Elsevier

The Lancet Neurology

Volume 11, Issue 3, March 2012, Pages 232-240
The Lancet Neurology

Articles
Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study

https://doi.org/10.1016/S1474-4422(12)70014-5Get rights and content

Summary

Background

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons, associated with frontotemporal dementia (FTD) in about 14% of incident cases. We assessed the frequency of the recently identified C9orf72 repeat expansion in familial and apparently sporadic cases of ALS and characterised the cognitive and clinical phenotype of patients with this expansion.

Methods

A population-based register of patients with ALS has been in operation in Ireland since 1995, and an associated DNA bank has been in place since 1999. 435 representative DNA samples from the bank were screened using repeat-primed PCR for the presence of a GGGGCC repeat expansion in C9orf72. We assessed clinical, cognitive, behavioural, MRI, and survival data from 191 (44%) of these patients, who comprised a population-based incident group and had previously participated in a longitudinal study of cognitive and behavioural changes in ALS.

Findings

Samples from the DNA bank included 49 cases of known familial ALS and 386 apparently sporadic cases. Of these samples, 20 (41%) cases of familial ALS and 19 (5%) cases of apparently sporadic ALS had the C9orf72 repeat expansion. Of the 191 patients for whom phenotype data were available, 21 (11%) had the repeat expansion. Age at disease onset was lower in patients with the repeat expansion (mean 56·3 [SD 8·3] years) than in those without (61·3 [10·6] years; p=0·043). A family history of ALS or FTD was present in 18 (86%) of those with the repeat expansion. Patients with the repeat expansion had significantly more co-morbid FTD than patients without the repeat (50% vs 12%), and a distinct pattern of non-motor cortex changes on high-resolution 3 T magnetic resonance structural neuroimaging. Age-matched univariate analysis showed shorter survival (20 months vs 26 months) in patients with the repeat expansion. Multivariable analysis showed an increased hazard rate of 1·9 (95% 1·1–3·7; p=0·035) in those patients with the repeat expansion compared with patients without the expansion

Interpretation

Patients with ALS and the C9orf72 repeat expansion seem to present a recognisable phenotype characterised by earlier disease onset, the presence of cognitive and behavioural impairment, specific neuroimaging changes, a family history of neurodegeneration with autosomal dominant inheritance, and reduced survival. Recognition of patients with ALS who carry an expanded repeat is likely to be important in the context of appropriate disease management, stratification in clinical trials, and in recognition of other related phenotypes in family members.

Funding

Health Seventh Framework Programme, Health Research Board, Research Motor Neuron, Irish Motor Neuron Disease Association, The Motor Neurone Disease Association of Great Britain and Northern Ireland, ALS Association.

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper and lower motor neurons. Cognitive impairment occurs in up to 50% of cases, and one in seven patients develops frank frontotemporal dementia (FTD).1 The existence of families with pure ALS, pure FTD, and ALS with co-morbid FTD (ALS-FTD) has been long recognised.2 A combination of clinical, neuroimaging, and neuropathological data suggest that ALS and FTD might form part of a disease continuum, with pure ALS at one extreme and pure FTD at the other. Detailed genetic studies including conventional linkage2 and genome-wide association studies of families with ALS and FTD have identified a reproducible locus on chromosome 9p21,3, 4, 5 and a disease-segregating expanded hexanucleotide repeat in the C9orf72 gene in that locus accounts for up to 60% of familial ALS and up to 10% of sporadic ALS.6, 7 Preliminary data suggest that hexanucleotide expansions of more than 23 are pathological, although further population-based control studies are warranted.6 Detailed phenotyping of patients with this pathological expansion has yet to be reported.

In this study, we characterised the clinical features, demographics, survival, neurocognitive profile, family history, and neuroimaging findings in a population-based cohort of Irish patients carrying the C9orf72 hexanucleotide repeat expansion.

Section snippets

Participants and study design

A population-based register of patients with ALS has been in operation in Ireland since 1995,8, 9 and an associated bank of DNA extracted from venous leucocytes has been in place since 1999. 435 representative samples were selected for screening from the DNA bank on the basis of the following criteria: Irish origin; both incident and prevalent cases; sufficiently high-quality and quantity to permit subsequent Southern blotting; and proportionate representation of the familial and sporadic ALS

Results

Of 435 banked DNA samples derived from the Irish ALS Register, 39 (9%) had the characteristic appearance of a GGGGCC hexanucleotide expansion, consisting of a decaying series of more than 23 peaks on a PCR electropherogram, and were therefore classed as having the C9orf72 repeat expansion. All samples from carriers of the expansion had 30 or more peaks that showed exponential decay, whereas the electropherograms of samples without the repeat expansion had 23 or fewer repeats and showed an

Discussion

We have shown that patients with ALS and the C9orf72 hexanucleotide repeat expansion represent a recognisable subphenotype characterised by a lower age of onset, presence of cognitive and behavioural impairment, specific neuroimaging changes, a strong family history of neurodegeneration, and reduced survival. In our cohort, the repeat expansion was not present in patients who had sporadic ALS and no behavioural abnormalities. Our findings show that detailed phenotyping and careful

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