Integrative genetic analysis illuminates ALS heritability and identifies risk genes.

Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10-03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.

[Epidemiology of amyotrophic lateral sclerosis]. / Épidémiologie de la sclérose latérale amyotrophique. Près de 6 000 cas en France, majoritairement sporadiques et sans facteurs de risque identifiés.

Epidemiology of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is the most common motorneuron disease. The incidence of ALS in France is 2.5/100 000 persons-years of follow-up, or 1,500 cases per year. The peak incidence is between 65 and 75 years. The prevalence of ALS is 8/100 000, or 6 000 cases in France with a sex ratio close to 1. The average survival time is close to 36 months after the onset of symptoms, with a large variation between patients. The main prognostic factors are the age of onset, initial site of involvement, the time to diagnosis, respiratory status and nutritional status. 5 to 10% of cases are family related to a mutation of the four major genes SOD1, FUS, TARDP and C9ORF72. In sporadic forms an interaction between a genetic susceptibility factor and an environmental factor is suspected. There is to date no association between exogenous risk factor for sporadic ALS occurrence of which could be demonstrated reproducibly with the notable exception of smoking.

Épidémiologie de la sclérose latérale amyotrophique. La sclérose latérale amyotrophique est la plus fréquente des maladies du motoneurone. Son incidence en France est de 2,5/100 000 personnes-années, soit 1 500 cas par an. Le pic d'incidence est compris entre 65 et 75 ans. Sa prévalence est de 8/100 000, soit 6 000 cas en France, avec un sex-ratio proche de 1. La durée moyenne de survie est proche de 36 mois après le début des premiers symptômes avec une importante variation selon les patients. Les principaux facteurs pronostiques sont l'âge de début, le siège initial de l'atteinte, le délai diagnostique, le statut respiratoire et l'état nutritionnel. Cinq à 10 % des cas sont familiaux, liés à une mutation des quatre principaux gènes SOD1, FUS, TARDP et C9ORF72. Dans les formes sporadiques, une interaction entre un facteur de susceptibilité génétique et un facteur environnemental est suspectée. Il n'existe à ce jour aucune association entre un facteur de risque exogène et la survenue d'une sclérose latérale amyotrophique sporadique qui ait pu être démontrée de manière reproductible, à l'exception notable du tabagisme qui favoriserait la survenue de la maladie.

[Epidemiology, clinical spectrum of ALS and differential diagnoses]. / Épidémiologie, spectre clinique de la SLA et diagnostics différentiels.

Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disease in adults. Its incidence in France is estimated at 2.5 per 100,000 population and its prevalence between 5 and 8 per 100,000 inhabitants. Good prognostic factors are age of early onset, a longer time to diagnosis, initial damage to the spinal onset, early management of undernutrition and restrictive respiratory failure. The diagnosis of ALS is primarily clinical and is based on the evidence of involvement of the central motor neuron and peripheral neuron (NMP) in different territories or spinal or bulbar. The EMG confirms the achievement of NMP, shows the extension to clinically preserved areas and allows to exclude some differential diagnoses. The clinical spectrum of ALS is broad: conventional forms beginning brachial, lower limb or bulbar onsets, rarer forms to start breathing, pyramidal forms, forms with cognitive and behavioural impairment. In 5-10% of cases, ALS is familial. In 15% of cases, it is associated with frontotemporal degeneration rather than orbito-frontal type. The main differential diagnoses are guided by the clinic: combining pure motor neuropathy with or without conduction block, post-polio syndrome, cramp-fasciculation syndrome, myasthenia gravis, paraneoplastic syndromes, Sjögren syndrome, retroviral infections, some endocrine disorders, some metabolic diseases, genetic diseases (Kennedy and SMA) and inclusion body myositis.