for participation.
“What we are trying to do is pull together the data from their current silos into one platform, and then make it generally available,” said Dr. Fink. As with IAMRARE, RDCA-DAP offers enormous potential.
“The primary challenge for those studying rare diseases is the small numbers of patients. Randomized clinical trials for some of these diseases are simply not feasible because there are not enough subjects to power two study arms,” said Dr. Fink in explaining why NORD has turned to novel strategies for data generation. One strategy for maximizing the potential value of data from these small populations of patients is data-sharing. For RDCA-DAP, data access will be open to all stakeholders after scientific review and approval.
“Anyone can get an account and request data from the platform,” said Dr. Fink, who expects this to spur more and novel types of research in rare disorders.
Another example of recent NORD initiatives to advance research and understanding of rare diseases is a study of metachromatic leukodystrophy (MLD) that is now enrolling patients, which also represents a partnership with the FDA. For this study, which is known as the HOME study, NORD hosts a platform where patients and caregivers enter data to capture the natural history of this disease. All MLD patients, even if they are already participating in a clinical trial or another registry, are invited. As with the IAMRARE registries, surveys capture patient or caregiver responses entered from a computer or smart device.
“We have always believed that the fact that so many rare diseases don’t have treatments or are not even being studied by researchers doesn’t reflect a lack of interest among academic or industry researchers. Rather, it reflects a lack of data to support research and to provide a fundamental understanding of the disease,” Dr. Fink said. “If NORD’s expanded research programs can draw the patient community together to provide that crucially needed data, we will have provided an important and essential service to patients, patient organizations, and researchers alike.”
Theodore Bosworth is a freelance journalist and editor specializing in medicine and health.
With the goal of advancing treatment of rare neurological diseases – or rare diseases of any type – the National Organization for Rare Disorders (NORD) has launched innovative new research initiatives in recent years to help patient advocacy organizations develop a precious asset: data to support better understanding of diseases and research that might lead to life-altering diagnostics or treatments.
“Most rare diseases still don’t have approved therapies, and the problem is often a lack of the basic information needed to advance research,” explained Aliza Fink, DSc, the director of research programs at NORD. “Our goal is to help patient organizations play a key role in the collection, analysis, and sharing of data to support better understanding of how a disease presents, its natural history, the types and severity of symptoms, and other unanswered questions.”
Over the past 2 decades, the Internet, social media, and other communications resources have provided patient organizations with unprecedented reach. As a result, these organizations are in a unique position to connect patients and caregivers around the world – those dealing with even the rarest of rare diseases – and become a repository of information on the disease and the patient experience.
Since the late 1980s, NORD has had a research grants program, and the grants this program provides to academic researchers have led to numerous significant discoveries and publications, as well as to two products that ultimately were approved by FDA. More recently, however, NORD’s research programs have been expanded to include an initiative known as IAMRARE, in which patient advocacy organizations are trained to conduct observational research and host natural history studies and registries on a platform developed by NORD.
“We work with the patient groups to determine what types of data would be most important to drive research, help develop the methodology for data collection, and advise them on protocols for supporting the quality and integrity of the data,” Dr. Fink said. “By systematically collecting data from the patients and families they serve, these groups are in a position to contribute enormously to understanding the disease and advancing research.”
NORD also helps with the practical aspects of conducting research of sufficient quality to be publishable, such as providing groups with guidelines and best practices for developing medical advisory committees, creating templates and materials to streamline their project’s submission to institutional review boards, ensuring data security and privacy in accordance with Health Insurance Portability and Accountability Act criteria, and developing other expected standards for data collection and analysis.
Unlike even academic medical centers with an interest in a given rare disease, leading patient advocacy groups for these specific disorders have unmatched access to affected patients and families. This includes patients being managed in diverse settings or those not yet receiving care at all. By harnessing this patient population to record the signs, symptoms, disease course, and other information, the patient advocacy groups can contribute greatly to the pool of available data and ultimately what is known about the disease.
Data empowers research
While NORD helps groups through the IAMRARE program to become research-ready and guides them in developing research protocols and goals, the data are ultimately owned by the patient advocacy groups themselves. This helps to ensure that the patient voice is heard. By controlling data collection and dissemination, the advocacy groups can take a leading role in defining the goals of research, including what outcome measures are important to them and what they agree are the most promising avenues for research to achieve those goals.
“By collecting the data to understand the disease, it sets the stage for the next steps in research,” explained Debbie Drell, the director of membership for NORD. She noted that IAMRARE has grown steadily since its inception in 2014 and that there are now close to 40 advocacy groups participating.
The value of this initiative is not difficult to grasp. Even though direct participation in research was not generally part of the agenda for some advocacy groups when IAMRARE was conceived, Ms. Drell said that this initiative is a compelling perk of becoming involved with NORD. Groups that elect to become research-ready in order to participate in IAMRARE fall into a category of membership that requires specific organizational structures – such as a medical advisory board – and NORD provides templates and guidance to help them meet these qualifications to successfully become research-ready.
Collaboration leads to progress
NORD was founded by an ad hoc committee of patient organizations that played a key role in enactment of the Orphan Drug Act nearly 40 years ago. Shortly after the Orphan Drug Act was passed by Congress and signed into law by President Ronald Reagan in 1983, the ad hoc committee formally united to create NORD to continue the momentum of this initial collaboration and support the rare disease community. According to Mary Dunkle, a senior advisor at NORD, passage of the Orphan Drug Act, which is widely considered a major driver of progress in development of treatments for rare diseases, made the advantages of their cooperation clear.
“The groups had so many issues in common across the spectrum of diseases that they decided to continue their collaboration,” she explained. ”They realized that, while each disease is rare, the challenges they present to patients, families, clinicians, and researchers have many similarities.”
The definition of rare disease, according to the National Institutes of Health, is a disorder that affects fewer than 200,000 people in the United States. More than 7,000 such disorders have been identified. Approximately one-third of rare diseases are neurological. Whether neurological or affecting different or multiple organ systems, most – perhaps 75%-80% – involve a genetic component, according to Ms. Dunkle.
Research reaps rewards
Altogether, today there are more than 1,000 patient organizations that provide various types of support and services for patients and caregivers affected by rare diseases. Approximately one-third of these organizations are members of NORD. For organizations that don’t yet meet the membership criteria or for other reasons have not yet formally joined NORD, there are still many opportunities to get involved and to learn best practices to strengthen their governance, infrastructure, and capacity to support their members.
Of these, the IAMRARE program is one of the best examples of ways to get involved. Beyond the many other ways these groups help patients and families cope with challenging diseases, participation in research takes rare disorder advocacy to a different level. Objective data can attract the attention of those with the resources to further study the disease, while also giving advocacy groups a seat at the table when researchers or industry become interested.
“Why create a registry? It removes competition between academic centers or industry working on their own. It creates one central source for data-sharing, and the advantage is that advocacy groups have a trusted relationship with the patient community because they are not-for-profit, community-run, and patient-driven,” Ms. Drell explained.
The registry platforms developed for IAMRARE are customizable. With guidance from NORD, the advocacy groups themselves decide what data to collect and what questions they wish to answer, according to Dr. Fink. Once the registries are created, patients and caregivers participate by responding to survey questions on disease onset, progression over time, types and severity of symptoms, and other topics. The data can be de-identified for research purposes. The advocacy groups decide how and when to share the data, including whether to publish findings.
“Some of the groups have been very successful in getting the data published and leveraging their results to drive research forward, but there is variability in the extent of dissemination across the groups,” said Dr. Fink. She noted that many of the registries that NORD has helped set up involve groups whose officers have had little or no prior research experience.
“We have advocacy groups that have had biomedical researchers on staff and other groups that are coming to research completely new,” Dr. Fink said. In trying to get them up to speed on quality data collection, “We try to meet them where they are,” she added, indicating that leading groups to a research-ready status is not just about logistics but can sometimes involve an organizational reorientation.
The examples of peer-reviewed publications that can be directly traced to IAMRARE registries are growing. One example is a registry on Prader-Willi syndrome, which is a complex neurodevelopmental disorder characterized by failure to thrive and by multiple endocrine abnormalities. The registry was developed in NORD’s IAMRARE program by the Foundation for Prader-Willi Research, a nonprofit created in 2003 by parents of children with this disorder.
By 2019, when the first data from the Global Prader-Willi Syndrome Registry were published, they drew from 23,550 surveys completed for 1,696 separate cases of the disorder in 37 countries. The surveys provided some preliminary findings on demographics and on the genetic subtypes most commonly encountered, as well as simply proof that the registry was viable. From its inception in 2015, a significant proportion of the Prader-Willi population in the United States had been enrolled, according to the study authors. With time, the serial accumulation of more data on more cases will be invaluable for documenting disease characteristics. It will be a constantly maturing resource even after fundamental questions on disease impact and prognosis are addressed.
Data accumulation
Only about 10% of rare diseases currently have approved treatments, but there is widespread belief in the rare community that collecting and analyzing the data that can promote understanding of the biology of the disease and identify therapeutic targets could accelerate the development of treatments for diseases that currently have none.
Therefore, data accumulation has become central to the mission of NORD. In addition to IAMRARE, the organization has embarked on several other important initiatives in data accumulation for rare diseases. One is the Rare Disease Cures Accelerator – Data and Analytics Platform (RDCA-DAP), an initiative in which NORD is partnering with the Critical Path Institute. The goal of this program is to gather disparate pools of existing data in a standardized format to increase their power.
“With funding from the Food and Drug Administration, we have helped to support this platform, which is designed specifically to provide a centralized structure for combining and sharing of data,” according to Dr. Fink. In RDCA-DAP, patient-level data is being assembled from a variety of resources, including academic centers, industry, registries, observational studies, and clinical trials. The program was launched in September 2021. In some cases, gaining access to data includes resolving privacy issues or addressing the proprietary concerns of those who currently have the data, but the value of the combined data is a compelling argument for participation.
“What we are trying to do is pull together the data from their current silos into one platform, and then make it generally available,” said Dr. Fink. As with IAMRARE, RDCA-DAP offers enormous potential.
“The primary challenge for those studying rare diseases is the small numbers of patients. Randomized clinical trials for some of these diseases are simply not feasible because there are not enough subjects to power two study arms,” said Dr. Fink in explaining why NORD has turned to novel strategies for data generation. One strategy for maximizing the potential value of data from these small populations of patients is data-sharing. For RDCA-DAP, data access will be open to all stakeholders after scientific review and approval.
“Anyone can get an account and request data from the platform,” said Dr. Fink, who expects this to spur more and novel types of research in rare disorders.
Another example of recent NORD initiatives to advance research and understanding of rare diseases is a study of metachromatic leukodystrophy (MLD) that is now enrolling patients, which also represents a partnership with the FDA. For this study, which is known as the HOME study, NORD hosts a platform where patients and caregivers enter data to capture the natural history of this disease. All MLD patients, even if they are already participating in a clinical trial or another registry, are invited. As with the IAMRARE registries, surveys capture patient or caregiver responses entered from a computer or smart device.
“We have always believed that the fact that so many rare diseases don’t have treatments or are not even being studied by researchers doesn’t reflect a lack of interest among academic or industry researchers. Rather, it reflects a lack of data to support research and to provide a fundamental understanding of the disease,” Dr. Fink said. “If NORD’s expanded research programs can draw the patient community together to provide that crucially needed data, we will have provided an important and essential service to patients, patient organizations, and researchers alike.”
Theodore Bosworth is a freelance journalist and editor specializing in medicine and health.
Rett syndrome: Looking to the future and the promise of gene therapy
The dream of curing genetic disorders has been a persistent but elusive goal, even before the human genome was mapped. Once mapping of the human genome was complete in 2001, an entirely new avenue of potential treatments and cures for genetic diseases and disorders was opened.1,2
The disorders best suited for targeted gene therapy are monogenic; however, tools and delivery methods for editing the human genome were limited and difficult to apply, until the advent of the CRISPR system in 2012.3 CRISPR (an acronym of clustered regularly interspaced short palindromic repeats) has changed the way in which gene therapy strategies are pursued, with dozens of companies leveraging a variety of platforms to create potentially life-changing therapies for devastating rare diseases and disorders.
One of the rare monogenic disorders that is embracing multiple gene therapy approaches is Rett syndrome, a rare, debilitating neurodevelopmental disorder. In this review, we explore the molecular cause of Rett syndrome, disease presentation, current treatments, ongoing clinical trials, and therapies that are on the horizon.
Underlying molecular cause
Rett syndrome is caused by mutations in, or the absence of, the MECP2 gene, which produces methyl-CpG binding protein 2 (MECP2). The syndrome was first described clinically in 1954 by the Austrian physician Andreas Rett; it would take until 1982 before the disorder was officially named, eponymously, in a seminal paper by Hagberg.4 After Hagberg’s characterization, Rett syndrome became the predominant global clinical diagnosis identified among cognitively impaired females, with an incidence of 1 in every 10,000 to 15,000.4
In 1999, mutations in, and deletions of, MECP2 were identified as the cause of Rett syndrome.4,5 MECP2 is located on the X chromosome, in the Xq28 region, making Rett syndrome an X-linked dominant disorder.6 Rett syndrome is seen predominantly in females who are mosaic for mutant or deleted MECP2. Random X chromosome inactivation results in some cells expressing the mutant MECP2 allele and other cells expressing the normal functioning MECP2 allele; the percentage of cells expressing the normal allele correlates with the degree of syndrome severity.7-9
The incidence of Rett syndrome is much lower in males, in whom the syndrome was originally thought to be lethal; many observed male cases are either mosaic or occur in XXY males.10,11
Approximately 95% of cases of Rett syndrome are due to de novo mutations in MECP2, with a handful of specific mutations and large deletions accounting for more than 85% of cases.12 The fact that Rett syndrome is monogenic and most cases are caused by, in total, only a handful of mutations or deletions makes the syndrome a promising candidate for gene therapy.
At the molecular level, it has been observed that the MECP2 mutations of Rett syndrome lead to loss of gene function, thus disrupting the ability of the MECP2 nuclear protein to regulate global gene transcription through its binding to methylated DNA sites.12 A large percentage of these missense and nonsense mutations lead to a truncated or nonfunctional protein.12
One of the ways in which MECP2 regulates transcription is as a component of heterochromatin condensates and by separation of heterochromatin and euchromatin.13-15 It has been observed that the cells of Rett syndrome patients have an altered chromatin state, potentially contributing to transcriptional dysregulation.16,17 Several mutations observed in Rett syndrome patients occur in crucial domains for heterochromatin condensate formation, which helps explain this cellular phenotype.13 Introduction of a engineered “mini” MECP2 in a murine model of Rett syndrome has resulted in partial rescue of heterochromatin condensate formation and transcriptional regulation – fostering the hypothesis that correcting those genetic changes could lead to a potential therapy.18
Beyond the role of MECP2 in heterochromatin condensate formation, the gene interacts with more than 40 proteins that have diverse roles in cellular function, epigenetic modulation, and neuronal development. This volume of interactions contributes to MECP2 being a global gene regulatory protein that has far-reaching effects on transcriptional regulation across the genome.19-22
Epigenetic dysregulation has been associated with neurodevelopmental and neuropsychiatric disorders.23 Both insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor are transcriptional targets of MECP2, and are involved in neuronal differentiation, synaptic function, and neurite outgrowth.12 This helps explain the neurodevelopmental phenotypes observed in MECP2-mutated patients.
Notably, although Rett syndrome patients experience neurodevelopmental phenotypes at the cellular level, neuronal death is not readily observed. That observation provides hope that an interventional therapy after onset of symptoms might still be of benefit.
Presentation
Early neurotypical development. A hallmark of Rett syndrome is neurotypical physical and mental development until 6 to 24 months of age.
Stagnation is the first stage of the syndrome, involving a small but rapid decline in habitual milestones, such motor and language skills.12 Subtle signs, such as microcephaly and hypotonia, can also arise at this time but might be missed.24
Rapid regression follows stagnation. Speech and motor delays and impaired gait and breathing occur;12,25 purposeful hand skills are lost, replaced by repetitive hand-wringing movements that are a hallmark of the syndrome.12,24 Seizures are observed; they become more common during the next stage.12
Plateau. Language advances can be observed, but further deficits are seen in motor skills and hand coordination.12
Late motor deterioration stage. Late physical deficits develop, leading to lifelong impairments. The physical deficits observed are the result of severe muscle weakness, usually resulting in wheelchair dependency.12
Plateau. Patients then reach a second plateau. Regression stops; deficient physical and cognitive states stabilize and are maintained.25
At all stages of Rett syndrome, the following are observed:
- Gastrointestinal problems.
- Sleep disturbances.
- Abnormal cardiorespiratory coupling.
- Greater-than-expected mortality.12
Final regression. The patient is fully dependent for the rest of their lifespan, partially due to seizure activity.26,27
A life-changing diagnosis
A diagnosis of Rett syndrome is life-changing for a patient’s family; access to supportive groups of other patients and their families is extremely beneficial. Two helpful organizations – the Rett Syndrome Research Trust28 and International Rett Syndrome Foundation,29 – offer patient support and community and fund research.
Because X chromosome inactivation is random in Rett syndrome, the individual patient can present with a wide variety of phenotypic combinations – making the patient, and their needs, unique.12 During stages of regression, patients often experience emotional dysregulation and anxiety, which is attributable to their increasing physical difficulties.30 They often exhibit combinations of uncontrolled movements, including repetitive rocking, scratching, and self-injurious behavior.30 For most, regression subsides after the first 5 years of alternating development and regression; after that, their ultimate symptoms persist for life.25
As patients mature, they need to be monitored for proper nutrition and scoliosis.25 As adults, they are at risk of pneumonia, respiratory distress, status epilepticus, osteopenia, and lack of adequate food or water because of impaired ability to feed.25
The lifespan of Rett syndrome patients has increased, thanks to improvements in health care, advances in technology, and early genetic testing, which allows for earlier diagnosis, intervention, and management of symptoms.
Current treatments
When a female patient presents with regression and loss of milestones, sequencing of MECP2 is performed to verify whether Rett syndrome is the cause, by detecting any of the known mutations. Multiplex ligation-dependent probe amplification is also performed to detect major deletions.25
All available treatments for Rett syndrome are symptomatic; intensive early intervention is practiced.31 Multidisciplinary management – medical, psychiatric, and physical – is introduced almost immediately after diagnosis. Following diagnosis, patients are prescribed anti-seizure, sleep, and anxiety medications.31 Electroencephalography can be performed to identify seizure type. Neuromuscular blockage drugs can be prescribed to help with gait and stereotypic hand movements.25
Handguards or splints to the elbows can be prescribed by an occupational therapist to improve hand movement.25 Physical therapy can improve mobility; hydrotherapy and hippotherapy have been successful in helping to maintain mobility and muscle support.32,33 Nutritional management is implemented to control caloric intake and maintain the vitamin D level.31 Some patients experience constipation and urinary retention, putting them at risk of nephrolithiasis.
Once the signs and symptoms of Rett syndrome progress, and milestones regress to a certain point, patients need constant, full-time care for the rest of their lives.34 As symptomatic interventions have greatly improved patient outcomes and it has been shown that about 70% can reach adulthood with a potential lifespan of about 50 years.25
Although there is no cure for Rett syndrome and treatments are symptomatic, ongoing studies – both clinical and preclinical – offer promise that treatments will be developed that work at molecular and genetic levels.
Clinical trials
Advances in understanding of Rett syndrome have led to many therapies in clinical trials, several of which show promise.
Trofinetide. One of the most promising targets for downstream therapy, mentioned earlier, is IGF-1, which was the target of a successful phase 3 clinical trial, LAVENDER (sponsored by Acadia Pharmaceuticals).35,36 This trial studied trofinetide, a synthetic IGF-1 analog that inhibits neuroinflammation, restores glial function, corrects synaptic deficiencies, and regulates oxidative stress response.12,37,38 Initial results from phase 2 and phase 3 trials indicate improved scores for treated patients in the Rett syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression–Improvement (CGI-I) scores, while also showing improvements in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist–Social composite score.36,39
The most common adverse events seen with trofinetide were diarrhea and vomiting.
Acadia Pharmaceuticals has filed for approval of a new drug application for trofinetide with the Food and Drug Administration, for which the company has been granted Fast Track Status and orphan drug designations. Most (95%) subjects in the phase 3 LAVENDER trial elected to continue taking trofinetide in the subsequent open-label Lilac and Lilac-2 extension studies.36 A current open-label phase 2/3 trial is recruiting patients 2 to 5 years of age to evaluate trofinetide.40 It is expected that, in the near future, this could be a drug given to Rett patients as an FDA-approved treatment.
Blarcamesine. Another small molecule drug, blarcamesine (also known as ANAVEX2-73), a sigma-1 receptor agonist, produced promising results in phase 2 clinical trials in adult Rett syndrome patients. The drug is in a phase 2/3 clinical trial for pediatric Rett syndrome patients (sponsored by Anavex Life Sciences).41-43
Phase 2 results indicated statistically significant and clinically meaningful improvement in RSBQ and CGI-I scores with blarcamesine. Improvement was initially observed within 4 weeks after the start of treatment and was sustained throughout the study. The drug was shown to be well tolerated, with minimal adverse effects; no serious adverse events were recorded. These results were observed in adult patients, demonstrating that improvements in Rett syndrome are possible even after regression.
Blarcamesine activates the sigma 1 receptor, which is pivotal to restoring cellular homeostasis and restoring neuroplasticity – deficiencies of which have been linked to autophagy and glutamate toxicity. The drug has also been explored as a potential treatment for other neurological disorders.44-47 Improvements in blarcamesine-treated patients further correlated with lower levels of glutamate in cerebrospinal fluid, which is a Rett syndrome biomarker, supporting the proposition that behavioral improvements were due to drug intervention.48,49 The phase 2 trial was modified into a phase 3 trial and additional endpoints were added.41-43
All patients in the phase 2 adult trial elected to continue in the extension study.
Based on these promising data, Anavex is pursuing an approval pathway for adult patients, while continuing dosage optimization phase 2/3 trials and recruitment for a pediatric trial.42,43
Is the future about gene therapy?
TSHA-102 (miniMECP2). Taysha Gene Therapies is developing a promising gene therapy, TSHA-102, for Rett syndrome, and is aiming to begin phase 1/2 clinical trials in 2022.50 The technology for this therapy relies on the delivery of a fragment of MECP2 (known as miniMECP2), which is regulated by a built-in microRNA regulator (miR-responsive auto-regulatory element, or miRARE) to help ameliorate MECP2 dosage toxicity. (Overexpression of MECP2 is toxic to neurons, which has made traditional [so to speak] gene replacement therapy difficult in Rett syndrome: Levels of MECP2 need to be tightly regulated, and the Taysha microRNA technology regulates levels of miniMECP2, thus reducing toxicity.)
The Taysha microRNA technology has yielded promising results in mouse studies for Rett syndrome; results indicate a lengthening of lifespan and delayed onset of gait abnormalities.51 TSHA-102 is in the preclinical stage but offers promise that it will be the first gene therapy for Rett syndrome to enter clinical trials.
As the field of gene therapy advances, several promising technologies are on the horizon that could potentially have disease-altering impacts on Rett syndrome. These therapies are divided into two broad categories: those at the gene level and those at the transcription and protein level. A few of these approaches are highlighted below.
Gene replacement involves adding a full or partial copy of MECP2 to neuronal cells. This type of therapy presents challenges, from delivery of the new gene to dosage concerns, because MECP2 can be toxic if overexpressed.52-54 Groundbreaking work was done in mouse models involving truncated MECP2, exhibiting phenotypic rescue and validating the gene-replacement approach.18 This strategy is being pursued by Neurogene, which has a uinique technology that allows for tuning of the gene’s expression to get the correct protein levels in the patient. Promising data was presented this year at the American Society of Gene and Cell Therapy conference.55
Early gene replacement therapy studies also laid the foundation for the minMECP2 and microRNA approach being used by Taysha Gene Therapies (discussed above).51
“Correcting” DNA mutations. A different approach at the genetic level involves “correcting” mutations in MECP2 at the DNA level. This is possible because, in a large subset of Rett syndrome patients who have the same missense or nonsense mutations, by using CRISPR, a gene editing tool (discussed above) a single base pair can be corrected.56,57 Previous research, in a Rett syndrome-model of induced pluripotent stem cells, showed that this type of editing is possible – and effective.52 An approach with particular promise involves use of a class of CRISPR proteins known as base editors that are able to specifically alter a single base of DNA.57 The technique has the potential to address many of the mutations seen in Rett syndrome; research on this type of technology is being pursued by Beam Therapeutics, and has the potential to impact Rett syndrome.58
Another promising “correction” approach is exonic editing, in which a much larger section of DNA – potentially, exons 3 and 4, which, taken together, comprise 97% of known MECP2 mutations seen in Rett syndrome – are replaced.59
In both CRISPR and exonic editing therapeutic approaches, endogenous levels of MECP2 expression would be maintained. Of note, both approaches are being pursued for use in treating other genetic disorders, which provides a boost in scaling-up work on addressing safety and efficacy concerns that accompany gene-editing approaches.58 One advantage to the DNA correction approach is that is has the potential to be a “one-and-done” treatment.
“Correcting” RNA. Beyond directly editing DNA, several therapeutic approaches are exploring the ability to edit RNA or to provide the protein directly to cells as enzyme replacement therapy. Such an RNA correction strategy leverages a technology that takes advantage of cells’ natural RNA editor, known as adenosine deaminase acting on RNA (ADAR), which corrects errors in cells’ RNA by providing specific guides to the cell. ADAR can be targeted to fix mutations in the MECP2 RNA transcript, resulting in a “corrected” MECP2 protein.60,61 This technology has delivered promising proof-of-concept evidence in cells and in murine models, and is in the therapeutic pipeline at VICO Therapeutics.62
Shape Therapeutics has also leveraged ADAR to “correct” mutated RNA; Rett syndrome is among the top priorities in the company’s pipeline.
Worth noting is that there are several advantages to the “correction” approach:
- Leveraging internal repair mechanisms minimizes the immune response.
- The flexibility of correction means that it can be used to address many of the mutations that cause Rett syndrome.63
Enzyme replacement therapy, in which the MECP2 protein produced by MECP2 would be directly replaced, is being explored in Rett syndrome patients. This technology has been used successfully in Pompe disease; however, Rett syndrome presents its own challenge because MECP2 needs to be delivered to the brain and neuronal cells.64
Where does this work stand? The technologies described in this section are in preclinical stages of study. Nonetheless, it is expected that several will enter human clinical trials during the next 5 years.
Conclusion
A diagnosis of Rett syndrome is a life-altering event for patients and their family. But there is more hope than ever for effective therapies and, eventually, a cure.
Multiple late-stage clinical trials in progress are demonstrating promising results from therapeutic products, with minimal adverse events. Remarkably, these interventions have delivered improvements to adult patients after regression has stabilized. With rapid progress being made in the field of gene therapy, several technologies for which are focused on Rett syndrome, a hopeful picture is emerging: that therapeutic intervention will be possible before regression, thus effectively treating and, potentially, even curing Rett syndrome.
The landscape is broadening. Add to this hope for approved therapies is the fact that Rett syndrome isn’t the only target being pursued with such strategies; in fact, researchers in the larger field of neurodevelopmental disorder study are working together to find common solutions to shared challenges – from how therapies are designed and delivered to how toxicity is minimized. Much of what is being explored in the Rett syndrome field is also under investigation in other neurodevelopmental syndromes, including Angelman, Prader-Willi, chromosome 15q11.2-13.1 duplication (dup15q), and Fragile X syndrome. This kind of parallel investigation benefits all parties and optimizes a treatment platform so that it can be applied across more than a single disorder.
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and vision, not just wide-eyed optimism. These words portend real promise for patients who carry the weight of a diagnosis of Rett syndrome, and for their families.
Ms. Ambrose is a student in the master’s of science in human genetics and genomic data analytics program, Keck Graduate Institute, Claremont, Calif. Dr. Bailus is an assistant professor of genetics, Keck Graduate Institute. The authors report no conflict of interest related to this article.
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21. Gabel HW et al. Disruption of DNA-methylation–dependent long gene repression in Rett syndrome. Nature. 2015 Jun 4;522(7554):89-93. doi: 10.1038/nature14319.
22. Lyst MJ, Bird A. Rett syndrome: A complex disorder with simple roots. Nat Rev Genet. 2015 May;16(5):261-75. doi: 10.1038/nrg3897.
23. Kuehner JN et al. Epigenetic regulations in neuropsychiatric disorders. Front Genet. 2019 Apr 4;10:268. doi: 10.3389/fgene.2019.00268.
24. Pejhan S, Rastegar M. Role of DNA methyl-CpG-binding protein MeCP2 in Rett syndrome pathobiology and mechanism of disease. Biomolecules. 2021 Jan;11(1):75. doi: 10.3390/biom11010075.
25. Fu C et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open. 2020;4(1):e000717. doi: 10.1136/bmjpo-2020-000717.
26. Operto FF et al. Epilepsy and genetic in Rett syndrome: A review. Brain Behav. 2019 May;9(5):e01250. doi: 10.1002/brb3.1250.
27. Nissenkorn A et al. Epilepsy in Rett syndrome – The experience of a National Rett Center. Epilepsia. 2010 Jul;51(7):1252-8. doi: 10.1111/j.1528-1167.2010.02597.x.
28. Welcome to the Rett cure community. Rett Syndrome Research Trust [Internet]. Updated Feb 8, 2022. Accessed Feb 23, 2022. https://reverserett.org.
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30. Singh J, Santosh P. Key issues in Rett syndrome: Emotional, behavioural and autonomic dysregulation (EBAD) – A target for clinical trials. Orphanet J Rare Dis. 2018 Jul 31;13(1):128. doi: 10.1186/s13023-018-0873-8.
31. Banerjee A et al. Towards a better diagnosis and treatment of Rett syndrome: A model synaptic disorder. Brain. 2019 Feb 1;142(2):239-48. doi: 10.1093/brain/awy323.
32. Ager S et al. Parental experiences of scoliosis management in Rett syndrome. Disabil Rehabil. 2009 Sep 19;31(23):1917-24. doi: 10.1080/09638280902846392.
33. Budden SS. Management of Rett syndrome: A ten year experience. Neuropediatrics. 1995;26(2):75-7. doi: 10.1055/s-2007-979727.
34. Ip JPK et al. Rett syndrome: Insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci. 2018 Jun;19(6):368-82. doi: 10.1038/s41583-018-0006-3.
35. Acadia Pharmaceuticals Inc. Study of trofinetide for the treatment of girls and women with Rett syndrome (LAVENDER™). ClinicalTrials.gov identifier: NCT04181723. Updated Feb 17, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04181723.
36. Acadia Pharmaceuticals announces positive top-line results from the pivotal phase 3 LAVENDER trial of trofinetide in Rett syndrome. Press release. Acadia Pharmaceuticals Inc. Dec 6, 2021. Accessed Feb 23, 2022. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-positive-top-line-results-1.
37. Copping NA et al. Emerging gene and small molecule therapies for the neurodevelopmental disorder Angelman syndrome. Neurotherapeutics. 2021 Jul;18(3):1535-47. doi: 10.1007/s13311-021-01082-x.
38. Riikonen R. Insulin-like growth factors in the pathogenesis of neurological diseases in children. Int J Mol Sci. 2017 Sep;18(10):2056. doi: 10.3390/ijms18102056.
39. Glaze DG et al; Rett 002 Study Group. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. 2019 April 16;92(16):e1912-e1925. doi: 10.1212/WNL.0000000000007316.
40. Acadia Pharmaceuticals Inc. An open-label study of trofinetide for the treatment of girls two to five years of age who have Rett syndrome (DAFFODIL™). ClinicalTrials.gov Identifier: NCT04988867. Updated Jan 24, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04988867.
41. Anavex Life Sciences announces ANAVEX®2-73 meets primary and secondary endpoints in clinical trial. Press release. Anavex Life Sciences Corp. Dec 15, 2020. Accessed Feb 23, 2022. http://www.anavex.com/post/anavex-life-sciences-announces-anavex-2-73-meets-primary-and-secondary-endpoints-in-clinical-trial.
42. Anavex Life Sciences Corp. ANAVEX2-73 study in patients with Rett syndrome (AVATAR). ClinicalTrials.gov Identifier: NCT03941444. Updated Jan 27, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT03941444.
43. Anavex Life Sciences Corp. ANAVEX2-73 study in pediatric patients with Rett syndrome (EXCELLENCE). ClinicalTrials.gov Identifier: NCT04304482. Updated Sep 28, 2021. Accessed Feb 23, 2022. http://www.clinicaltrials.gov/ct2/show/NCT04304482.
44.Christ MG et al. The Sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. 2020 Feb;43(2):79-81. doi: 10.1016/j.tins.2019.12.002.
45. Kaufmann WE et al. ANAVEX®2-73 (blarcamesine), a sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav. 2019 Dec;187:172796. doi: 10.1016/j.pbb.2019.172796.
46. Brimson JM et al. Dipentylammonium binds to the sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res. 2018 Aug;34(2):263-72. doi: 10.1007/s12640-018-9883-5.
47. Kourrich S et al. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012 Dec;35(12):762-71. doi: 10.1016/j.tins.2012.09.007.
48. Lappalainen R, Riikonen RS. High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatr Neurol. 1996 Oct;15(3):213-6. doi: 10.1016/s0887-8994(96)00218-4.
49. Hamberger A et al. Elevated CSF glutamate in Rett syndrome. Neuropediatrics. 1992;23(4):212-3. doi: 10.1055/s-2008-1071344.
50. Inacio P. FDA acts to support development of potential gene therapy, TSHA-102. Rett Syndrome News [Internet]. Oct 16, 2020. Accessed Feb 23, 2022. https://rettsyndromenews.com/2020/10/16/fda-grants-orphan-drug-rare-pediatric-disease-status-to-tsha-102-potential-rett-gene-therapy.
51. Sinnett SE et al. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain. 2021 Nov 29;144(10):3005-19. doi: 10.1093/brain/awab182.
52. Le TTH et al. Efficient and precise CRISPR/Cas9-mediated MECP2 modifications in human-induced pluripotent stem cells. Front Genet. 2019 Jul 2;10:625. doi: 10.3389/fgene.2019.00625.
53. Koerner MV et al. Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. Genes Dev. 2018;32(23-24):1514-24. doi: 10.1101/gad.320325.118.
54. Heckman LD et al. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014;3:e02676. doi: 10.7554/eLife.02676.
55. Neurogene announces new development program in Rett syndrome utilizing novel EXACT technology platform [Internet]. Accessed Aug 12, 2022. https://www.neurogene.com/press-releases/neurogene-announces-new-development-program-in-rett-syndrome-utilizing-novel-exact-technology-platform/
56. Anzalone AV et al. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020 Jul;38(7):824-44. doi: 10.1038/s41587-020-0561-9.
57. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A●T to G●C in genomic DNA without DNA cleavage. Nature. 2017 Nov 23;551(7681):464-71. doi: 10.1038/nature24644.
58. Coenraads M. How RSRT is driving the search for a Rett cure. Rett Syndrome Research Trust [Internet]. Dec 7, 2021. Accessed Feb 23, 2022. https://rettnews.org/articles/how-rsrt-is-driving-the-search-for-a-rett-cure.
59. Cutting-edge technologies to repair the underlying mutations that cause Rett. Rett Syndrome Research Trust [Internet]. Updated Nov 3, 2021. Accessed Feb 23, 2022. https://reverserett.org/research/cures/gene-editing.
60. Sinnamon JR et al. In vivo repair of a protein underlying a neurological disorder by programmable RNA editing. Cell Rep. 2020 Jul 14;32(2):107878. doi: 10.1016/j.celrep.2020.107878.
61. Sinnamon JR et al. Site-directed RNA repair of endogenous Mecp2 RNA in neurons. Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9395-E9402. doi: 10.1073/pnas.1715320114.
62. Pipeline. VICO Therapeutics [Internet]. Updated Nov 5, 2021. Accessed Feb 23, 2022. https://vicotx.com/pipeline.
63. Therapeutics platform. Shape Therapeutics [Internet]. Updated Feb 20, 2021. Accessed Feb 23, 2022.
https://live-shapetx.pantheonsite.io/therapeutics-platform.
64. Koeberl DD et al. Glycogen storage disease types I and II: Treatment updates. J Inherit Metab Dis. 2007 Apr;30(2):159-64. doi: 10.1007/s10545-007-0519-9.
The dream of curing genetic disorders has been a persistent but elusive goal, even before the human genome was mapped. Once mapping of the human genome was complete in 2001, an entirely new avenue of potential treatments and cures for genetic diseases and disorders was opened.1,2
The disorders best suited for targeted gene therapy are monogenic; however, tools and delivery methods for editing the human genome were limited and difficult to apply, until the advent of the CRISPR system in 2012.3 CRISPR (an acronym of clustered regularly interspaced short palindromic repeats) has changed the way in which gene therapy strategies are pursued, with dozens of companies leveraging a variety of platforms to create potentially life-changing therapies for devastating rare diseases and disorders.
One of the rare monogenic disorders that is embracing multiple gene therapy approaches is Rett syndrome, a rare, debilitating neurodevelopmental disorder. In this review, we explore the molecular cause of Rett syndrome, disease presentation, current treatments, ongoing clinical trials, and therapies that are on the horizon.
Underlying molecular cause
Rett syndrome is caused by mutations in, or the absence of, the MECP2 gene, which produces methyl-CpG binding protein 2 (MECP2). The syndrome was first described clinically in 1954 by the Austrian physician Andreas Rett; it would take until 1982 before the disorder was officially named, eponymously, in a seminal paper by Hagberg.4 After Hagberg’s characterization, Rett syndrome became the predominant global clinical diagnosis identified among cognitively impaired females, with an incidence of 1 in every 10,000 to 15,000.4
In 1999, mutations in, and deletions of, MECP2 were identified as the cause of Rett syndrome.4,5 MECP2 is located on the X chromosome, in the Xq28 region, making Rett syndrome an X-linked dominant disorder.6 Rett syndrome is seen predominantly in females who are mosaic for mutant or deleted MECP2. Random X chromosome inactivation results in some cells expressing the mutant MECP2 allele and other cells expressing the normal functioning MECP2 allele; the percentage of cells expressing the normal allele correlates with the degree of syndrome severity.7-9
The incidence of Rett syndrome is much lower in males, in whom the syndrome was originally thought to be lethal; many observed male cases are either mosaic or occur in XXY males.10,11
Approximately 95% of cases of Rett syndrome are due to de novo mutations in MECP2, with a handful of specific mutations and large deletions accounting for more than 85% of cases.12 The fact that Rett syndrome is monogenic and most cases are caused by, in total, only a handful of mutations or deletions makes the syndrome a promising candidate for gene therapy.
At the molecular level, it has been observed that the MECP2 mutations of Rett syndrome lead to loss of gene function, thus disrupting the ability of the MECP2 nuclear protein to regulate global gene transcription through its binding to methylated DNA sites.12 A large percentage of these missense and nonsense mutations lead to a truncated or nonfunctional protein.12
One of the ways in which MECP2 regulates transcription is as a component of heterochromatin condensates and by separation of heterochromatin and euchromatin.13-15 It has been observed that the cells of Rett syndrome patients have an altered chromatin state, potentially contributing to transcriptional dysregulation.16,17 Several mutations observed in Rett syndrome patients occur in crucial domains for heterochromatin condensate formation, which helps explain this cellular phenotype.13 Introduction of a engineered “mini” MECP2 in a murine model of Rett syndrome has resulted in partial rescue of heterochromatin condensate formation and transcriptional regulation – fostering the hypothesis that correcting those genetic changes could lead to a potential therapy.18
Beyond the role of MECP2 in heterochromatin condensate formation, the gene interacts with more than 40 proteins that have diverse roles in cellular function, epigenetic modulation, and neuronal development. This volume of interactions contributes to MECP2 being a global gene regulatory protein that has far-reaching effects on transcriptional regulation across the genome.19-22
Epigenetic dysregulation has been associated with neurodevelopmental and neuropsychiatric disorders.23 Both insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor are transcriptional targets of MECP2, and are involved in neuronal differentiation, synaptic function, and neurite outgrowth.12 This helps explain the neurodevelopmental phenotypes observed in MECP2-mutated patients.
Notably, although Rett syndrome patients experience neurodevelopmental phenotypes at the cellular level, neuronal death is not readily observed. That observation provides hope that an interventional therapy after onset of symptoms might still be of benefit.
Presentation
Early neurotypical development. A hallmark of Rett syndrome is neurotypical physical and mental development until 6 to 24 months of age.
Stagnation is the first stage of the syndrome, involving a small but rapid decline in habitual milestones, such motor and language skills.12 Subtle signs, such as microcephaly and hypotonia, can also arise at this time but might be missed.24
Rapid regression follows stagnation. Speech and motor delays and impaired gait and breathing occur;12,25 purposeful hand skills are lost, replaced by repetitive hand-wringing movements that are a hallmark of the syndrome.12,24 Seizures are observed; they become more common during the next stage.12
Plateau. Language advances can be observed, but further deficits are seen in motor skills and hand coordination.12
Late motor deterioration stage. Late physical deficits develop, leading to lifelong impairments. The physical deficits observed are the result of severe muscle weakness, usually resulting in wheelchair dependency.12
Plateau. Patients then reach a second plateau. Regression stops; deficient physical and cognitive states stabilize and are maintained.25
At all stages of Rett syndrome, the following are observed:
- Gastrointestinal problems.
- Sleep disturbances.
- Abnormal cardiorespiratory coupling.
- Greater-than-expected mortality.12
Final regression. The patient is fully dependent for the rest of their lifespan, partially due to seizure activity.26,27
A life-changing diagnosis
A diagnosis of Rett syndrome is life-changing for a patient’s family; access to supportive groups of other patients and their families is extremely beneficial. Two helpful organizations – the Rett Syndrome Research Trust28 and International Rett Syndrome Foundation,29 – offer patient support and community and fund research.
Because X chromosome inactivation is random in Rett syndrome, the individual patient can present with a wide variety of phenotypic combinations – making the patient, and their needs, unique.12 During stages of regression, patients often experience emotional dysregulation and anxiety, which is attributable to their increasing physical difficulties.30 They often exhibit combinations of uncontrolled movements, including repetitive rocking, scratching, and self-injurious behavior.30 For most, regression subsides after the first 5 years of alternating development and regression; after that, their ultimate symptoms persist for life.25
As patients mature, they need to be monitored for proper nutrition and scoliosis.25 As adults, they are at risk of pneumonia, respiratory distress, status epilepticus, osteopenia, and lack of adequate food or water because of impaired ability to feed.25
The lifespan of Rett syndrome patients has increased, thanks to improvements in health care, advances in technology, and early genetic testing, which allows for earlier diagnosis, intervention, and management of symptoms.
Current treatments
When a female patient presents with regression and loss of milestones, sequencing of MECP2 is performed to verify whether Rett syndrome is the cause, by detecting any of the known mutations. Multiplex ligation-dependent probe amplification is also performed to detect major deletions.25
All available treatments for Rett syndrome are symptomatic; intensive early intervention is practiced.31 Multidisciplinary management – medical, psychiatric, and physical – is introduced almost immediately after diagnosis. Following diagnosis, patients are prescribed anti-seizure, sleep, and anxiety medications.31 Electroencephalography can be performed to identify seizure type. Neuromuscular blockage drugs can be prescribed to help with gait and stereotypic hand movements.25
Handguards or splints to the elbows can be prescribed by an occupational therapist to improve hand movement.25 Physical therapy can improve mobility; hydrotherapy and hippotherapy have been successful in helping to maintain mobility and muscle support.32,33 Nutritional management is implemented to control caloric intake and maintain the vitamin D level.31 Some patients experience constipation and urinary retention, putting them at risk of nephrolithiasis.
Once the signs and symptoms of Rett syndrome progress, and milestones regress to a certain point, patients need constant, full-time care for the rest of their lives.34 As symptomatic interventions have greatly improved patient outcomes and it has been shown that about 70% can reach adulthood with a potential lifespan of about 50 years.25
Although there is no cure for Rett syndrome and treatments are symptomatic, ongoing studies – both clinical and preclinical – offer promise that treatments will be developed that work at molecular and genetic levels.
Clinical trials
Advances in understanding of Rett syndrome have led to many therapies in clinical trials, several of which show promise.
Trofinetide. One of the most promising targets for downstream therapy, mentioned earlier, is IGF-1, which was the target of a successful phase 3 clinical trial, LAVENDER (sponsored by Acadia Pharmaceuticals).35,36 This trial studied trofinetide, a synthetic IGF-1 analog that inhibits neuroinflammation, restores glial function, corrects synaptic deficiencies, and regulates oxidative stress response.12,37,38 Initial results from phase 2 and phase 3 trials indicate improved scores for treated patients in the Rett syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression–Improvement (CGI-I) scores, while also showing improvements in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist–Social composite score.36,39
The most common adverse events seen with trofinetide were diarrhea and vomiting.
Acadia Pharmaceuticals has filed for approval of a new drug application for trofinetide with the Food and Drug Administration, for which the company has been granted Fast Track Status and orphan drug designations. Most (95%) subjects in the phase 3 LAVENDER trial elected to continue taking trofinetide in the subsequent open-label Lilac and Lilac-2 extension studies.36 A current open-label phase 2/3 trial is recruiting patients 2 to 5 years of age to evaluate trofinetide.40 It is expected that, in the near future, this could be a drug given to Rett patients as an FDA-approved treatment.
Blarcamesine. Another small molecule drug, blarcamesine (also known as ANAVEX2-73), a sigma-1 receptor agonist, produced promising results in phase 2 clinical trials in adult Rett syndrome patients. The drug is in a phase 2/3 clinical trial for pediatric Rett syndrome patients (sponsored by Anavex Life Sciences).41-43
Phase 2 results indicated statistically significant and clinically meaningful improvement in RSBQ and CGI-I scores with blarcamesine. Improvement was initially observed within 4 weeks after the start of treatment and was sustained throughout the study. The drug was shown to be well tolerated, with minimal adverse effects; no serious adverse events were recorded. These results were observed in adult patients, demonstrating that improvements in Rett syndrome are possible even after regression.
Blarcamesine activates the sigma 1 receptor, which is pivotal to restoring cellular homeostasis and restoring neuroplasticity – deficiencies of which have been linked to autophagy and glutamate toxicity. The drug has also been explored as a potential treatment for other neurological disorders.44-47 Improvements in blarcamesine-treated patients further correlated with lower levels of glutamate in cerebrospinal fluid, which is a Rett syndrome biomarker, supporting the proposition that behavioral improvements were due to drug intervention.48,49 The phase 2 trial was modified into a phase 3 trial and additional endpoints were added.41-43
All patients in the phase 2 adult trial elected to continue in the extension study.
Based on these promising data, Anavex is pursuing an approval pathway for adult patients, while continuing dosage optimization phase 2/3 trials and recruitment for a pediatric trial.42,43
Is the future about gene therapy?
TSHA-102 (miniMECP2). Taysha Gene Therapies is developing a promising gene therapy, TSHA-102, for Rett syndrome, and is aiming to begin phase 1/2 clinical trials in 2022.50 The technology for this therapy relies on the delivery of a fragment of MECP2 (known as miniMECP2), which is regulated by a built-in microRNA regulator (miR-responsive auto-regulatory element, or miRARE) to help ameliorate MECP2 dosage toxicity. (Overexpression of MECP2 is toxic to neurons, which has made traditional [so to speak] gene replacement therapy difficult in Rett syndrome: Levels of MECP2 need to be tightly regulated, and the Taysha microRNA technology regulates levels of miniMECP2, thus reducing toxicity.)
The Taysha microRNA technology has yielded promising results in mouse studies for Rett syndrome; results indicate a lengthening of lifespan and delayed onset of gait abnormalities.51 TSHA-102 is in the preclinical stage but offers promise that it will be the first gene therapy for Rett syndrome to enter clinical trials.
As the field of gene therapy advances, several promising technologies are on the horizon that could potentially have disease-altering impacts on Rett syndrome. These therapies are divided into two broad categories: those at the gene level and those at the transcription and protein level. A few of these approaches are highlighted below.
Gene replacement involves adding a full or partial copy of MECP2 to neuronal cells. This type of therapy presents challenges, from delivery of the new gene to dosage concerns, because MECP2 can be toxic if overexpressed.52-54 Groundbreaking work was done in mouse models involving truncated MECP2, exhibiting phenotypic rescue and validating the gene-replacement approach.18 This strategy is being pursued by Neurogene, which has a uinique technology that allows for tuning of the gene’s expression to get the correct protein levels in the patient. Promising data was presented this year at the American Society of Gene and Cell Therapy conference.55
Early gene replacement therapy studies also laid the foundation for the minMECP2 and microRNA approach being used by Taysha Gene Therapies (discussed above).51
“Correcting” DNA mutations. A different approach at the genetic level involves “correcting” mutations in MECP2 at the DNA level. This is possible because, in a large subset of Rett syndrome patients who have the same missense or nonsense mutations, by using CRISPR, a gene editing tool (discussed above) a single base pair can be corrected.56,57 Previous research, in a Rett syndrome-model of induced pluripotent stem cells, showed that this type of editing is possible – and effective.52 An approach with particular promise involves use of a class of CRISPR proteins known as base editors that are able to specifically alter a single base of DNA.57 The technique has the potential to address many of the mutations seen in Rett syndrome; research on this type of technology is being pursued by Beam Therapeutics, and has the potential to impact Rett syndrome.58
Another promising “correction” approach is exonic editing, in which a much larger section of DNA – potentially, exons 3 and 4, which, taken together, comprise 97% of known MECP2 mutations seen in Rett syndrome – are replaced.59
In both CRISPR and exonic editing therapeutic approaches, endogenous levels of MECP2 expression would be maintained. Of note, both approaches are being pursued for use in treating other genetic disorders, which provides a boost in scaling-up work on addressing safety and efficacy concerns that accompany gene-editing approaches.58 One advantage to the DNA correction approach is that is has the potential to be a “one-and-done” treatment.
“Correcting” RNA. Beyond directly editing DNA, several therapeutic approaches are exploring the ability to edit RNA or to provide the protein directly to cells as enzyme replacement therapy. Such an RNA correction strategy leverages a technology that takes advantage of cells’ natural RNA editor, known as adenosine deaminase acting on RNA (ADAR), which corrects errors in cells’ RNA by providing specific guides to the cell. ADAR can be targeted to fix mutations in the MECP2 RNA transcript, resulting in a “corrected” MECP2 protein.60,61 This technology has delivered promising proof-of-concept evidence in cells and in murine models, and is in the therapeutic pipeline at VICO Therapeutics.62
Shape Therapeutics has also leveraged ADAR to “correct” mutated RNA; Rett syndrome is among the top priorities in the company’s pipeline.
Worth noting is that there are several advantages to the “correction” approach:
- Leveraging internal repair mechanisms minimizes the immune response.
- The flexibility of correction means that it can be used to address many of the mutations that cause Rett syndrome.63
Enzyme replacement therapy, in which the MECP2 protein produced by MECP2 would be directly replaced, is being explored in Rett syndrome patients. This technology has been used successfully in Pompe disease; however, Rett syndrome presents its own challenge because MECP2 needs to be delivered to the brain and neuronal cells.64
Where does this work stand? The technologies described in this section are in preclinical stages of study. Nonetheless, it is expected that several will enter human clinical trials during the next 5 years.
Conclusion
A diagnosis of Rett syndrome is a life-altering event for patients and their family. But there is more hope than ever for effective therapies and, eventually, a cure.
Multiple late-stage clinical trials in progress are demonstrating promising results from therapeutic products, with minimal adverse events. Remarkably, these interventions have delivered improvements to adult patients after regression has stabilized. With rapid progress being made in the field of gene therapy, several technologies for which are focused on Rett syndrome, a hopeful picture is emerging: that therapeutic intervention will be possible before regression, thus effectively treating and, potentially, even curing Rett syndrome.
The landscape is broadening. Add to this hope for approved therapies is the fact that Rett syndrome isn’t the only target being pursued with such strategies; in fact, researchers in the larger field of neurodevelopmental disorder study are working together to find common solutions to shared challenges – from how therapies are designed and delivered to how toxicity is minimized. Much of what is being explored in the Rett syndrome field is also under investigation in other neurodevelopmental syndromes, including Angelman, Prader-Willi, chromosome 15q11.2-13.1 duplication (dup15q), and Fragile X syndrome. This kind of parallel investigation benefits all parties and optimizes a treatment platform so that it can be applied across more than a single disorder.
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and vision, not just wide-eyed optimism. These words portend real promise for patients who carry the weight of a diagnosis of Rett syndrome, and for their families.
Ms. Ambrose is a student in the master’s of science in human genetics and genomic data analytics program, Keck Graduate Institute, Claremont, Calif. Dr. Bailus is an assistant professor of genetics, Keck Graduate Institute. The authors report no conflict of interest related to this article.
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18. Tillotson R et al. Radically truncated MeCP2 rescues Rett syndrome–like neurological defects. Nature. 2017 Oct 19;550(7676):398-401. doi: 10.1038/nature24058.
19. Connolly DR, Zhou Z. Genomic insights into MeCP2 function: A role for the maintenance of chromatin architecture. Curr Opin Neurobiol. 2019 Dec;59:174-9. doi: 10.1016/j.conb.2019.07.002.
20. Johnson BS et al. Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome. Nat Med. 2017 Oct;23(10):1203-14. doi: 10.1038/nm.4406.
21. Gabel HW et al. Disruption of DNA-methylation–dependent long gene repression in Rett syndrome. Nature. 2015 Jun 4;522(7554):89-93. doi: 10.1038/nature14319.
22. Lyst MJ, Bird A. Rett syndrome: A complex disorder with simple roots. Nat Rev Genet. 2015 May;16(5):261-75. doi: 10.1038/nrg3897.
23. Kuehner JN et al. Epigenetic regulations in neuropsychiatric disorders. Front Genet. 2019 Apr 4;10:268. doi: 10.3389/fgene.2019.00268.
24. Pejhan S, Rastegar M. Role of DNA methyl-CpG-binding protein MeCP2 in Rett syndrome pathobiology and mechanism of disease. Biomolecules. 2021 Jan;11(1):75. doi: 10.3390/biom11010075.
25. Fu C et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open. 2020;4(1):e000717. doi: 10.1136/bmjpo-2020-000717.
26. Operto FF et al. Epilepsy and genetic in Rett syndrome: A review. Brain Behav. 2019 May;9(5):e01250. doi: 10.1002/brb3.1250.
27. Nissenkorn A et al. Epilepsy in Rett syndrome – The experience of a National Rett Center. Epilepsia. 2010 Jul;51(7):1252-8. doi: 10.1111/j.1528-1167.2010.02597.x.
28. Welcome to the Rett cure community. Rett Syndrome Research Trust [Internet]. Updated Feb 8, 2022. Accessed Feb 23, 2022. https://reverserett.org.
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30. Singh J, Santosh P. Key issues in Rett syndrome: Emotional, behavioural and autonomic dysregulation (EBAD) – A target for clinical trials. Orphanet J Rare Dis. 2018 Jul 31;13(1):128. doi: 10.1186/s13023-018-0873-8.
31. Banerjee A et al. Towards a better diagnosis and treatment of Rett syndrome: A model synaptic disorder. Brain. 2019 Feb 1;142(2):239-48. doi: 10.1093/brain/awy323.
32. Ager S et al. Parental experiences of scoliosis management in Rett syndrome. Disabil Rehabil. 2009 Sep 19;31(23):1917-24. doi: 10.1080/09638280902846392.
33. Budden SS. Management of Rett syndrome: A ten year experience. Neuropediatrics. 1995;26(2):75-7. doi: 10.1055/s-2007-979727.
34. Ip JPK et al. Rett syndrome: Insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci. 2018 Jun;19(6):368-82. doi: 10.1038/s41583-018-0006-3.
35. Acadia Pharmaceuticals Inc. Study of trofinetide for the treatment of girls and women with Rett syndrome (LAVENDER™). ClinicalTrials.gov identifier: NCT04181723. Updated Feb 17, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04181723.
36. Acadia Pharmaceuticals announces positive top-line results from the pivotal phase 3 LAVENDER trial of trofinetide in Rett syndrome. Press release. Acadia Pharmaceuticals Inc. Dec 6, 2021. Accessed Feb 23, 2022. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-positive-top-line-results-1.
37. Copping NA et al. Emerging gene and small molecule therapies for the neurodevelopmental disorder Angelman syndrome. Neurotherapeutics. 2021 Jul;18(3):1535-47. doi: 10.1007/s13311-021-01082-x.
38. Riikonen R. Insulin-like growth factors in the pathogenesis of neurological diseases in children. Int J Mol Sci. 2017 Sep;18(10):2056. doi: 10.3390/ijms18102056.
39. Glaze DG et al; Rett 002 Study Group. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. 2019 April 16;92(16):e1912-e1925. doi: 10.1212/WNL.0000000000007316.
40. Acadia Pharmaceuticals Inc. An open-label study of trofinetide for the treatment of girls two to five years of age who have Rett syndrome (DAFFODIL™). ClinicalTrials.gov Identifier: NCT04988867. Updated Jan 24, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04988867.
41. Anavex Life Sciences announces ANAVEX®2-73 meets primary and secondary endpoints in clinical trial. Press release. Anavex Life Sciences Corp. Dec 15, 2020. Accessed Feb 23, 2022. http://www.anavex.com/post/anavex-life-sciences-announces-anavex-2-73-meets-primary-and-secondary-endpoints-in-clinical-trial.
42. Anavex Life Sciences Corp. ANAVEX2-73 study in patients with Rett syndrome (AVATAR). ClinicalTrials.gov Identifier: NCT03941444. Updated Jan 27, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT03941444.
43. Anavex Life Sciences Corp. ANAVEX2-73 study in pediatric patients with Rett syndrome (EXCELLENCE). ClinicalTrials.gov Identifier: NCT04304482. Updated Sep 28, 2021. Accessed Feb 23, 2022. http://www.clinicaltrials.gov/ct2/show/NCT04304482.
44.Christ MG et al. The Sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. 2020 Feb;43(2):79-81. doi: 10.1016/j.tins.2019.12.002.
45. Kaufmann WE et al. ANAVEX®2-73 (blarcamesine), a sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav. 2019 Dec;187:172796. doi: 10.1016/j.pbb.2019.172796.
46. Brimson JM et al. Dipentylammonium binds to the sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res. 2018 Aug;34(2):263-72. doi: 10.1007/s12640-018-9883-5.
47. Kourrich S et al. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012 Dec;35(12):762-71. doi: 10.1016/j.tins.2012.09.007.
48. Lappalainen R, Riikonen RS. High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatr Neurol. 1996 Oct;15(3):213-6. doi: 10.1016/s0887-8994(96)00218-4.
49. Hamberger A et al. Elevated CSF glutamate in Rett syndrome. Neuropediatrics. 1992;23(4):212-3. doi: 10.1055/s-2008-1071344.
50. Inacio P. FDA acts to support development of potential gene therapy, TSHA-102. Rett Syndrome News [Internet]. Oct 16, 2020. Accessed Feb 23, 2022. https://rettsyndromenews.com/2020/10/16/fda-grants-orphan-drug-rare-pediatric-disease-status-to-tsha-102-potential-rett-gene-therapy.
51. Sinnett SE et al. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain. 2021 Nov 29;144(10):3005-19. doi: 10.1093/brain/awab182.
52. Le TTH et al. Efficient and precise CRISPR/Cas9-mediated MECP2 modifications in human-induced pluripotent stem cells. Front Genet. 2019 Jul 2;10:625. doi: 10.3389/fgene.2019.00625.
53. Koerner MV et al. Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. Genes Dev. 2018;32(23-24):1514-24. doi: 10.1101/gad.320325.118.
54. Heckman LD et al. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014;3:e02676. doi: 10.7554/eLife.02676.
55. Neurogene announces new development program in Rett syndrome utilizing novel EXACT technology platform [Internet]. Accessed Aug 12, 2022. https://www.neurogene.com/press-releases/neurogene-announces-new-development-program-in-rett-syndrome-utilizing-novel-exact-technology-platform/
56. Anzalone AV et al. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020 Jul;38(7):824-44. doi: 10.1038/s41587-020-0561-9.
57. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A●T to G●C in genomic DNA without DNA cleavage. Nature. 2017 Nov 23;551(7681):464-71. doi: 10.1038/nature24644.
58. Coenraads M. How RSRT is driving the search for a Rett cure. Rett Syndrome Research Trust [Internet]. Dec 7, 2021. Accessed Feb 23, 2022. https://rettnews.org/articles/how-rsrt-is-driving-the-search-for-a-rett-cure.
59. Cutting-edge technologies to repair the underlying mutations that cause Rett. Rett Syndrome Research Trust [Internet]. Updated Nov 3, 2021. Accessed Feb 23, 2022. https://reverserett.org/research/cures/gene-editing.
60. Sinnamon JR et al. In vivo repair of a protein underlying a neurological disorder by programmable RNA editing. Cell Rep. 2020 Jul 14;32(2):107878. doi: 10.1016/j.celrep.2020.107878.
61. Sinnamon JR et al. Site-directed RNA repair of endogenous Mecp2 RNA in neurons. Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9395-E9402. doi: 10.1073/pnas.1715320114.
62. Pipeline. VICO Therapeutics [Internet]. Updated Nov 5, 2021. Accessed Feb 23, 2022. https://vicotx.com/pipeline.
63. Therapeutics platform. Shape Therapeutics [Internet]. Updated Feb 20, 2021. Accessed Feb 23, 2022.
https://live-shapetx.pantheonsite.io/therapeutics-platform.
64. Koeberl DD et al. Glycogen storage disease types I and II: Treatment updates. J Inherit Metab Dis. 2007 Apr;30(2):159-64. doi: 10.1007/s10545-007-0519-9.
The dream of curing genetic disorders has been a persistent but elusive goal, even before the human genome was mapped. Once mapping of the human genome was complete in 2001, an entirely new avenue of potential treatments and cures for genetic diseases and disorders was opened.1,2
The disorders best suited for targeted gene therapy are monogenic; however, tools and delivery methods for editing the human genome were limited and difficult to apply, until the advent of the CRISPR system in 2012.3 CRISPR (an acronym of clustered regularly interspaced short palindromic repeats) has changed the way in which gene therapy strategies are pursued, with dozens of companies leveraging a variety of platforms to create potentially life-changing therapies for devastating rare diseases and disorders.
One of the rare monogenic disorders that is embracing multiple gene therapy approaches is Rett syndrome, a rare, debilitating neurodevelopmental disorder. In this review, we explore the molecular cause of Rett syndrome, disease presentation, current treatments, ongoing clinical trials, and therapies that are on the horizon.
Underlying molecular cause
Rett syndrome is caused by mutations in, or the absence of, the MECP2 gene, which produces methyl-CpG binding protein 2 (MECP2). The syndrome was first described clinically in 1954 by the Austrian physician Andreas Rett; it would take until 1982 before the disorder was officially named, eponymously, in a seminal paper by Hagberg.4 After Hagberg’s characterization, Rett syndrome became the predominant global clinical diagnosis identified among cognitively impaired females, with an incidence of 1 in every 10,000 to 15,000.4
In 1999, mutations in, and deletions of, MECP2 were identified as the cause of Rett syndrome.4,5 MECP2 is located on the X chromosome, in the Xq28 region, making Rett syndrome an X-linked dominant disorder.6 Rett syndrome is seen predominantly in females who are mosaic for mutant or deleted MECP2. Random X chromosome inactivation results in some cells expressing the mutant MECP2 allele and other cells expressing the normal functioning MECP2 allele; the percentage of cells expressing the normal allele correlates with the degree of syndrome severity.7-9
The incidence of Rett syndrome is much lower in males, in whom the syndrome was originally thought to be lethal; many observed male cases are either mosaic or occur in XXY males.10,11
Approximately 95% of cases of Rett syndrome are due to de novo mutations in MECP2, with a handful of specific mutations and large deletions accounting for more than 85% of cases.12 The fact that Rett syndrome is monogenic and most cases are caused by, in total, only a handful of mutations or deletions makes the syndrome a promising candidate for gene therapy.
At the molecular level, it has been observed that the MECP2 mutations of Rett syndrome lead to loss of gene function, thus disrupting the ability of the MECP2 nuclear protein to regulate global gene transcription through its binding to methylated DNA sites.12 A large percentage of these missense and nonsense mutations lead to a truncated or nonfunctional protein.12
One of the ways in which MECP2 regulates transcription is as a component of heterochromatin condensates and by separation of heterochromatin and euchromatin.13-15 It has been observed that the cells of Rett syndrome patients have an altered chromatin state, potentially contributing to transcriptional dysregulation.16,17 Several mutations observed in Rett syndrome patients occur in crucial domains for heterochromatin condensate formation, which helps explain this cellular phenotype.13 Introduction of a engineered “mini” MECP2 in a murine model of Rett syndrome has resulted in partial rescue of heterochromatin condensate formation and transcriptional regulation – fostering the hypothesis that correcting those genetic changes could lead to a potential therapy.18
Beyond the role of MECP2 in heterochromatin condensate formation, the gene interacts with more than 40 proteins that have diverse roles in cellular function, epigenetic modulation, and neuronal development. This volume of interactions contributes to MECP2 being a global gene regulatory protein that has far-reaching effects on transcriptional regulation across the genome.19-22
Epigenetic dysregulation has been associated with neurodevelopmental and neuropsychiatric disorders.23 Both insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor are transcriptional targets of MECP2, and are involved in neuronal differentiation, synaptic function, and neurite outgrowth.12 This helps explain the neurodevelopmental phenotypes observed in MECP2-mutated patients.
Notably, although Rett syndrome patients experience neurodevelopmental phenotypes at the cellular level, neuronal death is not readily observed. That observation provides hope that an interventional therapy after onset of symptoms might still be of benefit.
Presentation
Early neurotypical development. A hallmark of Rett syndrome is neurotypical physical and mental development until 6 to 24 months of age.
Stagnation is the first stage of the syndrome, involving a small but rapid decline in habitual milestones, such motor and language skills.12 Subtle signs, such as microcephaly and hypotonia, can also arise at this time but might be missed.24
Rapid regression follows stagnation. Speech and motor delays and impaired gait and breathing occur;12,25 purposeful hand skills are lost, replaced by repetitive hand-wringing movements that are a hallmark of the syndrome.12,24 Seizures are observed; they become more common during the next stage.12
Plateau. Language advances can be observed, but further deficits are seen in motor skills and hand coordination.12
Late motor deterioration stage. Late physical deficits develop, leading to lifelong impairments. The physical deficits observed are the result of severe muscle weakness, usually resulting in wheelchair dependency.12
Plateau. Patients then reach a second plateau. Regression stops; deficient physical and cognitive states stabilize and are maintained.25
At all stages of Rett syndrome, the following are observed:
- Gastrointestinal problems.
- Sleep disturbances.
- Abnormal cardiorespiratory coupling.
- Greater-than-expected mortality.12
Final regression. The patient is fully dependent for the rest of their lifespan, partially due to seizure activity.26,27
A life-changing diagnosis
A diagnosis of Rett syndrome is life-changing for a patient’s family; access to supportive groups of other patients and their families is extremely beneficial. Two helpful organizations – the Rett Syndrome Research Trust28 and International Rett Syndrome Foundation,29 – offer patient support and community and fund research.
Because X chromosome inactivation is random in Rett syndrome, the individual patient can present with a wide variety of phenotypic combinations – making the patient, and their needs, unique.12 During stages of regression, patients often experience emotional dysregulation and anxiety, which is attributable to their increasing physical difficulties.30 They often exhibit combinations of uncontrolled movements, including repetitive rocking, scratching, and self-injurious behavior.30 For most, regression subsides after the first 5 years of alternating development and regression; after that, their ultimate symptoms persist for life.25
As patients mature, they need to be monitored for proper nutrition and scoliosis.25 As adults, they are at risk of pneumonia, respiratory distress, status epilepticus, osteopenia, and lack of adequate food or water because of impaired ability to feed.25
The lifespan of Rett syndrome patients has increased, thanks to improvements in health care, advances in technology, and early genetic testing, which allows for earlier diagnosis, intervention, and management of symptoms.
Current treatments
When a female patient presents with regression and loss of milestones, sequencing of MECP2 is performed to verify whether Rett syndrome is the cause, by detecting any of the known mutations. Multiplex ligation-dependent probe amplification is also performed to detect major deletions.25
All available treatments for Rett syndrome are symptomatic; intensive early intervention is practiced.31 Multidisciplinary management – medical, psychiatric, and physical – is introduced almost immediately after diagnosis. Following diagnosis, patients are prescribed anti-seizure, sleep, and anxiety medications.31 Electroencephalography can be performed to identify seizure type. Neuromuscular blockage drugs can be prescribed to help with gait and stereotypic hand movements.25
Handguards or splints to the elbows can be prescribed by an occupational therapist to improve hand movement.25 Physical therapy can improve mobility; hydrotherapy and hippotherapy have been successful in helping to maintain mobility and muscle support.32,33 Nutritional management is implemented to control caloric intake and maintain the vitamin D level.31 Some patients experience constipation and urinary retention, putting them at risk of nephrolithiasis.
Once the signs and symptoms of Rett syndrome progress, and milestones regress to a certain point, patients need constant, full-time care for the rest of their lives.34 As symptomatic interventions have greatly improved patient outcomes and it has been shown that about 70% can reach adulthood with a potential lifespan of about 50 years.25
Although there is no cure for Rett syndrome and treatments are symptomatic, ongoing studies – both clinical and preclinical – offer promise that treatments will be developed that work at molecular and genetic levels.
Clinical trials
Advances in understanding of Rett syndrome have led to many therapies in clinical trials, several of which show promise.
Trofinetide. One of the most promising targets for downstream therapy, mentioned earlier, is IGF-1, which was the target of a successful phase 3 clinical trial, LAVENDER (sponsored by Acadia Pharmaceuticals).35,36 This trial studied trofinetide, a synthetic IGF-1 analog that inhibits neuroinflammation, restores glial function, corrects synaptic deficiencies, and regulates oxidative stress response.12,37,38 Initial results from phase 2 and phase 3 trials indicate improved scores for treated patients in the Rett syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression–Improvement (CGI-I) scores, while also showing improvements in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist–Social composite score.36,39
The most common adverse events seen with trofinetide were diarrhea and vomiting.
Acadia Pharmaceuticals has filed for approval of a new drug application for trofinetide with the Food and Drug Administration, for which the company has been granted Fast Track Status and orphan drug designations. Most (95%) subjects in the phase 3 LAVENDER trial elected to continue taking trofinetide in the subsequent open-label Lilac and Lilac-2 extension studies.36 A current open-label phase 2/3 trial is recruiting patients 2 to 5 years of age to evaluate trofinetide.40 It is expected that, in the near future, this could be a drug given to Rett patients as an FDA-approved treatment.
Blarcamesine. Another small molecule drug, blarcamesine (also known as ANAVEX2-73), a sigma-1 receptor agonist, produced promising results in phase 2 clinical trials in adult Rett syndrome patients. The drug is in a phase 2/3 clinical trial for pediatric Rett syndrome patients (sponsored by Anavex Life Sciences).41-43
Phase 2 results indicated statistically significant and clinically meaningful improvement in RSBQ and CGI-I scores with blarcamesine. Improvement was initially observed within 4 weeks after the start of treatment and was sustained throughout the study. The drug was shown to be well tolerated, with minimal adverse effects; no serious adverse events were recorded. These results were observed in adult patients, demonstrating that improvements in Rett syndrome are possible even after regression.
Blarcamesine activates the sigma 1 receptor, which is pivotal to restoring cellular homeostasis and restoring neuroplasticity – deficiencies of which have been linked to autophagy and glutamate toxicity. The drug has also been explored as a potential treatment for other neurological disorders.44-47 Improvements in blarcamesine-treated patients further correlated with lower levels of glutamate in cerebrospinal fluid, which is a Rett syndrome biomarker, supporting the proposition that behavioral improvements were due to drug intervention.48,49 The phase 2 trial was modified into a phase 3 trial and additional endpoints were added.41-43
All patients in the phase 2 adult trial elected to continue in the extension study.
Based on these promising data, Anavex is pursuing an approval pathway for adult patients, while continuing dosage optimization phase 2/3 trials and recruitment for a pediatric trial.42,43
Is the future about gene therapy?
TSHA-102 (miniMECP2). Taysha Gene Therapies is developing a promising gene therapy, TSHA-102, for Rett syndrome, and is aiming to begin phase 1/2 clinical trials in 2022.50 The technology for this therapy relies on the delivery of a fragment of MECP2 (known as miniMECP2), which is regulated by a built-in microRNA regulator (miR-responsive auto-regulatory element, or miRARE) to help ameliorate MECP2 dosage toxicity. (Overexpression of MECP2 is toxic to neurons, which has made traditional [so to speak] gene replacement therapy difficult in Rett syndrome: Levels of MECP2 need to be tightly regulated, and the Taysha microRNA technology regulates levels of miniMECP2, thus reducing toxicity.)
The Taysha microRNA technology has yielded promising results in mouse studies for Rett syndrome; results indicate a lengthening of lifespan and delayed onset of gait abnormalities.51 TSHA-102 is in the preclinical stage but offers promise that it will be the first gene therapy for Rett syndrome to enter clinical trials.
As the field of gene therapy advances, several promising technologies are on the horizon that could potentially have disease-altering impacts on Rett syndrome. These therapies are divided into two broad categories: those at the gene level and those at the transcription and protein level. A few of these approaches are highlighted below.
Gene replacement involves adding a full or partial copy of MECP2 to neuronal cells. This type of therapy presents challenges, from delivery of the new gene to dosage concerns, because MECP2 can be toxic if overexpressed.52-54 Groundbreaking work was done in mouse models involving truncated MECP2, exhibiting phenotypic rescue and validating the gene-replacement approach.18 This strategy is being pursued by Neurogene, which has a uinique technology that allows for tuning of the gene’s expression to get the correct protein levels in the patient. Promising data was presented this year at the American Society of Gene and Cell Therapy conference.55
Early gene replacement therapy studies also laid the foundation for the minMECP2 and microRNA approach being used by Taysha Gene Therapies (discussed above).51
“Correcting” DNA mutations. A different approach at the genetic level involves “correcting” mutations in MECP2 at the DNA level. This is possible because, in a large subset of Rett syndrome patients who have the same missense or nonsense mutations, by using CRISPR, a gene editing tool (discussed above) a single base pair can be corrected.56,57 Previous research, in a Rett syndrome-model of induced pluripotent stem cells, showed that this type of editing is possible – and effective.52 An approach with particular promise involves use of a class of CRISPR proteins known as base editors that are able to specifically alter a single base of DNA.57 The technique has the potential to address many of the mutations seen in Rett syndrome; research on this type of technology is being pursued by Beam Therapeutics, and has the potential to impact Rett syndrome.58
Another promising “correction” approach is exonic editing, in which a much larger section of DNA – potentially, exons 3 and 4, which, taken together, comprise 97% of known MECP2 mutations seen in Rett syndrome – are replaced.59
In both CRISPR and exonic editing therapeutic approaches, endogenous levels of MECP2 expression would be maintained. Of note, both approaches are being pursued for use in treating other genetic disorders, which provides a boost in scaling-up work on addressing safety and efficacy concerns that accompany gene-editing approaches.58 One advantage to the DNA correction approach is that is has the potential to be a “one-and-done” treatment.
“Correcting” RNA. Beyond directly editing DNA, several therapeutic approaches are exploring the ability to edit RNA or to provide the protein directly to cells as enzyme replacement therapy. Such an RNA correction strategy leverages a technology that takes advantage of cells’ natural RNA editor, known as adenosine deaminase acting on RNA (ADAR), which corrects errors in cells’ RNA by providing specific guides to the cell. ADAR can be targeted to fix mutations in the MECP2 RNA transcript, resulting in a “corrected” MECP2 protein.60,61 This technology has delivered promising proof-of-concept evidence in cells and in murine models, and is in the therapeutic pipeline at VICO Therapeutics.62
Shape Therapeutics has also leveraged ADAR to “correct” mutated RNA; Rett syndrome is among the top priorities in the company’s pipeline.
Worth noting is that there are several advantages to the “correction” approach:
- Leveraging internal repair mechanisms minimizes the immune response.
- The flexibility of correction means that it can be used to address many of the mutations that cause Rett syndrome.63
Enzyme replacement therapy, in which the MECP2 protein produced by MECP2 would be directly replaced, is being explored in Rett syndrome patients. This technology has been used successfully in Pompe disease; however, Rett syndrome presents its own challenge because MECP2 needs to be delivered to the brain and neuronal cells.64
Where does this work stand? The technologies described in this section are in preclinical stages of study. Nonetheless, it is expected that several will enter human clinical trials during the next 5 years.
Conclusion
A diagnosis of Rett syndrome is a life-altering event for patients and their family. But there is more hope than ever for effective therapies and, eventually, a cure.
Multiple late-stage clinical trials in progress are demonstrating promising results from therapeutic products, with minimal adverse events. Remarkably, these interventions have delivered improvements to adult patients after regression has stabilized. With rapid progress being made in the field of gene therapy, several technologies for which are focused on Rett syndrome, a hopeful picture is emerging: that therapeutic intervention will be possible before regression, thus effectively treating and, potentially, even curing Rett syndrome.
The landscape is broadening. Add to this hope for approved therapies is the fact that Rett syndrome isn’t the only target being pursued with such strategies; in fact, researchers in the larger field of neurodevelopmental disorder study are working together to find common solutions to shared challenges – from how therapies are designed and delivered to how toxicity is minimized. Much of what is being explored in the Rett syndrome field is also under investigation in other neurodevelopmental syndromes, including Angelman, Prader-Willi, chromosome 15q11.2-13.1 duplication (dup15q), and Fragile X syndrome. This kind of parallel investigation benefits all parties and optimizes a treatment platform so that it can be applied across more than a single disorder.
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and vision, not just wide-eyed optimism. These words portend real promise for patients who carry the weight of a diagnosis of Rett syndrome, and for their families.
Ms. Ambrose is a student in the master’s of science in human genetics and genomic data analytics program, Keck Graduate Institute, Claremont, Calif. Dr. Bailus is an assistant professor of genetics, Keck Graduate Institute. The authors report no conflict of interest related to this article.
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24. Pejhan S, Rastegar M. Role of DNA methyl-CpG-binding protein MeCP2 in Rett syndrome pathobiology and mechanism of disease. Biomolecules. 2021 Jan;11(1):75. doi: 10.3390/biom11010075.
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31. Banerjee A et al. Towards a better diagnosis and treatment of Rett syndrome: A model synaptic disorder. Brain. 2019 Feb 1;142(2):239-48. doi: 10.1093/brain/awy323.
32. Ager S et al. Parental experiences of scoliosis management in Rett syndrome. Disabil Rehabil. 2009 Sep 19;31(23):1917-24. doi: 10.1080/09638280902846392.
33. Budden SS. Management of Rett syndrome: A ten year experience. Neuropediatrics. 1995;26(2):75-7. doi: 10.1055/s-2007-979727.
34. Ip JPK et al. Rett syndrome: Insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci. 2018 Jun;19(6):368-82. doi: 10.1038/s41583-018-0006-3.
35. Acadia Pharmaceuticals Inc. Study of trofinetide for the treatment of girls and women with Rett syndrome (LAVENDER™). ClinicalTrials.gov identifier: NCT04181723. Updated Feb 17, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04181723.
36. Acadia Pharmaceuticals announces positive top-line results from the pivotal phase 3 LAVENDER trial of trofinetide in Rett syndrome. Press release. Acadia Pharmaceuticals Inc. Dec 6, 2021. Accessed Feb 23, 2022. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-positive-top-line-results-1.
37. Copping NA et al. Emerging gene and small molecule therapies for the neurodevelopmental disorder Angelman syndrome. Neurotherapeutics. 2021 Jul;18(3):1535-47. doi: 10.1007/s13311-021-01082-x.
38. Riikonen R. Insulin-like growth factors in the pathogenesis of neurological diseases in children. Int J Mol Sci. 2017 Sep;18(10):2056. doi: 10.3390/ijms18102056.
39. Glaze DG et al; Rett 002 Study Group. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. 2019 April 16;92(16):e1912-e1925. doi: 10.1212/WNL.0000000000007316.
40. Acadia Pharmaceuticals Inc. An open-label study of trofinetide for the treatment of girls two to five years of age who have Rett syndrome (DAFFODIL™). ClinicalTrials.gov Identifier: NCT04988867. Updated Jan 24, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04988867.
41. Anavex Life Sciences announces ANAVEX®2-73 meets primary and secondary endpoints in clinical trial. Press release. Anavex Life Sciences Corp. Dec 15, 2020. Accessed Feb 23, 2022. http://www.anavex.com/post/anavex-life-sciences-announces-anavex-2-73-meets-primary-and-secondary-endpoints-in-clinical-trial.
42. Anavex Life Sciences Corp. ANAVEX2-73 study in patients with Rett syndrome (AVATAR). ClinicalTrials.gov Identifier: NCT03941444. Updated Jan 27, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT03941444.
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44.Christ MG et al. The Sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. 2020 Feb;43(2):79-81. doi: 10.1016/j.tins.2019.12.002.
45. Kaufmann WE et al. ANAVEX®2-73 (blarcamesine), a sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav. 2019 Dec;187:172796. doi: 10.1016/j.pbb.2019.172796.
46. Brimson JM et al. Dipentylammonium binds to the sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res. 2018 Aug;34(2):263-72. doi: 10.1007/s12640-018-9883-5.
47. Kourrich S et al. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012 Dec;35(12):762-71. doi: 10.1016/j.tins.2012.09.007.
48. Lappalainen R, Riikonen RS. High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatr Neurol. 1996 Oct;15(3):213-6. doi: 10.1016/s0887-8994(96)00218-4.
49. Hamberger A et al. Elevated CSF glutamate in Rett syndrome. Neuropediatrics. 1992;23(4):212-3. doi: 10.1055/s-2008-1071344.
50. Inacio P. FDA acts to support development of potential gene therapy, TSHA-102. Rett Syndrome News [Internet]. Oct 16, 2020. Accessed Feb 23, 2022. https://rettsyndromenews.com/2020/10/16/fda-grants-orphan-drug-rare-pediatric-disease-status-to-tsha-102-potential-rett-gene-therapy.
51. Sinnett SE et al. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain. 2021 Nov 29;144(10):3005-19. doi: 10.1093/brain/awab182.
52. Le TTH et al. Efficient and precise CRISPR/Cas9-mediated MECP2 modifications in human-induced pluripotent stem cells. Front Genet. 2019 Jul 2;10:625. doi: 10.3389/fgene.2019.00625.
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54. Heckman LD et al. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014;3:e02676. doi: 10.7554/eLife.02676.
55. Neurogene announces new development program in Rett syndrome utilizing novel EXACT technology platform [Internet]. Accessed Aug 12, 2022. https://www.neurogene.com/press-releases/neurogene-announces-new-development-program-in-rett-syndrome-utilizing-novel-exact-technology-platform/
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The paradox of Pompe disease
Until 2006, when a breakthrough therapy first made treatment possible, Pompe disease was a little-known metabolic myopathy fatal to infants. Those with later-onset disease experienced progressive, often severe disability into adulthood.
In this rare autosomal recessive disorder, which occurs in approximately one in 40,000 births worldwide, a deficiency or absence of the enzyme acid alpha-glucosidase causes glycogen to build up in the lysosomes of cells. While many tissues are affected, skeletal and cardiac muscle see the earliest involvement, with muscle hypotonia, cardiomyopathy, and breathing difficulties (mainly due to diaphragm weakness) comprising the hallmark symptoms of the infantile form. Muscle weakness and progressive respiratory failure are prominent in later-onset disease.
The spectrum of severity and age of onset in Pompe disease is linked to combinations of mutations on the GAA gene, some of which destroy the body’s ability to produce acid alpha-glucosidase whereas others merely hamper it. Less enzyme produced in the body generally corresponds with more severe disease activity.
The most severe end of the disease spectrum, or “classic infantile Pompe disease,” presents at birth and is recognized in early infancy. Until treatment with enzyme replacement therapy (ERT) became available, patients usually died of cardiorespiratory failure within their first year of life. With therapy, patients have survived into their 20s and beyond. Late-onset disease is a far broader category in which patients can present at any time from their first year, including into middle age.
The emergence in 2006 of alglucosidase alfa (Lumizyme, Sanofi Genzyme), an ERT used long-term to improve survival and slow progression in children and adults, resulted in a boom of research interest, a push to timelier diagnosis, and – with patients living longer – a more thorough understanding of the natural history of Pompe disease. In addition to the usual clinical picture of progressive muscle weakness, difficulty breathing, and cardiomyopathy, investigators are seeing nervous system involvement in patients with Pompe disease.
To learn more, Neurology Reviews talked to two global experts in Pompe disease: Priya Kishnani, MD, of Duke University in Durham, N.C., and Antonio Toscano, MD, of the University of Messina, in Messina, Italy.
Diagnosis: Still room to improve
“Most neurologists will encounter a patient with Pompe disease,” said Dr. Kishnani, who has been working with Pompe for her entire career as a pediatrician and medical geneticist, treating patients of all ages and disease phenotypes.
“In newborns, diagnosis is more straightforward, because you’ve got an enlarged heart,” she said. And thanks to efforts of researchers like Dr. Kishnani and Pompe advocacy groups, Pompe disease is now a part of the RUSP (Recommended Uniform Screening Panel) for newborns; currently 28 U.S. states are screening for Pompe disease.
“The challenge really is for the later-onset cases, which are 80% of all cases,” Dr. Kishnani said.
Previously, muscle biopsies were the first step toward diagnosis. Dried blot spot assays to detect enzyme deficiency have since become the standard, along with other biochemical tests. Confirmation of the diagnosis is through gene sequencing panels to detect GAA mutations.
“Now that there is a treatment for Pompe disease and the availability of blood-based testing, many previously undiagnosed patients with limb girdle weakness are evaluated and the diagnostic odyssey ends,” Dr. Kishnani said. “But there is still a diagnostic delay, and many cases remain undiagnosed.”
Routine blood tests for creatine kinase and for liver enzymes can help point to Pompe disease. But elevated liver enzymes are often misinterpreted. “It’s about the ratios,” Dr. Kishnani said. “ALT is usually much more elevated if it is coming from a liver cause, and AST is usually higher than ALT if it is coming from muscle. But patients often end up getting a liver biopsy due to so-called elevated liver enzymes. As the workup continues, it is often later recognized that the source of the elevated enzymes is muscle involvement, and a referral to the geneticist or neurologist is made. Only then is appropriate testing to confirm a diagnosis initiated.”
Dr. Toscano, a neurologist who specializes in Pompe disease and other myopathies and who has published on tools for diagnosing late-onset Pompe disease,1 said that clinicians should be vigilant when evaluating any patient with limb girdle weakness and elevated creatine kinase (CK) – “especially if the CK is under 2,000,” he said, “because it is very rare that patients with Pompe disease have a more elevated CK than that.”
“Elevated CK, myalgia, and exercise intolerance” should prompt clinicians to suspect Pompe disease in a patient of any age, Dr. Toscano said. “When you come across this, you should be very persistent and get to the end of the story.”
Dr. Toscano noted that the blood spot assay, while an important early step, is not fully diagnostic, “because you can have false positives.” The molecular GAA assay is used to confirm Pompe disease. But detecting pathogenic variants on the GAA gene – of which there are more than 500 – can be more complicated than it sounds. Whereas two mutations are required for Pompe disease, sometimes only one can be detected. Dr. Toscano said he also treated some patients for Pompe with only one known mutation but with unequivocal clinical and biochemical aspects of Pompe disease.
While delays in diagnosis for late-onset Pompe disease remain significant -- between 5 and 6 years on average for older patients, and up to 20 years for those with pediatric onset – both Dr. Kishnani and Dr. Toscano said they perceive them to be improving. With McArdle disease, another inherited glycogen storage disorder that is more common than Pompe disease but for which there is no treatment, “the delay is nearly 12 years,” Dr. Toscano said.
ERT: The sooner the better
Enzyme replacement therapy is indicated for all patients with Pompe disease. Currently two are commercially available: alglucosidase alfa (Lumizyme, Sanofi Genzyme), indicated for all forms of Pompe disease, and avalglucosidase alfa-ngpt (Nexviazyme, Sanofi Genzyme), approved in 2021 for later-onset Pompe, though its indications have yet to be fully defined.
The semimonthly infusions represent, to date, the only disease-modifying therapies commercially available. Enzyme replacement therapy can reverse cardiac damage seen in infants and allow them to meet developmental milestones previously unthinkable. In adults, it can slow progression, though many treated patients will still develop chronic disability and require a wheelchair, respiratory support, or both. “The phenotype of the patients we are seeing today is not as involved as it was prior to enzyme therapy,” said Dr. Kishnani, who was part of the research team that developed ERT and launched the first clinical trials. “This is across the disease spectrum.”
But optimal management means more than just getting a patient on therapy fast, Dr. Kishnani said.
“Very often the thinking is if the patient is on ERT, we’ve done right by the patient. Aspects we don’t look at enough include: Are we monitoring these patients well? Are patients being followed by a multidisciplinary team that includes cardiology, physical therapy, and pulmonary medicine? Are we doing appropriate musculoskeletal assessments? They might have sleep hypoventilation. The BiPap settings may not be correct. Or they have not been assessed for antibodies,” she said.
Many infants with severe phenotypes, notably those who produce no enzyme naturally, will develop immune reactions to the exogenous enzyme therapy. High antibody titers also have been seen and are associated with poor therapeutic response. While this is very clear in the infantile setting, late-onset patients also develop antibodies in response to ERT. In one study in 64 patients,2 Dr. Toscano and his colleagues saw that antibodies may affect clinical response during the first 3 years of treatment, while a small study3 by Dr. Kishnani’s group saw clinical decline associated with high antibody titers in patients with late-onset disease.
While the relationship of specific titers to therapeutic response remains unclear, it is important to consider antibodies, along with other factors, in the monitoring of patients with Pompe disease. “We need to always ask, if a patient is falling behind, what could be the reason?” Dr. Kishnani said. “These are the things we as clinicians can do to improve or enhance the impact of ERT.”
Dr. Toscano noted that a common misconception about late-onset Pompe disease is that cardiac manifestations are minimal or absent, whereas as many as about 20% of patients will have heart problems and need to be carefully monitored.
Neurological manifestations
With patients surviving longer on ERT, researchers have been able to develop a deeper understanding of the natural history of Pompe disease. Increasingly, they are seeing it as a multisystem disease that includes central nervous system involvement.
“Is Pompe an overt neurodegenerative disease? I would say no,” Dr. Kishnani said. “But there is a neurological component that we’ve got to understand and follow more.”
Glycogen accumulation, she noted, has been found in anterior horn cells, motor neurons, and other parts of the brain. “We have been doing MRIs on children with infantile Pompe, and we have seen some white matter hyperintensities. The clinical significance of this finding is still emerging. Sometimes it is present, but the child is cognitively intact. We have had college graduates who have white matter hyperintensities. So putting it in context will be important. But we know that glycogen is ubiquitous, and autopsy studies have shown that it is present in the brain.”
In recent years, Dr. Toscano’s group has investigated neurovascular complications of Pompe in late-onset patients. “This was something that really surprised us because for several years we have investigated mainly heart, muscle, or respiratory manifestations of the disease, but the central nervous system was really neglected,” he said.
“Occasionally we did some brain MRIs and we found in even young patients some ischemic areas. We thought this was related to slowed circulation – that blood vessels in these patients are weak because they are impaired by glycogen accumulation.” Dr. Toscano and his colleagues followed that observation with a study of late-onset patients,4 in which they found that more than half had cerebrovascular abnormalities. “Even in, say, patients 30 to 35 years old we saw this – it’s unusual to have a vascular disorder at that age.”
Dr. Toscano and his colleagues also reported cerebral aneurysms5 in patients with Pompe disease and have recommended that clinicians conduct MRI or cerebral angiograms on patients as part of routine follow-up. Blood pressure in Pompe patients should be carefully watched and managed with antihypertensive medication as needed, he said.
Part of the problem is that the proteins in ERT are not able to cross the blood-brain barrier, Dr. Toscano noted, adding that researchers are investigating other treatments that can.
Pompe disease as a research model
The successful development of ERT for Pompe disease marked a boom in research interest into not just Pompe – for which several experimental therapies are currently in the pipeline – but for other myopathies and glycogen storage disorders.
“I think that Pompe has served as a template both as a muscle disease and a lysosomal storage disease, and so some of our learnings from Pompe have been applied across different diseases,” Dr. Kishnani said.
Studies in spinal muscular atrophy, for example, “in some ways mirrored what was done for Pompe – treatment trials were initiated in babies at the most severe end of the disease population with infantile disease, and used similar clinical trial endpoints,” Dr. Kishnani said. “Even for the later-onset end of the spectrum, the endpoints we used in Pompe for muscle strength and function have been relevant to many other neuromuscular disorders.”
Pompe disease research also ushered in a new appreciation of immune responses in protein replacement therapies, Dr. Kishnani noted.
“In the field today, you hear the term cross-reactive immunological material, or CRIM, all the time,” she said. “But when we first started talking about it in the space of Pompe disease, there was a lot of scientific debate about what the significance of CRIM-negative status was in relationship to the risk for development of high and sustained antibody titer and a poor clinical response. To understand this involved a lot of going back to the data and digging into the small subset of nonresponders. One of the powers of rare disease research is that every patient matters, and it’s important to understand what’s going on at the patient level rather than just the group data level.”
A robust pipeline
The decade and a half since the advent of ERT has seen what Dr. Toscano described as “an explosion of interest” in Pompe disease.
“We’re seeing an extraordinary number of papers on everything from clinical, biomarkers, genetics, and rehabilitation – this disease is now considered from every point of view, and this is very important for patients,” Dr. Toscano said. Alongside this has come industry interest in this rare disease, with several companies investigating a range of treatment approaches.
The existence of a treatment, “while not perfect,” he said, “has interested the patient associations and doctors to try and improve service to patients. Patients with Pompe disease are well attended, probably more so than patients with degenerative disorders in which there is no therapy.”
Last year the second ERT, avalglucosidase alfa (Nexviazyme, Sanofi Genzyme) was approved by the U.S. Food and Drug Administration to treat late-onset Pompe disease. The drug, currently being investigated in infants as well, was designed to improve the delivery of the therapeutic enzyme to muscles and enhance glycogen clearance, and results from ongoing trials suggest some functional and clinical benefit over standard ERT.
Other drugs in development for Pompe disease include substrate reduction therapies, which aim to reduce the storage of glycogen in cells, and therapies that improve residual function of mutant GAA enzyme in the body. These and other therapies in development have the potential to modify nervous system manifestations of Pompe disease.6
Because a single gene is implicated in Pompe disease, it has long been considered a good candidate for gene therapies that prompt the body to make stable enzyme. Seven companies are now investigating gene therapies in Pompe disease.7 Some of these deliver to skeletal muscles and others aim for the liver, where proteins are synthesized and secreted and adverse immune responses might be more easily mitigated. Other gene therapies use an ex vivo approach, removing and replacing cells in bone marrow.
Dr. Kishnani’s research group at Duke University is leading a small clinical trial in late-onset patients of a GAA gene transfer to the liver using adeno-associated virus (AAV) vectors.8
“We have started AAV gene therapy trials in in adults with Pompe disease and will later evaluate children because ERT is available as a standard of care, and so from a safety perspective this makes the most sense,” Dr. Kishnani said. “We do have challenges in the field of gene therapy, but I think if we are able to overcome the immune responses, and … to treat at a lower dose, there’s a very good pathway forward.”
Dr. Toscano and Dr. Kishnani have received reimbursement from Sanofi and other manufacturers for participation on advisory boards and as speakers.
Jennie Smith is a freelance journalist and editor specializing in medicine and health.
References
1. Musumeci O, Toscano A. Diagnostic tools in late onset Pompe disease (LOPD). Ann Transl Med. 2019 Jul;7(13):286. doi: 10.21037/atm.2019.06.60.
2. Filosto M et al. Assessing the role of anti rh-GAA in modulating response to ERT in a late-onset Pompe disease cohort from the Italian GSDII Study Group. Adv Ther. 2019 May;36(5):1177-1189. doi: 10.1007/s12325-019-00926-5.
3. Patel TT et al. The impact of antibodies in late-onset Pompe disease: A case series and literature review. Mol Genet Metab. 2012 Jul;106(3):301-9. doi: 10.1016/j.ymgme.2012.04.027.
4. Montagnese F et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016 May;39(3):391-398. doi: 10.1007/s10545-015-9913-x.
5. Musumeci O et al. Central nervous system involvement in late-onset Pompe disease: Clues from neuroimaging and neuropsychological analysis. Eur J Neurol. 2019 Mar;26(3):442-e35. doi: 10.1111/ene.13835.
6. Edelmann MJ, Maegawa GHB. CNS-targeting therapies for lysosomal storage diseases: Current advances and challenges. Front Mol Biosci. 2020 Nov 12;7:559804. doi: 10.3389/fmolb.2020.559804
7. Ronzitti G et al. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):287. doi: 10.21037/atm.2019.04.67.
8. Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):288. doi: 10.21037/atm.2019.05.02.
Until 2006, when a breakthrough therapy first made treatment possible, Pompe disease was a little-known metabolic myopathy fatal to infants. Those with later-onset disease experienced progressive, often severe disability into adulthood.
In this rare autosomal recessive disorder, which occurs in approximately one in 40,000 births worldwide, a deficiency or absence of the enzyme acid alpha-glucosidase causes glycogen to build up in the lysosomes of cells. While many tissues are affected, skeletal and cardiac muscle see the earliest involvement, with muscle hypotonia, cardiomyopathy, and breathing difficulties (mainly due to diaphragm weakness) comprising the hallmark symptoms of the infantile form. Muscle weakness and progressive respiratory failure are prominent in later-onset disease.
The spectrum of severity and age of onset in Pompe disease is linked to combinations of mutations on the GAA gene, some of which destroy the body’s ability to produce acid alpha-glucosidase whereas others merely hamper it. Less enzyme produced in the body generally corresponds with more severe disease activity.
The most severe end of the disease spectrum, or “classic infantile Pompe disease,” presents at birth and is recognized in early infancy. Until treatment with enzyme replacement therapy (ERT) became available, patients usually died of cardiorespiratory failure within their first year of life. With therapy, patients have survived into their 20s and beyond. Late-onset disease is a far broader category in which patients can present at any time from their first year, including into middle age.
The emergence in 2006 of alglucosidase alfa (Lumizyme, Sanofi Genzyme), an ERT used long-term to improve survival and slow progression in children and adults, resulted in a boom of research interest, a push to timelier diagnosis, and – with patients living longer – a more thorough understanding of the natural history of Pompe disease. In addition to the usual clinical picture of progressive muscle weakness, difficulty breathing, and cardiomyopathy, investigators are seeing nervous system involvement in patients with Pompe disease.
To learn more, Neurology Reviews talked to two global experts in Pompe disease: Priya Kishnani, MD, of Duke University in Durham, N.C., and Antonio Toscano, MD, of the University of Messina, in Messina, Italy.
Diagnosis: Still room to improve
“Most neurologists will encounter a patient with Pompe disease,” said Dr. Kishnani, who has been working with Pompe for her entire career as a pediatrician and medical geneticist, treating patients of all ages and disease phenotypes.
“In newborns, diagnosis is more straightforward, because you’ve got an enlarged heart,” she said. And thanks to efforts of researchers like Dr. Kishnani and Pompe advocacy groups, Pompe disease is now a part of the RUSP (Recommended Uniform Screening Panel) for newborns; currently 28 U.S. states are screening for Pompe disease.
“The challenge really is for the later-onset cases, which are 80% of all cases,” Dr. Kishnani said.
Previously, muscle biopsies were the first step toward diagnosis. Dried blot spot assays to detect enzyme deficiency have since become the standard, along with other biochemical tests. Confirmation of the diagnosis is through gene sequencing panels to detect GAA mutations.
“Now that there is a treatment for Pompe disease and the availability of blood-based testing, many previously undiagnosed patients with limb girdle weakness are evaluated and the diagnostic odyssey ends,” Dr. Kishnani said. “But there is still a diagnostic delay, and many cases remain undiagnosed.”
Routine blood tests for creatine kinase and for liver enzymes can help point to Pompe disease. But elevated liver enzymes are often misinterpreted. “It’s about the ratios,” Dr. Kishnani said. “ALT is usually much more elevated if it is coming from a liver cause, and AST is usually higher than ALT if it is coming from muscle. But patients often end up getting a liver biopsy due to so-called elevated liver enzymes. As the workup continues, it is often later recognized that the source of the elevated enzymes is muscle involvement, and a referral to the geneticist or neurologist is made. Only then is appropriate testing to confirm a diagnosis initiated.”
Dr. Toscano, a neurologist who specializes in Pompe disease and other myopathies and who has published on tools for diagnosing late-onset Pompe disease,1 said that clinicians should be vigilant when evaluating any patient with limb girdle weakness and elevated creatine kinase (CK) – “especially if the CK is under 2,000,” he said, “because it is very rare that patients with Pompe disease have a more elevated CK than that.”
“Elevated CK, myalgia, and exercise intolerance” should prompt clinicians to suspect Pompe disease in a patient of any age, Dr. Toscano said. “When you come across this, you should be very persistent and get to the end of the story.”
Dr. Toscano noted that the blood spot assay, while an important early step, is not fully diagnostic, “because you can have false positives.” The molecular GAA assay is used to confirm Pompe disease. But detecting pathogenic variants on the GAA gene – of which there are more than 500 – can be more complicated than it sounds. Whereas two mutations are required for Pompe disease, sometimes only one can be detected. Dr. Toscano said he also treated some patients for Pompe with only one known mutation but with unequivocal clinical and biochemical aspects of Pompe disease.
While delays in diagnosis for late-onset Pompe disease remain significant -- between 5 and 6 years on average for older patients, and up to 20 years for those with pediatric onset – both Dr. Kishnani and Dr. Toscano said they perceive them to be improving. With McArdle disease, another inherited glycogen storage disorder that is more common than Pompe disease but for which there is no treatment, “the delay is nearly 12 years,” Dr. Toscano said.
ERT: The sooner the better
Enzyme replacement therapy is indicated for all patients with Pompe disease. Currently two are commercially available: alglucosidase alfa (Lumizyme, Sanofi Genzyme), indicated for all forms of Pompe disease, and avalglucosidase alfa-ngpt (Nexviazyme, Sanofi Genzyme), approved in 2021 for later-onset Pompe, though its indications have yet to be fully defined.
The semimonthly infusions represent, to date, the only disease-modifying therapies commercially available. Enzyme replacement therapy can reverse cardiac damage seen in infants and allow them to meet developmental milestones previously unthinkable. In adults, it can slow progression, though many treated patients will still develop chronic disability and require a wheelchair, respiratory support, or both. “The phenotype of the patients we are seeing today is not as involved as it was prior to enzyme therapy,” said Dr. Kishnani, who was part of the research team that developed ERT and launched the first clinical trials. “This is across the disease spectrum.”
But optimal management means more than just getting a patient on therapy fast, Dr. Kishnani said.
“Very often the thinking is if the patient is on ERT, we’ve done right by the patient. Aspects we don’t look at enough include: Are we monitoring these patients well? Are patients being followed by a multidisciplinary team that includes cardiology, physical therapy, and pulmonary medicine? Are we doing appropriate musculoskeletal assessments? They might have sleep hypoventilation. The BiPap settings may not be correct. Or they have not been assessed for antibodies,” she said.
Many infants with severe phenotypes, notably those who produce no enzyme naturally, will develop immune reactions to the exogenous enzyme therapy. High antibody titers also have been seen and are associated with poor therapeutic response. While this is very clear in the infantile setting, late-onset patients also develop antibodies in response to ERT. In one study in 64 patients,2 Dr. Toscano and his colleagues saw that antibodies may affect clinical response during the first 3 years of treatment, while a small study3 by Dr. Kishnani’s group saw clinical decline associated with high antibody titers in patients with late-onset disease.
While the relationship of specific titers to therapeutic response remains unclear, it is important to consider antibodies, along with other factors, in the monitoring of patients with Pompe disease. “We need to always ask, if a patient is falling behind, what could be the reason?” Dr. Kishnani said. “These are the things we as clinicians can do to improve or enhance the impact of ERT.”
Dr. Toscano noted that a common misconception about late-onset Pompe disease is that cardiac manifestations are minimal or absent, whereas as many as about 20% of patients will have heart problems and need to be carefully monitored.
Neurological manifestations
With patients surviving longer on ERT, researchers have been able to develop a deeper understanding of the natural history of Pompe disease. Increasingly, they are seeing it as a multisystem disease that includes central nervous system involvement.
“Is Pompe an overt neurodegenerative disease? I would say no,” Dr. Kishnani said. “But there is a neurological component that we’ve got to understand and follow more.”
Glycogen accumulation, she noted, has been found in anterior horn cells, motor neurons, and other parts of the brain. “We have been doing MRIs on children with infantile Pompe, and we have seen some white matter hyperintensities. The clinical significance of this finding is still emerging. Sometimes it is present, but the child is cognitively intact. We have had college graduates who have white matter hyperintensities. So putting it in context will be important. But we know that glycogen is ubiquitous, and autopsy studies have shown that it is present in the brain.”
In recent years, Dr. Toscano’s group has investigated neurovascular complications of Pompe in late-onset patients. “This was something that really surprised us because for several years we have investigated mainly heart, muscle, or respiratory manifestations of the disease, but the central nervous system was really neglected,” he said.
“Occasionally we did some brain MRIs and we found in even young patients some ischemic areas. We thought this was related to slowed circulation – that blood vessels in these patients are weak because they are impaired by glycogen accumulation.” Dr. Toscano and his colleagues followed that observation with a study of late-onset patients,4 in which they found that more than half had cerebrovascular abnormalities. “Even in, say, patients 30 to 35 years old we saw this – it’s unusual to have a vascular disorder at that age.”
Dr. Toscano and his colleagues also reported cerebral aneurysms5 in patients with Pompe disease and have recommended that clinicians conduct MRI or cerebral angiograms on patients as part of routine follow-up. Blood pressure in Pompe patients should be carefully watched and managed with antihypertensive medication as needed, he said.
Part of the problem is that the proteins in ERT are not able to cross the blood-brain barrier, Dr. Toscano noted, adding that researchers are investigating other treatments that can.
Pompe disease as a research model
The successful development of ERT for Pompe disease marked a boom in research interest into not just Pompe – for which several experimental therapies are currently in the pipeline – but for other myopathies and glycogen storage disorders.
“I think that Pompe has served as a template both as a muscle disease and a lysosomal storage disease, and so some of our learnings from Pompe have been applied across different diseases,” Dr. Kishnani said.
Studies in spinal muscular atrophy, for example, “in some ways mirrored what was done for Pompe – treatment trials were initiated in babies at the most severe end of the disease population with infantile disease, and used similar clinical trial endpoints,” Dr. Kishnani said. “Even for the later-onset end of the spectrum, the endpoints we used in Pompe for muscle strength and function have been relevant to many other neuromuscular disorders.”
Pompe disease research also ushered in a new appreciation of immune responses in protein replacement therapies, Dr. Kishnani noted.
“In the field today, you hear the term cross-reactive immunological material, or CRIM, all the time,” she said. “But when we first started talking about it in the space of Pompe disease, there was a lot of scientific debate about what the significance of CRIM-negative status was in relationship to the risk for development of high and sustained antibody titer and a poor clinical response. To understand this involved a lot of going back to the data and digging into the small subset of nonresponders. One of the powers of rare disease research is that every patient matters, and it’s important to understand what’s going on at the patient level rather than just the group data level.”
A robust pipeline
The decade and a half since the advent of ERT has seen what Dr. Toscano described as “an explosion of interest” in Pompe disease.
“We’re seeing an extraordinary number of papers on everything from clinical, biomarkers, genetics, and rehabilitation – this disease is now considered from every point of view, and this is very important for patients,” Dr. Toscano said. Alongside this has come industry interest in this rare disease, with several companies investigating a range of treatment approaches.
The existence of a treatment, “while not perfect,” he said, “has interested the patient associations and doctors to try and improve service to patients. Patients with Pompe disease are well attended, probably more so than patients with degenerative disorders in which there is no therapy.”
Last year the second ERT, avalglucosidase alfa (Nexviazyme, Sanofi Genzyme) was approved by the U.S. Food and Drug Administration to treat late-onset Pompe disease. The drug, currently being investigated in infants as well, was designed to improve the delivery of the therapeutic enzyme to muscles and enhance glycogen clearance, and results from ongoing trials suggest some functional and clinical benefit over standard ERT.
Other drugs in development for Pompe disease include substrate reduction therapies, which aim to reduce the storage of glycogen in cells, and therapies that improve residual function of mutant GAA enzyme in the body. These and other therapies in development have the potential to modify nervous system manifestations of Pompe disease.6
Because a single gene is implicated in Pompe disease, it has long been considered a good candidate for gene therapies that prompt the body to make stable enzyme. Seven companies are now investigating gene therapies in Pompe disease.7 Some of these deliver to skeletal muscles and others aim for the liver, where proteins are synthesized and secreted and adverse immune responses might be more easily mitigated. Other gene therapies use an ex vivo approach, removing and replacing cells in bone marrow.
Dr. Kishnani’s research group at Duke University is leading a small clinical trial in late-onset patients of a GAA gene transfer to the liver using adeno-associated virus (AAV) vectors.8
“We have started AAV gene therapy trials in in adults with Pompe disease and will later evaluate children because ERT is available as a standard of care, and so from a safety perspective this makes the most sense,” Dr. Kishnani said. “We do have challenges in the field of gene therapy, but I think if we are able to overcome the immune responses, and … to treat at a lower dose, there’s a very good pathway forward.”
Dr. Toscano and Dr. Kishnani have received reimbursement from Sanofi and other manufacturers for participation on advisory boards and as speakers.
Jennie Smith is a freelance journalist and editor specializing in medicine and health.
References
1. Musumeci O, Toscano A. Diagnostic tools in late onset Pompe disease (LOPD). Ann Transl Med. 2019 Jul;7(13):286. doi: 10.21037/atm.2019.06.60.
2. Filosto M et al. Assessing the role of anti rh-GAA in modulating response to ERT in a late-onset Pompe disease cohort from the Italian GSDII Study Group. Adv Ther. 2019 May;36(5):1177-1189. doi: 10.1007/s12325-019-00926-5.
3. Patel TT et al. The impact of antibodies in late-onset Pompe disease: A case series and literature review. Mol Genet Metab. 2012 Jul;106(3):301-9. doi: 10.1016/j.ymgme.2012.04.027.
4. Montagnese F et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016 May;39(3):391-398. doi: 10.1007/s10545-015-9913-x.
5. Musumeci O et al. Central nervous system involvement in late-onset Pompe disease: Clues from neuroimaging and neuropsychological analysis. Eur J Neurol. 2019 Mar;26(3):442-e35. doi: 10.1111/ene.13835.
6. Edelmann MJ, Maegawa GHB. CNS-targeting therapies for lysosomal storage diseases: Current advances and challenges. Front Mol Biosci. 2020 Nov 12;7:559804. doi: 10.3389/fmolb.2020.559804
7. Ronzitti G et al. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):287. doi: 10.21037/atm.2019.04.67.
8. Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):288. doi: 10.21037/atm.2019.05.02.
Until 2006, when a breakthrough therapy first made treatment possible, Pompe disease was a little-known metabolic myopathy fatal to infants. Those with later-onset disease experienced progressive, often severe disability into adulthood.
In this rare autosomal recessive disorder, which occurs in approximately one in 40,000 births worldwide, a deficiency or absence of the enzyme acid alpha-glucosidase causes glycogen to build up in the lysosomes of cells. While many tissues are affected, skeletal and cardiac muscle see the earliest involvement, with muscle hypotonia, cardiomyopathy, and breathing difficulties (mainly due to diaphragm weakness) comprising the hallmark symptoms of the infantile form. Muscle weakness and progressive respiratory failure are prominent in later-onset disease.
The spectrum of severity and age of onset in Pompe disease is linked to combinations of mutations on the GAA gene, some of which destroy the body’s ability to produce acid alpha-glucosidase whereas others merely hamper it. Less enzyme produced in the body generally corresponds with more severe disease activity.
The most severe end of the disease spectrum, or “classic infantile Pompe disease,” presents at birth and is recognized in early infancy. Until treatment with enzyme replacement therapy (ERT) became available, patients usually died of cardiorespiratory failure within their first year of life. With therapy, patients have survived into their 20s and beyond. Late-onset disease is a far broader category in which patients can present at any time from their first year, including into middle age.
The emergence in 2006 of alglucosidase alfa (Lumizyme, Sanofi Genzyme), an ERT used long-term to improve survival and slow progression in children and adults, resulted in a boom of research interest, a push to timelier diagnosis, and – with patients living longer – a more thorough understanding of the natural history of Pompe disease. In addition to the usual clinical picture of progressive muscle weakness, difficulty breathing, and cardiomyopathy, investigators are seeing nervous system involvement in patients with Pompe disease.
To learn more, Neurology Reviews talked to two global experts in Pompe disease: Priya Kishnani, MD, of Duke University in Durham, N.C., and Antonio Toscano, MD, of the University of Messina, in Messina, Italy.
Diagnosis: Still room to improve
“Most neurologists will encounter a patient with Pompe disease,” said Dr. Kishnani, who has been working with Pompe for her entire career as a pediatrician and medical geneticist, treating patients of all ages and disease phenotypes.
“In newborns, diagnosis is more straightforward, because you’ve got an enlarged heart,” she said. And thanks to efforts of researchers like Dr. Kishnani and Pompe advocacy groups, Pompe disease is now a part of the RUSP (Recommended Uniform Screening Panel) for newborns; currently 28 U.S. states are screening for Pompe disease.
“The challenge really is for the later-onset cases, which are 80% of all cases,” Dr. Kishnani said.
Previously, muscle biopsies were the first step toward diagnosis. Dried blot spot assays to detect enzyme deficiency have since become the standard, along with other biochemical tests. Confirmation of the diagnosis is through gene sequencing panels to detect GAA mutations.
“Now that there is a treatment for Pompe disease and the availability of blood-based testing, many previously undiagnosed patients with limb girdle weakness are evaluated and the diagnostic odyssey ends,” Dr. Kishnani said. “But there is still a diagnostic delay, and many cases remain undiagnosed.”
Routine blood tests for creatine kinase and for liver enzymes can help point to Pompe disease. But elevated liver enzymes are often misinterpreted. “It’s about the ratios,” Dr. Kishnani said. “ALT is usually much more elevated if it is coming from a liver cause, and AST is usually higher than ALT if it is coming from muscle. But patients often end up getting a liver biopsy due to so-called elevated liver enzymes. As the workup continues, it is often later recognized that the source of the elevated enzymes is muscle involvement, and a referral to the geneticist or neurologist is made. Only then is appropriate testing to confirm a diagnosis initiated.”
Dr. Toscano, a neurologist who specializes in Pompe disease and other myopathies and who has published on tools for diagnosing late-onset Pompe disease,1 said that clinicians should be vigilant when evaluating any patient with limb girdle weakness and elevated creatine kinase (CK) – “especially if the CK is under 2,000,” he said, “because it is very rare that patients with Pompe disease have a more elevated CK than that.”
“Elevated CK, myalgia, and exercise intolerance” should prompt clinicians to suspect Pompe disease in a patient of any age, Dr. Toscano said. “When you come across this, you should be very persistent and get to the end of the story.”
Dr. Toscano noted that the blood spot assay, while an important early step, is not fully diagnostic, “because you can have false positives.” The molecular GAA assay is used to confirm Pompe disease. But detecting pathogenic variants on the GAA gene – of which there are more than 500 – can be more complicated than it sounds. Whereas two mutations are required for Pompe disease, sometimes only one can be detected. Dr. Toscano said he also treated some patients for Pompe with only one known mutation but with unequivocal clinical and biochemical aspects of Pompe disease.
While delays in diagnosis for late-onset Pompe disease remain significant -- between 5 and 6 years on average for older patients, and up to 20 years for those with pediatric onset – both Dr. Kishnani and Dr. Toscano said they perceive them to be improving. With McArdle disease, another inherited glycogen storage disorder that is more common than Pompe disease but for which there is no treatment, “the delay is nearly 12 years,” Dr. Toscano said.
ERT: The sooner the better
Enzyme replacement therapy is indicated for all patients with Pompe disease. Currently two are commercially available: alglucosidase alfa (Lumizyme, Sanofi Genzyme), indicated for all forms of Pompe disease, and avalglucosidase alfa-ngpt (Nexviazyme, Sanofi Genzyme), approved in 2021 for later-onset Pompe, though its indications have yet to be fully defined.
The semimonthly infusions represent, to date, the only disease-modifying therapies commercially available. Enzyme replacement therapy can reverse cardiac damage seen in infants and allow them to meet developmental milestones previously unthinkable. In adults, it can slow progression, though many treated patients will still develop chronic disability and require a wheelchair, respiratory support, or both. “The phenotype of the patients we are seeing today is not as involved as it was prior to enzyme therapy,” said Dr. Kishnani, who was part of the research team that developed ERT and launched the first clinical trials. “This is across the disease spectrum.”
But optimal management means more than just getting a patient on therapy fast, Dr. Kishnani said.
“Very often the thinking is if the patient is on ERT, we’ve done right by the patient. Aspects we don’t look at enough include: Are we monitoring these patients well? Are patients being followed by a multidisciplinary team that includes cardiology, physical therapy, and pulmonary medicine? Are we doing appropriate musculoskeletal assessments? They might have sleep hypoventilation. The BiPap settings may not be correct. Or they have not been assessed for antibodies,” she said.
Many infants with severe phenotypes, notably those who produce no enzyme naturally, will develop immune reactions to the exogenous enzyme therapy. High antibody titers also have been seen and are associated with poor therapeutic response. While this is very clear in the infantile setting, late-onset patients also develop antibodies in response to ERT. In one study in 64 patients,2 Dr. Toscano and his colleagues saw that antibodies may affect clinical response during the first 3 years of treatment, while a small study3 by Dr. Kishnani’s group saw clinical decline associated with high antibody titers in patients with late-onset disease.
While the relationship of specific titers to therapeutic response remains unclear, it is important to consider antibodies, along with other factors, in the monitoring of patients with Pompe disease. “We need to always ask, if a patient is falling behind, what could be the reason?” Dr. Kishnani said. “These are the things we as clinicians can do to improve or enhance the impact of ERT.”
Dr. Toscano noted that a common misconception about late-onset Pompe disease is that cardiac manifestations are minimal or absent, whereas as many as about 20% of patients will have heart problems and need to be carefully monitored.
Neurological manifestations
With patients surviving longer on ERT, researchers have been able to develop a deeper understanding of the natural history of Pompe disease. Increasingly, they are seeing it as a multisystem disease that includes central nervous system involvement.
“Is Pompe an overt neurodegenerative disease? I would say no,” Dr. Kishnani said. “But there is a neurological component that we’ve got to understand and follow more.”
Glycogen accumulation, she noted, has been found in anterior horn cells, motor neurons, and other parts of the brain. “We have been doing MRIs on children with infantile Pompe, and we have seen some white matter hyperintensities. The clinical significance of this finding is still emerging. Sometimes it is present, but the child is cognitively intact. We have had college graduates who have white matter hyperintensities. So putting it in context will be important. But we know that glycogen is ubiquitous, and autopsy studies have shown that it is present in the brain.”
In recent years, Dr. Toscano’s group has investigated neurovascular complications of Pompe in late-onset patients. “This was something that really surprised us because for several years we have investigated mainly heart, muscle, or respiratory manifestations of the disease, but the central nervous system was really neglected,” he said.
“Occasionally we did some brain MRIs and we found in even young patients some ischemic areas. We thought this was related to slowed circulation – that blood vessels in these patients are weak because they are impaired by glycogen accumulation.” Dr. Toscano and his colleagues followed that observation with a study of late-onset patients,4 in which they found that more than half had cerebrovascular abnormalities. “Even in, say, patients 30 to 35 years old we saw this – it’s unusual to have a vascular disorder at that age.”
Dr. Toscano and his colleagues also reported cerebral aneurysms5 in patients with Pompe disease and have recommended that clinicians conduct MRI or cerebral angiograms on patients as part of routine follow-up. Blood pressure in Pompe patients should be carefully watched and managed with antihypertensive medication as needed, he said.
Part of the problem is that the proteins in ERT are not able to cross the blood-brain barrier, Dr. Toscano noted, adding that researchers are investigating other treatments that can.
Pompe disease as a research model
The successful development of ERT for Pompe disease marked a boom in research interest into not just Pompe – for which several experimental therapies are currently in the pipeline – but for other myopathies and glycogen storage disorders.
“I think that Pompe has served as a template both as a muscle disease and a lysosomal storage disease, and so some of our learnings from Pompe have been applied across different diseases,” Dr. Kishnani said.
Studies in spinal muscular atrophy, for example, “in some ways mirrored what was done for Pompe – treatment trials were initiated in babies at the most severe end of the disease population with infantile disease, and used similar clinical trial endpoints,” Dr. Kishnani said. “Even for the later-onset end of the spectrum, the endpoints we used in Pompe for muscle strength and function have been relevant to many other neuromuscular disorders.”
Pompe disease research also ushered in a new appreciation of immune responses in protein replacement therapies, Dr. Kishnani noted.
“In the field today, you hear the term cross-reactive immunological material, or CRIM, all the time,” she said. “But when we first started talking about it in the space of Pompe disease, there was a lot of scientific debate about what the significance of CRIM-negative status was in relationship to the risk for development of high and sustained antibody titer and a poor clinical response. To understand this involved a lot of going back to the data and digging into the small subset of nonresponders. One of the powers of rare disease research is that every patient matters, and it’s important to understand what’s going on at the patient level rather than just the group data level.”
A robust pipeline
The decade and a half since the advent of ERT has seen what Dr. Toscano described as “an explosion of interest” in Pompe disease.
“We’re seeing an extraordinary number of papers on everything from clinical, biomarkers, genetics, and rehabilitation – this disease is now considered from every point of view, and this is very important for patients,” Dr. Toscano said. Alongside this has come industry interest in this rare disease, with several companies investigating a range of treatment approaches.
The existence of a treatment, “while not perfect,” he said, “has interested the patient associations and doctors to try and improve service to patients. Patients with Pompe disease are well attended, probably more so than patients with degenerative disorders in which there is no therapy.”
Last year the second ERT, avalglucosidase alfa (Nexviazyme, Sanofi Genzyme) was approved by the U.S. Food and Drug Administration to treat late-onset Pompe disease. The drug, currently being investigated in infants as well, was designed to improve the delivery of the therapeutic enzyme to muscles and enhance glycogen clearance, and results from ongoing trials suggest some functional and clinical benefit over standard ERT.
Other drugs in development for Pompe disease include substrate reduction therapies, which aim to reduce the storage of glycogen in cells, and therapies that improve residual function of mutant GAA enzyme in the body. These and other therapies in development have the potential to modify nervous system manifestations of Pompe disease.6
Because a single gene is implicated in Pompe disease, it has long been considered a good candidate for gene therapies that prompt the body to make stable enzyme. Seven companies are now investigating gene therapies in Pompe disease.7 Some of these deliver to skeletal muscles and others aim for the liver, where proteins are synthesized and secreted and adverse immune responses might be more easily mitigated. Other gene therapies use an ex vivo approach, removing and replacing cells in bone marrow.
Dr. Kishnani’s research group at Duke University is leading a small clinical trial in late-onset patients of a GAA gene transfer to the liver using adeno-associated virus (AAV) vectors.8
“We have started AAV gene therapy trials in in adults with Pompe disease and will later evaluate children because ERT is available as a standard of care, and so from a safety perspective this makes the most sense,” Dr. Kishnani said. “We do have challenges in the field of gene therapy, but I think if we are able to overcome the immune responses, and … to treat at a lower dose, there’s a very good pathway forward.”
Dr. Toscano and Dr. Kishnani have received reimbursement from Sanofi and other manufacturers for participation on advisory boards and as speakers.
Jennie Smith is a freelance journalist and editor specializing in medicine and health.
References
1. Musumeci O, Toscano A. Diagnostic tools in late onset Pompe disease (LOPD). Ann Transl Med. 2019 Jul;7(13):286. doi: 10.21037/atm.2019.06.60.
2. Filosto M et al. Assessing the role of anti rh-GAA in modulating response to ERT in a late-onset Pompe disease cohort from the Italian GSDII Study Group. Adv Ther. 2019 May;36(5):1177-1189. doi: 10.1007/s12325-019-00926-5.
3. Patel TT et al. The impact of antibodies in late-onset Pompe disease: A case series and literature review. Mol Genet Metab. 2012 Jul;106(3):301-9. doi: 10.1016/j.ymgme.2012.04.027.
4. Montagnese F et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016 May;39(3):391-398. doi: 10.1007/s10545-015-9913-x.
5. Musumeci O et al. Central nervous system involvement in late-onset Pompe disease: Clues from neuroimaging and neuropsychological analysis. Eur J Neurol. 2019 Mar;26(3):442-e35. doi: 10.1111/ene.13835.
6. Edelmann MJ, Maegawa GHB. CNS-targeting therapies for lysosomal storage diseases: Current advances and challenges. Front Mol Biosci. 2020 Nov 12;7:559804. doi: 10.3389/fmolb.2020.559804
7. Ronzitti G et al. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):287. doi: 10.21037/atm.2019.04.67.
8. Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):288. doi: 10.21037/atm.2019.05.02.
Health care providers should have higher suspicion for rare diseases
The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.
Rare diseases have collectively emerged as a unique field of medicine with an “entirely new generation of conditions,” said Marshall L. Summar, MD, chief of the division of genetics and metabolism at Children’s National Hospital in Washington, DC. He places the number of rare diseases closer to 8,000, and said it is “growing by a rate of 10 to 12 a week.”
Although the field has made significant advancements in health care providers’ ability to diagnose rare diseases, it has also highlighted what isn’t known as well, said Dr. Summar, who is also past president and a former scientific advisory board member with the National Organization for Rare Disorders (NORD).
Keeping up to date on the latest rare diseases may seem like a daunting task to the average health care professional. However, while rare diseases remain the domain of the subspecialists, the generalist “can make a tremendous impact for their patients” early in the process by having a higher suspicion for rare diseases in their practice, said Dr. Summar.
Thinking of rare diseases in categories
Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.
However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.
From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”
During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.
When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.
The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.
In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.
Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
Rare disease warning signs
Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.
Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.
A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.
Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
Learning more about rare diseases
Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.
“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”
For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.
Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
Will rare disease screening tools come to primary care?
Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.
Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.
“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”
Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.
Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.
“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”
Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.
One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.
“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.
Jeff Craven is a freelance journalist specializing in medicine and health.
Suggested reading
Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.
The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.
Rare diseases have collectively emerged as a unique field of medicine with an “entirely new generation of conditions,” said Marshall L. Summar, MD, chief of the division of genetics and metabolism at Children’s National Hospital in Washington, DC. He places the number of rare diseases closer to 8,000, and said it is “growing by a rate of 10 to 12 a week.”
Although the field has made significant advancements in health care providers’ ability to diagnose rare diseases, it has also highlighted what isn’t known as well, said Dr. Summar, who is also past president and a former scientific advisory board member with the National Organization for Rare Disorders (NORD).
Keeping up to date on the latest rare diseases may seem like a daunting task to the average health care professional. However, while rare diseases remain the domain of the subspecialists, the generalist “can make a tremendous impact for their patients” early in the process by having a higher suspicion for rare diseases in their practice, said Dr. Summar.
Thinking of rare diseases in categories
Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.
However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.
From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”
During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.
When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.
The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.
In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.
Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
Rare disease warning signs
Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.
Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.
A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.
Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
Learning more about rare diseases
Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.
“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”
For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.
Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
Will rare disease screening tools come to primary care?
Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.
Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.
“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”
Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.
Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.
“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”
Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.
One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.
“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.
Jeff Craven is a freelance journalist specializing in medicine and health.
Suggested reading
Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.
The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.
Rare diseases have collectively emerged as a unique field of medicine with an “entirely new generation of conditions,” said Marshall L. Summar, MD, chief of the division of genetics and metabolism at Children’s National Hospital in Washington, DC. He places the number of rare diseases closer to 8,000, and said it is “growing by a rate of 10 to 12 a week.”
Although the field has made significant advancements in health care providers’ ability to diagnose rare diseases, it has also highlighted what isn’t known as well, said Dr. Summar, who is also past president and a former scientific advisory board member with the National Organization for Rare Disorders (NORD).
Keeping up to date on the latest rare diseases may seem like a daunting task to the average health care professional. However, while rare diseases remain the domain of the subspecialists, the generalist “can make a tremendous impact for their patients” early in the process by having a higher suspicion for rare diseases in their practice, said Dr. Summar.
Thinking of rare diseases in categories
Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.
However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.
From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”
During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.
When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.
The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.
The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.
In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.
Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
Rare disease warning signs
Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.
Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.
A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.
Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
Learning more about rare diseases
Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.
“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”
For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.
Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
Will rare disease screening tools come to primary care?
Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.
Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.
“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”
Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.
Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.
“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”
Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.
One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.
“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.
Jeff Craven is a freelance journalist specializing in medicine and health.
Suggested reading
Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.
A note from NORD
The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.
As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.
You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”
This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.
Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.
An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.
We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.
Peter L. Saltonstall, president and CEO
National Organization for Rare Disorders (NORD)
The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.
As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.
You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”
This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.
Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.
An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.
We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.
Peter L. Saltonstall, president and CEO
National Organization for Rare Disorders (NORD)
The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.
As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.
Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.
You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”
This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.
Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.
An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.
We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.
Peter L. Saltonstall, president and CEO
National Organization for Rare Disorders (NORD)
Editor’s note
Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.
For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.
—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology
Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.
For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.
—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology
Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.
For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.
—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology
Myasthenia gravis: Finding strength in treatment options
The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.1 The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.2,3
Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.4 Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).3,5
Pathophysiology
MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.4,8,9
The activity of these antibodies is key to understanding the importance of subgrouping the types of MG on the basis of antigen-specific autoimmune interactions. Specifically, the four categories of disease following a diagnosis of MG2,7 are:
- AChR antibody-positive.
- MuSK antibody-positive.
- LRP4 antibody-positive.
- Seronegative MG.
Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.2
Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.10
In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.
Diagnosis
Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.11
Upon clinical examination of observable myasthenic weakness, next steps would require assays for anti-AChR and anti-MuSK.1 If either of those tests are inconclusive, assays for anti-LRP4 are available (although the LRP4 antibody is also a marker in other neurological disorders).12
In the MG diagnostic algorithm, next steps include an electromyography repetitive stimulation test, which, if inconclusive, is followed by single-fiber electromyography.1 If any of these tests return positive, computed tomography or magnetic resonance imaging is necessary for thymus screening.
What follows this diagnostic schema is pharmacotherapeutic or surgical intervention to reduce, or even eliminate, symptoms of MG.1
Consensus on treatment standards
A quantitative assessment of best options for treating MG was conducted by leading experts,13 who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.13
Pyridostigmine, an acetylcholinesterase inhibitor, is recommended as part of the initial treatment plan for MG patients. Pyridostigmine prevents normal breakdown of acetylcholine, thus increasing acetylcholine levels and allowing signal transmission at the neuromuscular junction.14 Not all patients reach the aforementioned treatment goals when taking pyridostigmine, however; some require corticosteroids or immunosuppressive agents, or both, in addition.
Steroids, such as prednisone and prednisolone, occupy the second line in MG patients because of their ability to produce a rapid response, availability, and economy.1,15 Initial dosages of these medications are gradually adjusted to a maintenance dosage and schedule, as tolerated, to maintain control of symptoms.15
In MG patients who are in respiratory crisis, it is recommended that high-dosage prednisone be given in conjunction with plasmapheresis or intravenous immunoglobulin (IVIg).15 When the response to steroids is inadequate, adverse effects cannot be tolerated, or the patient experiences symptomatic relapse, nonsteroidal immunosuppressive agents are started.
Immunosuppressives are used to weaken the immune response or block production of self-antibodies. Several agents have been identified for use in MG, including azathioprine and mycophenolate mofetil; their use is limited, however, by a lack of supporting evidence from randomized clinical trials or the potential for serious adverse effects.13
Referral and specialized treatments. Patients who are refractory to all the aforementioned treatments should be referred to a physician who is expert in the management of MG. At this point, treatment guidelines recommend chronic IVIg infusion or plasmapheresis, which removes complement, cytokines, and antibodies from the blood.14 Additionally, monoclonal antibody therapies, such as eculizumab, have been shown to have efficacy in severe, refractory AChR antibody–positive generalized MG.16
Thymectomy has been a mainstay and, sometimes, first-line treatment of MG for nearly 80 years.15 The thymus has largely been implicated in the immunopathology of AChR-positive MG. Models suggest that increased expression of inflammatory factors causes an imbalance among immune cells, resulting in lymphofollicular hyperplasia or thymoma.17
Despite the growing body of evidence implicating the thymus in the progression of MG, some patients and physicians are reluctant to proceed with surgical intervention. This could be due to a disparity in surgical treatment options offered by surgeons, and facilities, with varying experience or ability to conduct newer techniques. Minimally invasive approaches, such as video-assisted thoracoscopic surgery and robotic thymectomy, have been found to be superior to traditional open surgical techniques.18,19 Minimally invasive techniques result in significantly fewer postoperative complications, less blood loss, and shorter length of hospital stay.19
In addition to the reduced risk offered by newer operative techniques, thymectomy has also been shown to have a beneficial effect by allowing the dosage of prednisone to be reduced in MG patients. In a randomized clinical trial conducted by Wolfe and coworkers,20 thymectomy produced improvement in two endpoints after 3 years in patients with nonthymomatous MG: the Quantitative MG Score and a lower average prednisone dosage. Although thymectomy is not a necessary precursor to remission in MG patients, it is still pertinent in reducing the adverse effects of long-term steroid use – providing objective evidence to support thymectomy as a treatment option.
Emerging therapies
Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.21 These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.21 As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.12
These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.18
Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.22 Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.22 This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.22 In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.23
Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.25 Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.18,24
Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.26 Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.27 If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.26
Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.28 Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.29
Looking forward
Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.30 As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.
Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.
References
1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.
3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.
4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.
5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.
6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.
7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.
8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.
9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.
10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.
11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.
12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.
13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.
14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.
15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.
16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.
17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.
18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.
19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.
20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.
21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.
22. Howard JF Jr et al; . Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.
23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.
24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.
25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.
26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.
27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.
28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.
29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.
30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.
The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.1 The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.2,3
Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.4 Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).3,5
Pathophysiology
MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.4,8,9
The activity of these antibodies is key to understanding the importance of subgrouping the types of MG on the basis of antigen-specific autoimmune interactions. Specifically, the four categories of disease following a diagnosis of MG2,7 are:
- AChR antibody-positive.
- MuSK antibody-positive.
- LRP4 antibody-positive.
- Seronegative MG.
Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.2
Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.10
In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.
Diagnosis
Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.11
Upon clinical examination of observable myasthenic weakness, next steps would require assays for anti-AChR and anti-MuSK.1 If either of those tests are inconclusive, assays for anti-LRP4 are available (although the LRP4 antibody is also a marker in other neurological disorders).12
In the MG diagnostic algorithm, next steps include an electromyography repetitive stimulation test, which, if inconclusive, is followed by single-fiber electromyography.1 If any of these tests return positive, computed tomography or magnetic resonance imaging is necessary for thymus screening.
What follows this diagnostic schema is pharmacotherapeutic or surgical intervention to reduce, or even eliminate, symptoms of MG.1
Consensus on treatment standards
A quantitative assessment of best options for treating MG was conducted by leading experts,13 who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.13
Pyridostigmine, an acetylcholinesterase inhibitor, is recommended as part of the initial treatment plan for MG patients. Pyridostigmine prevents normal breakdown of acetylcholine, thus increasing acetylcholine levels and allowing signal transmission at the neuromuscular junction.14 Not all patients reach the aforementioned treatment goals when taking pyridostigmine, however; some require corticosteroids or immunosuppressive agents, or both, in addition.
Steroids, such as prednisone and prednisolone, occupy the second line in MG patients because of their ability to produce a rapid response, availability, and economy.1,15 Initial dosages of these medications are gradually adjusted to a maintenance dosage and schedule, as tolerated, to maintain control of symptoms.15
In MG patients who are in respiratory crisis, it is recommended that high-dosage prednisone be given in conjunction with plasmapheresis or intravenous immunoglobulin (IVIg).15 When the response to steroids is inadequate, adverse effects cannot be tolerated, or the patient experiences symptomatic relapse, nonsteroidal immunosuppressive agents are started.
Immunosuppressives are used to weaken the immune response or block production of self-antibodies. Several agents have been identified for use in MG, including azathioprine and mycophenolate mofetil; their use is limited, however, by a lack of supporting evidence from randomized clinical trials or the potential for serious adverse effects.13
Referral and specialized treatments. Patients who are refractory to all the aforementioned treatments should be referred to a physician who is expert in the management of MG. At this point, treatment guidelines recommend chronic IVIg infusion or plasmapheresis, which removes complement, cytokines, and antibodies from the blood.14 Additionally, monoclonal antibody therapies, such as eculizumab, have been shown to have efficacy in severe, refractory AChR antibody–positive generalized MG.16
Thymectomy has been a mainstay and, sometimes, first-line treatment of MG for nearly 80 years.15 The thymus has largely been implicated in the immunopathology of AChR-positive MG. Models suggest that increased expression of inflammatory factors causes an imbalance among immune cells, resulting in lymphofollicular hyperplasia or thymoma.17
Despite the growing body of evidence implicating the thymus in the progression of MG, some patients and physicians are reluctant to proceed with surgical intervention. This could be due to a disparity in surgical treatment options offered by surgeons, and facilities, with varying experience or ability to conduct newer techniques. Minimally invasive approaches, such as video-assisted thoracoscopic surgery and robotic thymectomy, have been found to be superior to traditional open surgical techniques.18,19 Minimally invasive techniques result in significantly fewer postoperative complications, less blood loss, and shorter length of hospital stay.19
In addition to the reduced risk offered by newer operative techniques, thymectomy has also been shown to have a beneficial effect by allowing the dosage of prednisone to be reduced in MG patients. In a randomized clinical trial conducted by Wolfe and coworkers,20 thymectomy produced improvement in two endpoints after 3 years in patients with nonthymomatous MG: the Quantitative MG Score and a lower average prednisone dosage. Although thymectomy is not a necessary precursor to remission in MG patients, it is still pertinent in reducing the adverse effects of long-term steroid use – providing objective evidence to support thymectomy as a treatment option.
Emerging therapies
Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.21 These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.21 As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.12
These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.18
Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.22 Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.22 This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.22 In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.23
Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.25 Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.18,24
Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.26 Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.27 If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.26
Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.28 Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.29
Looking forward
Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.30 As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.
Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.
References
1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.
3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.
4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.
5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.
6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.
7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.
8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.
9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.
10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.
11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.
12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.
13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.
14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.
15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.
16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.
17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.
18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.
19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.
20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.
21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.
22. Howard JF Jr et al; . Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.
23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.
24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.
25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.
26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.
27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.
28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.
29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.
30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.
The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.1 The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.2,3
Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.4 Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).3,5
Pathophysiology
MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.4,8,9
The activity of these antibodies is key to understanding the importance of subgrouping the types of MG on the basis of antigen-specific autoimmune interactions. Specifically, the four categories of disease following a diagnosis of MG2,7 are:
- AChR antibody-positive.
- MuSK antibody-positive.
- LRP4 antibody-positive.
- Seronegative MG.
Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.2
Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.10
In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.
Diagnosis
Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.11
Upon clinical examination of observable myasthenic weakness, next steps would require assays for anti-AChR and anti-MuSK.1 If either of those tests are inconclusive, assays for anti-LRP4 are available (although the LRP4 antibody is also a marker in other neurological disorders).12
In the MG diagnostic algorithm, next steps include an electromyography repetitive stimulation test, which, if inconclusive, is followed by single-fiber electromyography.1 If any of these tests return positive, computed tomography or magnetic resonance imaging is necessary for thymus screening.
What follows this diagnostic schema is pharmacotherapeutic or surgical intervention to reduce, or even eliminate, symptoms of MG.1
Consensus on treatment standards
A quantitative assessment of best options for treating MG was conducted by leading experts,13 who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.13
Pyridostigmine, an acetylcholinesterase inhibitor, is recommended as part of the initial treatment plan for MG patients. Pyridostigmine prevents normal breakdown of acetylcholine, thus increasing acetylcholine levels and allowing signal transmission at the neuromuscular junction.14 Not all patients reach the aforementioned treatment goals when taking pyridostigmine, however; some require corticosteroids or immunosuppressive agents, or both, in addition.
Steroids, such as prednisone and prednisolone, occupy the second line in MG patients because of their ability to produce a rapid response, availability, and economy.1,15 Initial dosages of these medications are gradually adjusted to a maintenance dosage and schedule, as tolerated, to maintain control of symptoms.15
In MG patients who are in respiratory crisis, it is recommended that high-dosage prednisone be given in conjunction with plasmapheresis or intravenous immunoglobulin (IVIg).15 When the response to steroids is inadequate, adverse effects cannot be tolerated, or the patient experiences symptomatic relapse, nonsteroidal immunosuppressive agents are started.
Immunosuppressives are used to weaken the immune response or block production of self-antibodies. Several agents have been identified for use in MG, including azathioprine and mycophenolate mofetil; their use is limited, however, by a lack of supporting evidence from randomized clinical trials or the potential for serious adverse effects.13
Referral and specialized treatments. Patients who are refractory to all the aforementioned treatments should be referred to a physician who is expert in the management of MG. At this point, treatment guidelines recommend chronic IVIg infusion or plasmapheresis, which removes complement, cytokines, and antibodies from the blood.14 Additionally, monoclonal antibody therapies, such as eculizumab, have been shown to have efficacy in severe, refractory AChR antibody–positive generalized MG.16
Thymectomy has been a mainstay and, sometimes, first-line treatment of MG for nearly 80 years.15 The thymus has largely been implicated in the immunopathology of AChR-positive MG. Models suggest that increased expression of inflammatory factors causes an imbalance among immune cells, resulting in lymphofollicular hyperplasia or thymoma.17
Despite the growing body of evidence implicating the thymus in the progression of MG, some patients and physicians are reluctant to proceed with surgical intervention. This could be due to a disparity in surgical treatment options offered by surgeons, and facilities, with varying experience or ability to conduct newer techniques. Minimally invasive approaches, such as video-assisted thoracoscopic surgery and robotic thymectomy, have been found to be superior to traditional open surgical techniques.18,19 Minimally invasive techniques result in significantly fewer postoperative complications, less blood loss, and shorter length of hospital stay.19
In addition to the reduced risk offered by newer operative techniques, thymectomy has also been shown to have a beneficial effect by allowing the dosage of prednisone to be reduced in MG patients. In a randomized clinical trial conducted by Wolfe and coworkers,20 thymectomy produced improvement in two endpoints after 3 years in patients with nonthymomatous MG: the Quantitative MG Score and a lower average prednisone dosage. Although thymectomy is not a necessary precursor to remission in MG patients, it is still pertinent in reducing the adverse effects of long-term steroid use – providing objective evidence to support thymectomy as a treatment option.
Emerging therapies
Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.21 These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.21 As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.12
These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.18
Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.22 Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.22 This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.22 In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.23
Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.25 Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.18,24
Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.26 Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.27 If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.26
Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.28 Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.29
Looking forward
Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.30 As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.
Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.
References
1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.
3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.
4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.
5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.
6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.
7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.
8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.
9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.
10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.
11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.
12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.
13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.
14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.
15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.
16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.
17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.
18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.
19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.
20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.
21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.
22. Howard JF Jr et al; . Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.
23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.
24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.
25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.
26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.
27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.
28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.
29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.
30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.
Birth weight below 25th percentile linked to child development problems
Babies born from the 37th week of pregnancy who are mild to moderately small for gestational age (SGA) could benefit from monitoring to check for developmental problems, a study suggested.
A team of researchers at Coventry (England) University found that birth weight below the 25th percentile was associated with more developmental concerns in early childhood than a weight between the 25th and 74th percentile.
Those difficulties were apparent at percentiles higher than the conventional threshold defining SGA, they noted.
Low and high extremes of birth weight have been associated with adverse pregnancy and neonatal health outcomes, but little is known about the effects on motor skills, socialization, language, and other developmental markers for the entire range of birth weights for nonpremature babies.
Study linked health databases to child assessment results
To find out more, researchers conducted a population-based cohort study of 686,284 singleton infants born from 37 weeks of gestation, linking pregnancy and birth records from health databases covering all of Scotland to child development assessments carried out between the ages of 2 and 3.5 years.
The researchers looked for associations between birth weight and early childhood developmental concerns, taking into account confounders, such as maternal age, the mother’s medical history during pregnancy, early pregnancy body mass index, deprivation, ethnicity, alcohol use, and smoking history.
The study, published in the open access journal PLOS Medicine, found that babies born below the 25th percentile for birth weight had a higher risk of developmental concerns, compared with babies born between the 25th and 74th percentiles, with the infants who had the lowest birth weight most at risk of later developmental difficulties.
Those born between the 10th and 24th percentile had a relative risk of 1.07 (95% confidence interval, 1.03-1.12; P < .001); between the 3rd and 9th percentile, the RR was 1.18 (95% CI, 1.12-1.25, P < .001), and below the 3rd percentile the RR was 1.37 (95% CI, 1.24-1.50; P < .001).
No substantial increase in the risk of early childhood developmental concerns was identified for larger birth weight categories in the 75th-89th percentile range, the researchers reported.
Monitoring and support
The researchers concluded that having mild to moderate SGA “is an unrecognized, potentially important contributor to the prevalence of developmental concerns.”
Before this study, babies below the 10th percentile were usually considered at risk for developmental concerns. However, the investigation found a greater number of babies within the 10th-24th percentile range of birth weights with these issues, simply because there were a larger number of babies within that population.
Abiodun Adanikin, MBBS, PhD, MPH, of Coventry University’s Centre for Healthcare Research, and study first author, said: “Though it is mostly unrecognized, babies who are mild to moderately small at birth are key contributors to the burden of childhood developmental concerns. They may need closer monitoring and increased support to reduce the risk of developmental concerns.”
The study also involved colleagues from the University of Bristol (England), the University of Glasgow, the University of Cambridge (England), and Queen Mary University of London.
This work was supported by a Wellbeing of Women Research Grant. One author has received research support from Roche Diagnostics, GSK, Illumina, and Sera Prognostics (fetal growth restriction, preeclampsia and preterm birth). He has been a paid consultant to GSK (preterm birth) and is a member of a Data Monitoring Committee for GSK trials of RSV vaccination in pregnancy. He is one of three named inventors on a patent application filed by Cambridge Enterprise for novel predictive test for fetal growth disorder. He is an academic editor on PLOS Medicine’s editorial board. The authors declare no other competing interest.
A version of this article first appeared on Medscape UK.
Babies born from the 37th week of pregnancy who are mild to moderately small for gestational age (SGA) could benefit from monitoring to check for developmental problems, a study suggested.
A team of researchers at Coventry (England) University found that birth weight below the 25th percentile was associated with more developmental concerns in early childhood than a weight between the 25th and 74th percentile.
Those difficulties were apparent at percentiles higher than the conventional threshold defining SGA, they noted.
Low and high extremes of birth weight have been associated with adverse pregnancy and neonatal health outcomes, but little is known about the effects on motor skills, socialization, language, and other developmental markers for the entire range of birth weights for nonpremature babies.
Study linked health databases to child assessment results
To find out more, researchers conducted a population-based cohort study of 686,284 singleton infants born from 37 weeks of gestation, linking pregnancy and birth records from health databases covering all of Scotland to child development assessments carried out between the ages of 2 and 3.5 years.
The researchers looked for associations between birth weight and early childhood developmental concerns, taking into account confounders, such as maternal age, the mother’s medical history during pregnancy, early pregnancy body mass index, deprivation, ethnicity, alcohol use, and smoking history.
The study, published in the open access journal PLOS Medicine, found that babies born below the 25th percentile for birth weight had a higher risk of developmental concerns, compared with babies born between the 25th and 74th percentiles, with the infants who had the lowest birth weight most at risk of later developmental difficulties.
Those born between the 10th and 24th percentile had a relative risk of 1.07 (95% confidence interval, 1.03-1.12; P < .001); between the 3rd and 9th percentile, the RR was 1.18 (95% CI, 1.12-1.25, P < .001), and below the 3rd percentile the RR was 1.37 (95% CI, 1.24-1.50; P < .001).
No substantial increase in the risk of early childhood developmental concerns was identified for larger birth weight categories in the 75th-89th percentile range, the researchers reported.
Monitoring and support
The researchers concluded that having mild to moderate SGA “is an unrecognized, potentially important contributor to the prevalence of developmental concerns.”
Before this study, babies below the 10th percentile were usually considered at risk for developmental concerns. However, the investigation found a greater number of babies within the 10th-24th percentile range of birth weights with these issues, simply because there were a larger number of babies within that population.
Abiodun Adanikin, MBBS, PhD, MPH, of Coventry University’s Centre for Healthcare Research, and study first author, said: “Though it is mostly unrecognized, babies who are mild to moderately small at birth are key contributors to the burden of childhood developmental concerns. They may need closer monitoring and increased support to reduce the risk of developmental concerns.”
The study also involved colleagues from the University of Bristol (England), the University of Glasgow, the University of Cambridge (England), and Queen Mary University of London.
This work was supported by a Wellbeing of Women Research Grant. One author has received research support from Roche Diagnostics, GSK, Illumina, and Sera Prognostics (fetal growth restriction, preeclampsia and preterm birth). He has been a paid consultant to GSK (preterm birth) and is a member of a Data Monitoring Committee for GSK trials of RSV vaccination in pregnancy. He is one of three named inventors on a patent application filed by Cambridge Enterprise for novel predictive test for fetal growth disorder. He is an academic editor on PLOS Medicine’s editorial board. The authors declare no other competing interest.
A version of this article first appeared on Medscape UK.
Babies born from the 37th week of pregnancy who are mild to moderately small for gestational age (SGA) could benefit from monitoring to check for developmental problems, a study suggested.
A team of researchers at Coventry (England) University found that birth weight below the 25th percentile was associated with more developmental concerns in early childhood than a weight between the 25th and 74th percentile.
Those difficulties were apparent at percentiles higher than the conventional threshold defining SGA, they noted.
Low and high extremes of birth weight have been associated with adverse pregnancy and neonatal health outcomes, but little is known about the effects on motor skills, socialization, language, and other developmental markers for the entire range of birth weights for nonpremature babies.
Study linked health databases to child assessment results
To find out more, researchers conducted a population-based cohort study of 686,284 singleton infants born from 37 weeks of gestation, linking pregnancy and birth records from health databases covering all of Scotland to child development assessments carried out between the ages of 2 and 3.5 years.
The researchers looked for associations between birth weight and early childhood developmental concerns, taking into account confounders, such as maternal age, the mother’s medical history during pregnancy, early pregnancy body mass index, deprivation, ethnicity, alcohol use, and smoking history.
The study, published in the open access journal PLOS Medicine, found that babies born below the 25th percentile for birth weight had a higher risk of developmental concerns, compared with babies born between the 25th and 74th percentiles, with the infants who had the lowest birth weight most at risk of later developmental difficulties.
Those born between the 10th and 24th percentile had a relative risk of 1.07 (95% confidence interval, 1.03-1.12; P < .001); between the 3rd and 9th percentile, the RR was 1.18 (95% CI, 1.12-1.25, P < .001), and below the 3rd percentile the RR was 1.37 (95% CI, 1.24-1.50; P < .001).
No substantial increase in the risk of early childhood developmental concerns was identified for larger birth weight categories in the 75th-89th percentile range, the researchers reported.
Monitoring and support
The researchers concluded that having mild to moderate SGA “is an unrecognized, potentially important contributor to the prevalence of developmental concerns.”
Before this study, babies below the 10th percentile were usually considered at risk for developmental concerns. However, the investigation found a greater number of babies within the 10th-24th percentile range of birth weights with these issues, simply because there were a larger number of babies within that population.
Abiodun Adanikin, MBBS, PhD, MPH, of Coventry University’s Centre for Healthcare Research, and study first author, said: “Though it is mostly unrecognized, babies who are mild to moderately small at birth are key contributors to the burden of childhood developmental concerns. They may need closer monitoring and increased support to reduce the risk of developmental concerns.”
The study also involved colleagues from the University of Bristol (England), the University of Glasgow, the University of Cambridge (England), and Queen Mary University of London.
This work was supported by a Wellbeing of Women Research Grant. One author has received research support from Roche Diagnostics, GSK, Illumina, and Sera Prognostics (fetal growth restriction, preeclampsia and preterm birth). He has been a paid consultant to GSK (preterm birth) and is a member of a Data Monitoring Committee for GSK trials of RSV vaccination in pregnancy. He is one of three named inventors on a patent application filed by Cambridge Enterprise for novel predictive test for fetal growth disorder. He is an academic editor on PLOS Medicine’s editorial board. The authors declare no other competing interest.
A version of this article first appeared on Medscape UK.
FROM PLOS MEDICINE
First they get long COVID, then they lose their health care
It’s a devastating series of setbacks for long COVID patients. First, they get the debilitating symptoms of their condition. Then they are forced to give up their jobs, or severely curtail their work hours, as their symptoms linger. And next, for many, they lose their employer-sponsored health insurance.
While not all long COVID patients are debilitated, the CDC’s ongoing survey on long COVID found a quarter of adults with long COVID report it significantly affects their day-to-day living activities.
Estimates have shown that long COVID has disrupted the lives of anywhere from 16 million to 34 million Americans between the ages of 18 and 65.
While hard data is still limited, a Kaiser Family Foundation analysis found that more than half of adults with long COVID who worked before getting the virus are now either out of work or working fewer hours.
According to data from the Census Bureau’s Household Pulse Survey, out of the estimated 16 million working-age adults who currently have long COVID, 2 million to 4 million of them are out of work because of their symptoms. The cost of those lost wages ranges from $170 billion a year to as much as $230 billion, the Census Bureau says. And given that approximately 155 million Americans have employer-sponsored health insurance, the welfare of working-age adults may be under serious threat.
“Millions of people are now impacted by long COVID, and oftentimes along with that comes the inability to work,” says Megan Cole Brahim, PhD, an assistant professor in the department of health law, policy, and management at Boston University and codirector of the school’s Medicaid policy lab. “And because a lot of people get their health insurance coverage through employer-sponsored coverage, no longer being able to work means you may not have access to the health insurance that you once had.”
The CDC defines long COVID as a wide array of health conditions, including malaise, fatigue, shortness of breath, mental health issues, problems with the part of the nervous system that controls body functions, and more.
Gwen Bishop was working remotely for the human resources department at the University of Washington Medical Centers, Seattle, when she got COVID-19. When the infection passed, Ms. Bishop, 39, thought she’d start feeling well enough to get back to work – but that didn’t happen.
“When I would log in to work and just try to read emails,” she says, “it was like they were written in Greek. It made no sense and was incredibly stressful.”
This falls in line with what researchers have found out about the nervous system issues reported by people with long COVID. People who have survived acute COVID infections have reported lasting sensory and motor function problems, brain fog, and memory problems.
Ms. Bishop, who was diagnosed with ADHD when she was in grade school, says another complication she got from her long COVID was a new intolerance to stimulants like coffee and her ADHD medication, Vyvanse, which were normal parts of her everyday life.
“Every time I would take my ADHD medicine or have a cup of coffee, I would have a panic attack until it wore off,” says Ms. Bishop. “Vyvanse is a very long-acting stimulant, so that would be an entire day of an endless panic attack.”
In order for her to get a medical leave approved, Ms. Bishop needed to get documents by a certain date from her doctor’s office that confirmed her long COVID diagnosis. She was able to get a couple of extensions, but Bishop says that with the burden that has been placed on our medical systems, getting in to see a doctor through her employer insurance was taking much longer than expected. By the time she got an appointment, she says, she had already been fired for missing too much work. Emails she provided showing exchanges between her and her employer verify her story. And without her health insurance, her appointment through that provider would no longer have been covered.
In July 2021, the U.S. Department of Health & Human Services issued guidance recognizing long COVID as a disability “if the person’s condition or any of its symptoms is a ‘physical or mental’ impairment that ‘substantially limits’ one or more major life activities.”
But getting access to disability benefits hasn’t been easy for people with long COVID. On top of having to be out of work for 12 months before being able to qualify for Social Security Disability Insurance, some of those who have applied say they have had to put up a fight to actually gain access to disability insurance. The Social Security Administration has yet to reveal just how many applications that cited long COVID have been denied so far.
David Barnett, a former bartender in the Seattle area in his early 40s, got COVID-19 in March 2020. Before his infection, he spent much of his time working on his feet, bodybuilding, and hiking with his partner. But for the last nearly 3 years, even just going for a walk has been a major challenge. He says he has spent much of his post-COVID life either chair-bound or bed-bound because of his symptoms.
He is currently on his partner’s health insurance plan but is still responsible for copays and out-of-network appointments and treatments. After being unable to bartend any more, he started a GoFundMe account and dug into his personal savings. He says he applied for food stamps and is getting ready to sell his truck. Mr. Barnett applied for disability in March of this year but says he was denied benefits by the Social Security Administration and has hired a lawyer to appeal.
He runs a 24-hour online support group on Zoom for people with long COVID and says that no one in his close circle has successfully gotten access to disability payments.
Alba Azola, MD, codirector of Johns Hopkins University’s Post-Acute COVID-19 Team, says at least half of her patients need some level of accommodations to get back to work; most can, if given the proper accommodations, such as switching to a job that can be done sitting down, or with limited time standing. But there are still patients who have been more severely disabled by their long COVID symptoms.
“Work is such a part of people’s identity. The people who are very impaired, all they want to do is to get back to work and their normal lives,” she says.
Many of Dr. Azola’s long COVID patients aren’t able to return to their original jobs. She says they often have to find new positions more tailored to their new realities. One patient, a nurse and mother of five who previously worked in a facility where she got COVID-19, was out of work for 9 months after her infection. She ultimately lost her job, and Dr. Azola says the patient’s employer was hesitant to provide her with any accommodations. The patient was finally able to find a different job as a nurse coordinator where she doesn’t have to be standing for more than 10 minutes at a time.
Ge Bai, PhD, a professor of health policy and management at Johns Hopkins Bloomberg School of Public Health, says the novelty of long COVID and the continued uncertainty around it raise questions for health insurance providers.
“There’s no well-defined pathway to treat or cure this condition,” Dr. Bai says. “Right now, employers have discretion to determine when a condition is being covered or not being covered. So people with long COVID do have a risk that their treatments won’t be covered.”
A version of this article first appeared on WebMD.com.
It’s a devastating series of setbacks for long COVID patients. First, they get the debilitating symptoms of their condition. Then they are forced to give up their jobs, or severely curtail their work hours, as their symptoms linger. And next, for many, they lose their employer-sponsored health insurance.
While not all long COVID patients are debilitated, the CDC’s ongoing survey on long COVID found a quarter of adults with long COVID report it significantly affects their day-to-day living activities.
Estimates have shown that long COVID has disrupted the lives of anywhere from 16 million to 34 million Americans between the ages of 18 and 65.
While hard data is still limited, a Kaiser Family Foundation analysis found that more than half of adults with long COVID who worked before getting the virus are now either out of work or working fewer hours.
According to data from the Census Bureau’s Household Pulse Survey, out of the estimated 16 million working-age adults who currently have long COVID, 2 million to 4 million of them are out of work because of their symptoms. The cost of those lost wages ranges from $170 billion a year to as much as $230 billion, the Census Bureau says. And given that approximately 155 million Americans have employer-sponsored health insurance, the welfare of working-age adults may be under serious threat.
“Millions of people are now impacted by long COVID, and oftentimes along with that comes the inability to work,” says Megan Cole Brahim, PhD, an assistant professor in the department of health law, policy, and management at Boston University and codirector of the school’s Medicaid policy lab. “And because a lot of people get their health insurance coverage through employer-sponsored coverage, no longer being able to work means you may not have access to the health insurance that you once had.”
The CDC defines long COVID as a wide array of health conditions, including malaise, fatigue, shortness of breath, mental health issues, problems with the part of the nervous system that controls body functions, and more.
Gwen Bishop was working remotely for the human resources department at the University of Washington Medical Centers, Seattle, when she got COVID-19. When the infection passed, Ms. Bishop, 39, thought she’d start feeling well enough to get back to work – but that didn’t happen.
“When I would log in to work and just try to read emails,” she says, “it was like they were written in Greek. It made no sense and was incredibly stressful.”
This falls in line with what researchers have found out about the nervous system issues reported by people with long COVID. People who have survived acute COVID infections have reported lasting sensory and motor function problems, brain fog, and memory problems.
Ms. Bishop, who was diagnosed with ADHD when she was in grade school, says another complication she got from her long COVID was a new intolerance to stimulants like coffee and her ADHD medication, Vyvanse, which were normal parts of her everyday life.
“Every time I would take my ADHD medicine or have a cup of coffee, I would have a panic attack until it wore off,” says Ms. Bishop. “Vyvanse is a very long-acting stimulant, so that would be an entire day of an endless panic attack.”
In order for her to get a medical leave approved, Ms. Bishop needed to get documents by a certain date from her doctor’s office that confirmed her long COVID diagnosis. She was able to get a couple of extensions, but Bishop says that with the burden that has been placed on our medical systems, getting in to see a doctor through her employer insurance was taking much longer than expected. By the time she got an appointment, she says, she had already been fired for missing too much work. Emails she provided showing exchanges between her and her employer verify her story. And without her health insurance, her appointment through that provider would no longer have been covered.
In July 2021, the U.S. Department of Health & Human Services issued guidance recognizing long COVID as a disability “if the person’s condition or any of its symptoms is a ‘physical or mental’ impairment that ‘substantially limits’ one or more major life activities.”
But getting access to disability benefits hasn’t been easy for people with long COVID. On top of having to be out of work for 12 months before being able to qualify for Social Security Disability Insurance, some of those who have applied say they have had to put up a fight to actually gain access to disability insurance. The Social Security Administration has yet to reveal just how many applications that cited long COVID have been denied so far.
David Barnett, a former bartender in the Seattle area in his early 40s, got COVID-19 in March 2020. Before his infection, he spent much of his time working on his feet, bodybuilding, and hiking with his partner. But for the last nearly 3 years, even just going for a walk has been a major challenge. He says he has spent much of his post-COVID life either chair-bound or bed-bound because of his symptoms.
He is currently on his partner’s health insurance plan but is still responsible for copays and out-of-network appointments and treatments. After being unable to bartend any more, he started a GoFundMe account and dug into his personal savings. He says he applied for food stamps and is getting ready to sell his truck. Mr. Barnett applied for disability in March of this year but says he was denied benefits by the Social Security Administration and has hired a lawyer to appeal.
He runs a 24-hour online support group on Zoom for people with long COVID and says that no one in his close circle has successfully gotten access to disability payments.
Alba Azola, MD, codirector of Johns Hopkins University’s Post-Acute COVID-19 Team, says at least half of her patients need some level of accommodations to get back to work; most can, if given the proper accommodations, such as switching to a job that can be done sitting down, or with limited time standing. But there are still patients who have been more severely disabled by their long COVID symptoms.
“Work is such a part of people’s identity. The people who are very impaired, all they want to do is to get back to work and their normal lives,” she says.
Many of Dr. Azola’s long COVID patients aren’t able to return to their original jobs. She says they often have to find new positions more tailored to their new realities. One patient, a nurse and mother of five who previously worked in a facility where she got COVID-19, was out of work for 9 months after her infection. She ultimately lost her job, and Dr. Azola says the patient’s employer was hesitant to provide her with any accommodations. The patient was finally able to find a different job as a nurse coordinator where she doesn’t have to be standing for more than 10 minutes at a time.
Ge Bai, PhD, a professor of health policy and management at Johns Hopkins Bloomberg School of Public Health, says the novelty of long COVID and the continued uncertainty around it raise questions for health insurance providers.
“There’s no well-defined pathway to treat or cure this condition,” Dr. Bai says. “Right now, employers have discretion to determine when a condition is being covered or not being covered. So people with long COVID do have a risk that their treatments won’t be covered.”
A version of this article first appeared on WebMD.com.
It’s a devastating series of setbacks for long COVID patients. First, they get the debilitating symptoms of their condition. Then they are forced to give up their jobs, or severely curtail their work hours, as their symptoms linger. And next, for many, they lose their employer-sponsored health insurance.
While not all long COVID patients are debilitated, the CDC’s ongoing survey on long COVID found a quarter of adults with long COVID report it significantly affects their day-to-day living activities.
Estimates have shown that long COVID has disrupted the lives of anywhere from 16 million to 34 million Americans between the ages of 18 and 65.
While hard data is still limited, a Kaiser Family Foundation analysis found that more than half of adults with long COVID who worked before getting the virus are now either out of work or working fewer hours.
According to data from the Census Bureau’s Household Pulse Survey, out of the estimated 16 million working-age adults who currently have long COVID, 2 million to 4 million of them are out of work because of their symptoms. The cost of those lost wages ranges from $170 billion a year to as much as $230 billion, the Census Bureau says. And given that approximately 155 million Americans have employer-sponsored health insurance, the welfare of working-age adults may be under serious threat.
“Millions of people are now impacted by long COVID, and oftentimes along with that comes the inability to work,” says Megan Cole Brahim, PhD, an assistant professor in the department of health law, policy, and management at Boston University and codirector of the school’s Medicaid policy lab. “And because a lot of people get their health insurance coverage through employer-sponsored coverage, no longer being able to work means you may not have access to the health insurance that you once had.”
The CDC defines long COVID as a wide array of health conditions, including malaise, fatigue, shortness of breath, mental health issues, problems with the part of the nervous system that controls body functions, and more.
Gwen Bishop was working remotely for the human resources department at the University of Washington Medical Centers, Seattle, when she got COVID-19. When the infection passed, Ms. Bishop, 39, thought she’d start feeling well enough to get back to work – but that didn’t happen.
“When I would log in to work and just try to read emails,” she says, “it was like they were written in Greek. It made no sense and was incredibly stressful.”
This falls in line with what researchers have found out about the nervous system issues reported by people with long COVID. People who have survived acute COVID infections have reported lasting sensory and motor function problems, brain fog, and memory problems.
Ms. Bishop, who was diagnosed with ADHD when she was in grade school, says another complication she got from her long COVID was a new intolerance to stimulants like coffee and her ADHD medication, Vyvanse, which were normal parts of her everyday life.
“Every time I would take my ADHD medicine or have a cup of coffee, I would have a panic attack until it wore off,” says Ms. Bishop. “Vyvanse is a very long-acting stimulant, so that would be an entire day of an endless panic attack.”
In order for her to get a medical leave approved, Ms. Bishop needed to get documents by a certain date from her doctor’s office that confirmed her long COVID diagnosis. She was able to get a couple of extensions, but Bishop says that with the burden that has been placed on our medical systems, getting in to see a doctor through her employer insurance was taking much longer than expected. By the time she got an appointment, she says, she had already been fired for missing too much work. Emails she provided showing exchanges between her and her employer verify her story. And without her health insurance, her appointment through that provider would no longer have been covered.
In July 2021, the U.S. Department of Health & Human Services issued guidance recognizing long COVID as a disability “if the person’s condition or any of its symptoms is a ‘physical or mental’ impairment that ‘substantially limits’ one or more major life activities.”
But getting access to disability benefits hasn’t been easy for people with long COVID. On top of having to be out of work for 12 months before being able to qualify for Social Security Disability Insurance, some of those who have applied say they have had to put up a fight to actually gain access to disability insurance. The Social Security Administration has yet to reveal just how many applications that cited long COVID have been denied so far.
David Barnett, a former bartender in the Seattle area in his early 40s, got COVID-19 in March 2020. Before his infection, he spent much of his time working on his feet, bodybuilding, and hiking with his partner. But for the last nearly 3 years, even just going for a walk has been a major challenge. He says he has spent much of his post-COVID life either chair-bound or bed-bound because of his symptoms.
He is currently on his partner’s health insurance plan but is still responsible for copays and out-of-network appointments and treatments. After being unable to bartend any more, he started a GoFundMe account and dug into his personal savings. He says he applied for food stamps and is getting ready to sell his truck. Mr. Barnett applied for disability in March of this year but says he was denied benefits by the Social Security Administration and has hired a lawyer to appeal.
He runs a 24-hour online support group on Zoom for people with long COVID and says that no one in his close circle has successfully gotten access to disability payments.
Alba Azola, MD, codirector of Johns Hopkins University’s Post-Acute COVID-19 Team, says at least half of her patients need some level of accommodations to get back to work; most can, if given the proper accommodations, such as switching to a job that can be done sitting down, or with limited time standing. But there are still patients who have been more severely disabled by their long COVID symptoms.
“Work is such a part of people’s identity. The people who are very impaired, all they want to do is to get back to work and their normal lives,” she says.
Many of Dr. Azola’s long COVID patients aren’t able to return to their original jobs. She says they often have to find new positions more tailored to their new realities. One patient, a nurse and mother of five who previously worked in a facility where she got COVID-19, was out of work for 9 months after her infection. She ultimately lost her job, and Dr. Azola says the patient’s employer was hesitant to provide her with any accommodations. The patient was finally able to find a different job as a nurse coordinator where she doesn’t have to be standing for more than 10 minutes at a time.
Ge Bai, PhD, a professor of health policy and management at Johns Hopkins Bloomberg School of Public Health, says the novelty of long COVID and the continued uncertainty around it raise questions for health insurance providers.
“There’s no well-defined pathway to treat or cure this condition,” Dr. Bai says. “Right now, employers have discretion to determine when a condition is being covered or not being covered. So people with long COVID do have a risk that their treatments won’t be covered.”
A version of this article first appeared on WebMD.com.