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Progranulin and Heterogeneity in Frontotemporal Dementia

Despite identical FTD mutations, patients within a large kindred show considerable clinical differences.

Frontotemporal dementia (FTD) is a group of disorders with clinical, pathological, and genetic heterogeneity. Mutations in the gene for progranulin (PGRN) account for a substantial proportion of familial cases with tau-negative, ubiquitinated, TDP-43–positive inclusions (FTLD-U). These researchers sought the frequency of PGRN mutations in a clinically defined cohort of 78 independent patients with FTD (23 familial).

The researchers found only one mutation, a novel frame-shift mutation in the proband of a large, previously described FTD family (B-family). This mutation was not found within a separate case-control dataset from the same geographic region, including 96 unrelated FTD subjects (42 familial) and 109 healthy controls. The authors reexamined the B-family and identified 19 carriers of the mutation, including 10 presymptomatic individuals. Among affected members of the kindred, age at onset spanned 5 decades but was uninfluenced by the H1/H2 MAPT haplotype or apolipoprotein E genotype. Four affected individuals lacked the mutation and were thought to represent FTD phenocopies. Clinical presentation in phenocopies resembled that among mutation carriers except for age at disease onset (mean, 74.8 years), which was approximately 10 years younger among mutation carriers.

Comment: This study adds nuance to a rapidly evolving area of research by suggesting that, despite identical FTD mutations, patients within a large kindred may show considerable clinical differences. The study further highlights opportunities to characterize this form of FTD in presymptomatic mutation carriers and to find new FTD genes in patients who lack MAPT, PGRN, and CHMP2B mutations. Unfortunately, the researchers could assess PGRN mutation frequency only among clinically, not pathologically, defined FTD. In a cohort of 78 FTD patients, only 40 would be expected to have FTLD-U pathology, making the progranulin mutation frequency of <1% quoted by the authors difficult to interpret in relation to previous work (Hum Mol Genet 2006; 15:2988). When autopsy confirmation is unavailable, contemporary clinical diagnostic criteria (Neurology 1998; 51:1546), though imperfect, may aid the segregation of clinical FTD into pathologically homogeneous subgroups.

— William W. Seeley, MD

Dr. Seeley is Assistant Professor of Neurology, Memory and Aging Center, University of California, San Francisco.

Published in Journal Watch Neurology August 28, 2007

Citation(s):

Bruni AC et al. Heterogeneity within a large kindred with frontotemporal dementia: A novel progranulin mutation. Neurology 2007 Jul 10; 69:140-7.

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