0
Original Contribution |

C9orf72 Hexanucleotide Repeat Expansions in Clinical Alzheimer Disease

Matthew Harms, MD; Bruno A. Benitez, MD; Nigel Cairns, PhD; Breanna Cooper, BS; Paul Cooper, BS; Kevin Mayo, BA; David Carrell, BS; Kelley Faber, MS; Jennifer Williamson, MS; Tom Bird, MD; Ramon Diaz-Arrastia, MD; Tatiana M. Foroud, PhD; Bradley F. Boeve, MD; Neill R. Graff-Radford, MBChB; Richard Mayeux, MD, MS; Sumitra Chakraverty, MS; Alison M. Goate, PhD; Carlos Cruchaga, PhD; for the NIA-LOAD/NCRAD Family Study Consortium
JAMA Neurol. 2013;70(6):736-741. doi:10.1001/2013.jamaneurol.537.
Text Size: A A A
Published online

Importance Hexanucleotide repeat expansions in the chromosome 9 open reading frame 72 (C9orf72) gene underlie a significant fraction of frontotemporal dementia and amyotrophic lateral sclerosis.

Objective To investigate the frequency of C9orf72 repeat expansions in clinically diagnosed late-onset Alzheimer disease (AD).

Design, Setting, and Patients This case-control study genotyped the C9orf72 repeat expansion in 872 unrelated familial AD cases and 888 control subjects recruited as part of the National Institute on Aging Late-Onset Alzheimer Disease Family Study cohort, a multisite collaboration studying 1000 families with 2 or more individuals clinically diagnosed as having late-onset AD.

Main Outcomes and Measures We determined the presence or absence of the C9orf72 repeat expansion by repeat-primed polymerase chain reaction, the length of the longest nonexpanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers.

Results Three families showed large C9orf72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the National Institute on Aging Late-Onset Alzheimer Disease Family Study series, the C9orf72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions.

Conclusions and Relevance C9orf72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and they highlight the necessity of screening frontotemporal dementia genes in clinical AD cases with strong family history.

Figures in this Article

Sign In to Access Full Content

Don't have Access?

Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more

Subscribe for full-text access to content from 1998 forward and a host of useful features

Activate your current subscription (AMA members and current subscribers)

Purchase Online Access to this article for 24 hours

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Alzheimer disease (AD) pedigrees carrying abnormal C9orf72 repeat expansions. Fully shaded symbols indicate autopsy-confirmed AD. Clinical diagnoses were made using National Institute of Neurological and Communication Disorders and Stroke–Alzheimer Disease and Related Disorders Association criteria, with three-quarters and one-half shading indicating probable and possible AD, respectively. + indicates the presence of repeat expansion genotypes and − indicates their absence. The absence of a genotype symbol indicates that DNA was not available for analysis. An arrow marks the proband of each pedigree. ALV indicates age at last visit; AO, age at onset.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2.C9orf72 repeat expansions correlate with an earlier age at onset. Age at onset was analyzed for association with repeat expansion genotypes by the Kaplan-Meier method and tested for significant differences using a proportional hazards model (proc PHREG; SAS Institute Inc). Repeat expansion carriers show an earlier age at onset than noncarriers (mean [SD], 68.25 [5.8] vs 71.4 [6.8] years; P = .04).

Tables

References

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 8

Sign In to Access Full Content

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Resolution

Users' Guides to the Medical Literature
Clinical Scenario

brightcove.createExperiences();