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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by progressive paralysis, leading to death from respiratory failure within 3–7 years. Approximately 5% of the cases are familial in nature, mostly inherited in an autosomal dominant mode. A relatively high rate of concurrence of ALS and multiple sclerosis (MS), a progressive inflammatory disorder of the central nervous system, has recently been reported.1 Interestingly, 80% of these ALS–MS cases were found to carry hexanucleotide repeat expansions in C9ORF72, which is a major ALS gene (found in 37% of familial ALS patients and 6.1% of sporadic ALS patients in the Netherlands2). Repeat expansions in C9ORF72 are also a major cause of frontotemporal dementia and have also been implicated in Alzheimer's disease, Parkinsonism, ataxia and psychosis. It is therefore considered to be a pleiotropic gene and could perhaps also play a role in MS pathogenesis.
The coincidence of ALS and MS is not undisputed. The available studies are mostly case reports or case series and are subject to referral and publication bias. A population based study approach is better to avoid this bias and to determine the relationship between ALS and MS. In a large prospective, population based ALS study in the Netherlands we identified all patients with ALS and MS and subsequently screened them for repeat expansions in the C9ORF72 gene.
Patients were identified from 1 January 2006 to 1 September 2011 in …