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

Abstract

SummaryBackgroundAmyotrophic 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.MethodsA 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.FindingsSamples 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 expansionInterpretationPatients 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.FundingHealth 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.

The phenotypic variability of amyotrophic lateral sclerosis

“…1 Patients with a hexanucleotide (GGGGCC) expansion mutation in the C9orf72 gene have shorter survival than the average ALS patient. [25][26][27][28] Even within families in which members carry the same mutation, variability in progression rates is large. [29][30][31] This finding suggests that there is no straightforward relationship between the genetic cause and phenotype but, rather, that factors-either genetic or e nvironmental-modify the phenotypic expression, and in particular age at onset and disease progression.…”

The genetic basis of amyotrophic lateral sclerosis: recent breakthroughs

“…111 Additional phenotypes include Parkinsonism, ataxia, and psychosis. 112,113 In addition, a large variation in disease onset (27-83 years) and duration (3-264 months) is evident among C9orf72 subjects. 111 Interestingly, some C9orf72 patients harbor variations in other ALS-and/or FTD-associated genes, 111,114 a finding of possible pathogenic significance.…”

Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)

“…Thus, it is possible that C19orf12 gene maps to the same metabolic pathway as PANK2 and PLA2G6. The C19orf12 gene abnormality should not be confused with disorders associated with mutation in the C9orf12 gene, located on chromosome 9 and associated with familial fronto-temporal dementia and motor neuron disease [123][124][125].…”