Extensive genetics of ALS

Abstract

Objective: To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epide-miologic series of cases. Methods: The study population includes all ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, and C9ORF72 have been assessed. Results: Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p 0.001), and age at onset 54 years (odds ratio 1.79; p 0.012). Conclusions: We have found that 11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease. Neurology ® 2012;79:1983-1989 GLOSSARY ALS amyotrophic lateral sclerosis; bvFTD behavioral variant frontotemporal dementia; CI confidence interval; fALS familial ALS; FTD frontotemporal dementia; OR odds ratio; PARALS Piemonte and Valle d'Aosta register for ALS; sALS sporadic ALS. Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of adult age involving the motor system, with a progressive and invariably fatal course. In 5% of cases it is considered to be genetically transmitted (familial ALS [fALS]) 1,2 while in the remaining cases it occurs sporadically in the population (sporadic ALS [sALS]). Mutations in several genes have been found to cause ALS, namely superoxide dismutase 1 (SOD1), 3 TAR DNA binding protein (TARDBP), 4 angiogenin (ANG), 5 fused in sarcoma (FUS), 6,7 optineurin (OPTN), 8 and the recently described chromosome 9 open reading frame 72 (C9ORF72). 9,10 Several studies have assessed the frequency of mutations of single genes, 11 but few studies have compared relative frequencies of SOD1, TARDBP, ANG, and FUS 11-15 ; all these studies were based on tertiary center series of cases, and were consequently skewed toward a younger population of patients with a larger number of fALS 16 ; moreover, only one of them reported data on C9ORF72, which is now From the ALS Center (A. Chiò, A. Calvo, C.