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

Abstract

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.

Figure 1

Kaplan-Meier survival probabilities for patients with amyotrophic lateral sclerosis stratified for the presence of the C9orf72 hexanucleotide repeat expansion Kaplan-Meier survival probabilities for all patients with amyotrophic lateral sclerosis (ALS) in the population-based cohort (191 patients; A), and for the subgroup of patients with behavioural variant frontotemporal dementia (25 patients; B).

Figure 2

Voxel-based morphometry analysis Clusters of significant grey-matter atrophy in a cohort of ten patients with amyotrophic lateral sclerosis (ALS) and the pathological expanded C9orf72 hexanucleotide repeat compared with 30 matched patients with ALS without the repeat expansion. The four columns show the four clusters (from left to right: in the right inferior frontal gyrus, right superior frontal gyrus, left anterior cingulate gyrus, and the right precentral gyrus) in the three main radiological planes in each row (top to bottom: axial, coronal, saggital). R=right hemisphere. L=left hemisphere.

Figure 3

Screening algorithm Numbers are numbers of patients from our population-based incident cohort. ALS=amyotrophic lateral sclerosis. FTD=frontotemporal dementia.