User login
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care.
“An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care.
“An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care.
“An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC