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 epidemiologic 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 ϭ 0.001), and age at onset Յ54 years (odds ratio 1.79; p ϭ 0.012). Conclusions:We have found that ϳ11% of patients with ALS carry a genetic mutation, with 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] Several studies have assessed the frequency of mutations of single genes, 11 but few studies have compared relative frequencies of SOD1, TARDBP, ANG, ; 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

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.…”

Molecular Structure of Amyotrophic Lateral Sclerosis in Russian Population

“…Также в данном исследовании в 1,05 % случаев были обнару-жены мутации в гене ANG и в 0,35 % -в гене DCTN1. Выявленные нами частоты мутаций для вышеназван-ных генов сопоставимы с таковыми для других евро-пейских популяций [19,20].…”

Amyotrophic Lateral Sclerosis

“…Currently, therefore, the cutoff value of 30 should be used with caution [35,36]. Anticipation is also being investigated in C9orf72, as occurrence of earlier ages of onset in subsequent generations has been reported, but the significance has not been proven [37].…”