title: Atypical familial amyotrophic lateral sclerosis with initial symptoms of pain or tremor in a Chinese family harboring VAPB-P56S mutation.
abstract: Amyotrophic lateral sclerosis (ALS) is the most prevalent fatal motor neuron disease and ~10% of cases are hereditary. Mutations associated with ALS have been identified in more than 20 genes, but ALS type 8 (ALS8), which is caused by mutations in vesicle-associated membrane protein-associated protein B (VAPB), is rare. To date, the dominant missense mutation P56S, which is in the major sperm protein domain of VAPB, has been described in nine families of Portuguese-Brazilian origin and one family of German origin. Here, we report a Chinese family spanning three generations with ALS8 caused by the same VAPB-P56S mutation detected in these cohorts, but which in its initial manifestation displays different features. We also detected a R545Q variant of optineurin (OPTN) in this family and which was previously considered a pathogenic mutation. However, our analysis showed that OPTN-R545Q is benign and that VAPB-P56S accounts for the phenotype. Haplotype tests revealed that VAPB-P56S in the Chinese family has arisen independently from the Brazilian cohorts. To our knowledge, this is the first study to report ALS caused by a VAPB mutation in a Chinese population.
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Chang Chun Street, Beijing, 100053, China.
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Chang Chun Street, Beijing, 100053, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Chang Chun Street, Beijing, 100053, China. dayuwei100@hotmail.com.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Da
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Chang Chun Street, Beijing, 100053, China.
authors.forename: Suobing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Shen
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010146:Pain / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014202:Tremor / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C496748:VAPB protein, human; D033921:Vesicular Transport Proteins
keywords: ALS type 8; Amyotrophic lateral sclerosis; Optineurin; Vesicle-associated membrane protein-associated protein B