Gene Mutation Tied to 5% of Frontotemporal Dementia

SALZBURG, AUSTRIA – Mutations in the progranulin gene are found in about 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or younger. About 35%–50% of patients with FTD have a family history of dementia, which suggests the existence of a strong genetic component to the disease.

In 1998, researchers reported that mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients. In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4). Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the FTD community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD, with some being followed for over 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” said Dr. Pickering-Brown, who noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his cohort.

Clinically, the 14 patients had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, said Dr. Pickering-Brown. “All the cases had a family history of disease,” he added.

The researchers also genotyped several single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they found no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients. He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men. The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years). “Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” Dr. Kelley said.

Like the Manchester cohort, the clinical diagnosis varied widely and included FTD with and without parkinsonism, mild cognitive impairment, and Alzheimer's.

The discovery of this gene will not change clinical practice at this point, said Dr. Zbigniew Wszolek, a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., who chaired the session. In addition, Dr. Wszolek said he did not think clinical genetic testing was available yet, but patents have been filed.

SALZBURG, AUSTRIA – Mutations in the progranulin gene are found in about 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or younger. About 35%–50% of patients with FTD have a family history of dementia, which suggests the existence of a strong genetic component to the disease.

In 1998, researchers reported that mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients. In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4). Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the FTD community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD, with some being followed for over 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” said Dr. Pickering-Brown, who noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his cohort.

Clinically, the 14 patients had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, said Dr. Pickering-Brown. “All the cases had a family history of disease,” he added.

The researchers also genotyped several single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they found no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients. He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men. The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years). “Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” Dr. Kelley said.

Like the Manchester cohort, the clinical diagnosis varied widely and included FTD with and without parkinsonism, mild cognitive impairment, and Alzheimer's.

The discovery of this gene will not change clinical practice at this point, said Dr. Zbigniew Wszolek, a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., who chaired the session. In addition, Dr. Wszolek said he did not think clinical genetic testing was available yet, but patents have been filed.

SALZBURG, AUSTRIA – Mutations in the progranulin gene are found in about 5% of patients with frontotemporal dementia, according to research presented at the 8th International Conference on Alzheimer's and Parkinson's Diseases.

Frontotemporal dementia (FTD) is the second most common cause of dementia, after Alzheimer's disease, in patients aged 65 years or younger. About 35%–50% of patients with FTD have a family history of dementia, which suggests the existence of a strong genetic component to the disease.

In 1998, researchers reported that mutations in the gene encoding the microtubule-associated protein tau (MAPT) caused familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). However, not all families who showed linkage to the same region on chromosome 17 had mutations in MAPT, suggesting that mutations in at least one other gene were responsible for the disease in these patients. In addition, these patients had ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) but not tau-immunoreactive inclusion pathology.

In July 2006, two studies found that FTDU-17 is caused by mutations in progranulin, a polypeptide with growth-modulatory activity, leading to a loss of protein function (Nature 2006;442:916–9; Nature 2006;442:920–4). Since then, researchers have been screening their patient populations for the mutations to determine their prevalence in the FTD community.

Stuart Pickering-Brown, Ph.D., who works at the University of Manchester (England), presented data from the Manchester Cohort that currently includes 272 patients with FTD, with some being followed for over 20 years.

“We recently finished sequencing for progranulin mutations and found 14 cases,” said Dr. Pickering-Brown, who noted that this frequency (5%) is about the same as for tau gene mutations (6%) in his cohort.

Clinically, the 14 patients had been diagnosed with frontotemporal dementias, primary progressive aphasia, and corticobasal degeneration, said Dr. Pickering-Brown. “All the cases had a family history of disease,” he added.

The researchers also genotyped several single nucleotide polymorphisms (SNPs) spanning the progranulin gene to determine whether a common variation at the locus increases the risk of sporadic disease, but they found no evidence of allelic association of any of the SNPs.

Dr. Brendan Kelley presented the latest data from the Mayo Clinic cohort of patients. He reported on the clinical characterization of eight kindreds, which included 31 individuals with progranulin mutations, of whom 16 were men. The patients were aged 49–83 years at disease onset (mean age 63 years) and had a disease duration of 1–12 years (mean 6.5 years). “Two individuals who died within 1 year both had accidents that may have been related to disinhibited behaviors,” Dr. Kelley said.

Like the Manchester cohort, the clinical diagnosis varied widely and included FTD with and without parkinsonism, mild cognitive impairment, and Alzheimer's.

The discovery of this gene will not change clinical practice at this point, said Dr. Zbigniew Wszolek, a professor of neurology at the Mayo Clinic College of Medicine, Jacksonville, Fla., who chaired the session. In addition, Dr. Wszolek said he did not think clinical genetic testing was available yet, but patents have been filed.