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C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease
Matthew Harms1, Bruno A Benitez, Nigel Cairns
1Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA.
JAMA Neurology
|April 17, 2013
Summary
Hexanucleotide repeat expansions in the C9orf72 gene are a common cause of frontotemporal dementia and ALS. This study found these expansions in a small subset of Alzheimer disease patients, suggesting genetic overlap.
Area of Science:
- Neuroscience
- Genetics
- Neurology
Background:
- Hexanucleotide repeat expansions in the chromosome 9 open reading frame 72 (C9orf72) gene are a known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
- The genetic overlap between FTD, ALS, and Alzheimer disease (AD) is complex and not fully understood.
Purpose of the Study:
- To determine the frequency of C9orf72 repeat expansions in individuals diagnosed with late-onset Alzheimer disease (AD).
- To investigate the clinical presentation and genetic segregation of C9orf72 repeat expansions in AD families.
Main Methods:
- A case-control study genotyped 872 familial late-onset AD cases and 888 controls using repeat-primed polymerase chain reaction to detect C9orf72 repeat expansions.
- Analysis included determining repeat length, segregation with disease, and clinical features of carriers.
Main Results:
- C9orf72 repeat expansions were identified in 5 families, with 3 showing large expansions and segregation with disease.
- One carrier presented with neuropathology consistent with AD.
- C9orf72 repeat expansions were the second most common pathogenic mutation in this AD cohort, after PSEN1 A79V.
Conclusions:
- C9orf72 repeat expansions account for a small percentage of clinically diagnosed AD cases, particularly those with a strong family history.
- These findings underscore the importance of screening for FTD-associated genes, like C9orf72, in AD patients presenting with familial clustering.
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