G.P.233: Mutated HSPB8 causes both neurogenic and myopathic disease with muscle proteinopathy

Small heat-shock protein-beta 8 (HSPB8) belongs to the superfamily of small heat-shock proteins that act as stress proteins with chaperon-like activity in the cells. Missense mutations in a gene encoding HSPB8 protein have been associated with neuromuscular diseases: distal hereditary motor neuropathy 2A (dHMN2A) and Charcot–Marie–Tooth disease (CMT2L). Mutations located in the α-crystallin domain of HspB8 cause decreased chaperone-like activity and incomplete clearance of aggregated proteins. We identified the same mutation (c.421A > G p.K141E) that has earlier been associated to dHMN2A and CMT2L diseases in a family clinically classified as a distal myopathy. In addition, we identified a new mutation, c.515insC p.P173SfsX43, in another distal myopathy family. Thorough clinical, electrophysiology, imaging and pathology examinations show that the HSPB8 mutations in these families lead to both motor neuropathic as well as myopathic changes accounting for the distal presentation. The pathological changes in the muscle were characterized by both neurogenic findings and myofibrillar myopathy with autophagic rimmed vacuoles. The extensive immune histochemical and immunofluorescence muscle pathology studies in this chaperonopathy will be presented together with muscle imaging