Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research.
Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve 49: 786-803, 2014.
Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Xiaowei W
XW
Su
James R
JR
Broach
James R
JR
Connor
Glenn S
GS
Gerhard
Zachary
Z
Simmons
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D035843:Biomedical Research / Q000639:trends*; D004358:Drug Therapy; D057890:Epigenomics; D018740:Genetic Heterogeneity; D006801:Humans; D009154:Mutation / Q000235:genetics; D010818:Practice Patterns, Physicians' / Q000639:trends*; D011379:Prognosis
amyotrophic lateral sclerosis; clinical trials; genetics; genomics; personalized medicine