ArticlesCognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study
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
References (27)
- et al.
Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study
Lancet Neurol
(2010) - et al.
Chromosome (p21 in amyotrophic lateral sclerosis in Finland: a genome wide association study
Lancet Neurol
(2010) - et al.
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p-21 linked ALS-FTD
Neuron
(2011) - et al.
Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering
Am J Hum Genet
(2007) - et al.
Voxel-based morphometry-the methods
Neuroimage
(2000) - et al.
The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III)
J Neurol Sci
(1999) - et al.
Neural correlates of distance and congruity effects in a numerical Stroop task: An event-related fMRI study
Neuroimage
(2005) - et al.
A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study
Lancet Neurol
(2012) - et al.
The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study
J Neurol Neurosurg Psychiatry
(2011) - et al.
A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia
Neurology
(2006)