The expansions of ALS.

Neurology 2012;79:842–843 Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition of upper and lower motor neurons. Clinical presentation is heterogeneous and is usually segregated by site of onset (bulbar vs spinal). Extreme phenotypes with better prognosis include primary lateral sclerosis (PLS) (pure upper motor neuron involvement) and progressive muscular atrophy (PMA) (pure lower motor neuron involvement).1 Although primarily a disorder of the motor system, ALS also has nonmotor features. Cognitive impairment occurs in up to 50% of cases, and 1 patient in 8 develops frank frontotemporal dementia (FTD).2 There is some evidence that ALS and FTD may form part of a disease continuum, with “pure” ALS at one extreme and “pure” FTD at the other. A mendelian inheritance pattern has long been recognized in approximately 5% of ALS cases.3 Candidate gene, and recent genome-wide association studies of sporadic ALS have also identified a number of reproducible susceptibility loci, including a strong signal on chromosome 9p21.4 Using conventional segregation analysis and next generation sequencing of families with ALS and FTD, 2 groups reported an expanded hexanucleotide repeat in the intronic region of a previously unknown gene: C9ORF72.5,6 Disease segregating with the expanded hexanucleotide repeat in the C9ORF72 gene accounted for up to 60% of familial ALS and 10% of sporadic ALS in Finland.6 The article by van Rheenen et al.7 in this issue of Neurology is one of a series of phenotyping studies to characterize the frequency, phenotype, outcome, and clinical relevance of this C9ORF72 hexanucleotide expansion. Using a very large and wellcharacterized population-based cohort, including familial and apparently sporadic cases, they found the hexanucleotide expansion in 37% of all familial ALS, in 6.1% of apparently sporadic ALS, in 1.6% of patients with PMA, and in 0.9% of patients with PLS. Those with the expanded repeat had an earlier age at onset and shorter survival than those without the expansion, and were more likely to have a family history of dementia. A limitation of the study is the absence of detailed cognitive and behavioral information. These findings are similar to other recently reported clinicand population-based studies of the C9ORF72 expanded hexanucleotide repeat.8 The presence of the repeat expansion in a few patients with PMA and PLS is of interest, although not entirely surprising—a PLS phenotype has been reported in familial ALS, and neuropathology studies of PMA demonstrate subclinical upper motor neuron involvement in a sizeable proportion.1 All studies have shown that this repeat expansion accounts for a substantial component of all familial ALS (ranging from 37% to 60%), considerably higher than mutations in SOD1. However, the reported populations have all been of European ancestry and the vast majority of their expansions share a common haplotype at C9p21, suggesting a common founder effect with a distinct geographic distribution.5–8 This is of interest as it may account for some of the geographic differences in ALS distribution and phenotype. The presence of the expanded repeat in those with apparently sporadic ALS presents a conundrum. This is in part because there is no real consensus as to the precise definition of familial ALS.9 The observation that the C9ORF72 repeat expansion is associated with both ALS and FTD strongly indicates that a family history of FTD should also be included as part of the criterion of familial disease. Is the C9ORF72 expansion a game changer? Yes. The existence of the C9ORF72 repeat confirms the heterogeneity of ALS. Clinically there are at least 2 major groups in ALS: those with pure sporadic ALS (no cognitive or behavioral impairment and no reported family history of ALS or FTD) and those with a predominance of executive cognitive impairment and behavioral change.2 A high proportion of the lat-