Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Communiquer avec une sclérose latérale amyotrophie: comparaison d'un système de Brain Computer Interface et d'un système d'eye tracker

National audienc

Evaluation of the application of the European guidelines for diagnosis and clinical care of Amyotrophic Lateral Sclerosis.

International audienceObjective: To evaluate the degree of application of the recommendations edited by the European Academy of Neurology (EAN) on the management of amyotrophic lateral sclerosis (ALS) in clinical practice. Background: The management of ALS is based on a multidisciplinary approach led by guidelines published by scientific communities. The EAN published guidelines in 2005 and 2012. Methods: Multicenter cross-sectional observational study involving six French ALS-referral centers and including prevalent and incident cases. Good practice points were translated into ad-hoc questions referring to key steps in the management. The application was evaluated by an independent clinical research assistant who examined the medical charts (MCs). When needed, an independent board-certified neurologist was in charge of answering the questions based on the examination of MCs and interview of the caring neurologist. Questions regarding diagnosis and communication were asked to patients through a self-administered questionnaire. Results: We included 376 ALS patients (176 incident, 200 prevalent cases). Median age at diagnosis was 62.8 years (IQR 55.7-72.3) and the sex-ratio was 1.37. A bulbar onset was present in 27.3[percnt] of cases. We evaluated all the topics covered in the EAN guidelines: diagnosis delay (e.g.mean 13.6 months, associated with age and onset), breaking the news (e.g.in more than 90[percnt], satisfaction of criteria for communication quality), multidisciplinary and sustained support (e.g.in 90[percnt], clinic visits scheduled at every 2-3 months), riluzole (e.g.offered and safety monitored in all patients), symptom management, genetic testing, ventilation, troubles of communication, enteral nutrition, and palliative and end-of-care. We also identified characteristics associated with poor compliance to guidelines. Conclusion: This is the first time for ALS clinicians to evaluate the application of the EAN recommendations for the management of ALS. This work will also allow us to propose (i) eventual modifications of impractical recommendations and (ii) sources of improvement for caring neurologists

Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: The TUDCA-ALS trial protocol

Background: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects. Methods: The TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers. Conclusion: This trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care