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Gene Study of Familial Frontotemporal Dementia Reveals Variants

Dutch researchers studying families at risk for frontotemporal dementia (FTD) — the second most common form of dementia after Alzheimer disease (AD) — have discovered several distinct subtypes, some caused by known genetic mutations and others by as-yet unidentified defects, including one newly identified variant that might be a unique disease entity entirely.

In recent years, genetic mutations have been linked to abnormal inclusions, or deposits, of proteins in the neurons and glial cells of patients with neurodegenerative disorders, including FTD. These include mutations in the genes for MAPT (microtubule-associate protein in tau), which is also associated with AD, and GRN (progranulin protein).

Mutations in MAPT and GRN have been identified as the most common genetic causes of FTD, with a wide range of onset (between 45- and 80-years) and a wide clinical spectrum (including Alzheimer-like disease and motor disorders). Other mutations involve TAR DNA binding protein, or TDP-43, which is also associated with amyotrophic lateral sclerosis (ALS). The mutations cause the insoluble proteins to accumulate in cells in the brain and nervous system.

Reporting online Aug. 12 in advance of the Oct. 14 print edition of Neurology, researchers led by John C. van Swieten, MD, PhD, professor of neurology at Erasmus University Medical Center in Rotterdam, the Netherlands, describe genetic, clinical, and pathological findings from a prospective study of 364 FTD patients, including autopsy examinations of the brains for MAPT, GRN, TDP-43, and ubiquitin, an important regulatory protein that removes defective or excessive buildup of these proteins.

The researchers discovered autosomal dominant forms of FTD in 27 percent of the patients;11 percent had MAPT mutations and 6 percent had variants in GRN. The remaining 10 percent had another form, although the specific genetic defect remains unknown. The team also identified a new GRN mutation in one patient with sporadic FTD.

Autosomal mutations can occur on any of the 22 non-sex-linked chromosomes and, because they are gender-neutral, are more likely to give rise to genetic diseases between generations. FTD has shown a strong familial component with a positive family history in 30–50 percent of patients.

“FTD research has advanced quickly over the last two decades, with major implications for clinical practice,” Dr. van Swieten noted in an e-mail to Neurology Today. Different clinical symptoms — behavioral, aphasic, and motor neuron disease — are today recognized as being part of the clinical spectrum of FTD.

In addition, the disease can be divided into two major pathological subtypes: frontotemporal lobar degeneration (FTLD) with neuronal and glial tau inclusions (FTLD-tau), and FTLD with ubiquitin and TDP-43 positive neuronal and glial inclusions (FTLD-U), he said.

FTD onset occurred later among patients in the GRN group (mean age was 61.8 years) than in patients with MAPT defects (at an average of 52.4 years).

Future genetic studies need to identify genetic defects in at least these two distinct familial forms of frontotemporal dementia, according to Dr. van Swieten.


Clinicians need to be aware of the wide clinical spectrum of FTD, including the different clinical variants, variation in age at onset, and the existence of pathological subtypes and distinct genetic forms of the disease, Dr. van Swieten stressed.

The new GRN gene mutation in a sporadic patient with pathologic-proven FTD, together with the wide range in age at onset of other GRN mutations, has important implications for genetic counseling, he noted.

“In our view, GRN screening should not be restricted to patients with a family history strongly suggestive for an autosomal dominant inheritance,” he said. “In cases with a positive family history, clinicians have to offer genetic counseling to patients and families to discuss diagnostic DNA testing. Geneticists should take into account the possibility of incomplete penetrance of GRN mutations (especially in small nuclear families), and should search for affected second-degree relatives in families,” he added.

In addition, future genetic studies need to identify the two remaining autosomal dominant forms — frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease — and find genetic and environmental factors that might modulate variations in GRN mutations, according to the report.

“Also, it is important that we better understand how GRN mutations lead to the accumulation of pathological [TDP-43] protein in neurons, which is essential for developing potential therapeutic interventions in the future,” said Dr. van Swieten.


According to John Q. Trojanowski, MD, PhD, the Schnabel Professor of Geriatric Medicine and Gerontology and director of the Institute on Aging at the University of Pennsylvania School of Medicine in Philadelphia, the findings should help speed development of animal models of FTD, identify biomarkers, and eventually test targeted drug therapies.

“Things are moving much faster now. We need to develop an animal model of TDP-43 with or without progranulin, or a progranulin knockout mouse to study the mechanism of its action on TDP-43,” he told Neurology Today in a telephone interview.

The tau protein was first identified in 1998, progranulin and TDP-43 in 2006, and the mutations in TDP-43 were discovered only earlier this year. There are currently two drugs in clinical trials for tau, but it took nearly 16 years between the identification of tau and these trials, he noted.

“We don't know much yet about the mechanism of the mutation on the protein in FTD, but this shouldn't take nearly as long as it has with tau or amyloid beta in Alzheimer disease, which took nearly 18 years. In just two years we've made it this far.”


• Seelaar H, Kamphorst W, van Swieten JC, et al. Distinct genetic forms of frontotemporal dementia. Neurology 2008; E-pub 2008 Aug. 12.