Atypical familial amyotrophic lateral sclerosis with initial symptoms of pain or tremor in a Chinese family harboring VAPB-P56S mutation

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.