A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy.

Mutations in heat shock protein B8 were initially identified in inherited neuropathies and were more recently found to cause a predominantly distal myopathy with myofibrillar pathology and rimmed vacuoles. Rare patients also had proximal weakness. Only very few pathogenic variants have been identified in HSPB8. Disruption of the chaperone activity of heat shock protein B8 impairs chaperone-assisted selective autophagy and results in protein aggregation. We report a 23-year-old patient who presented with a 4-year history of predominantly proximal lower limb weakness due to a novel variant in HSPB8. The creatine kinase level was mildly elevated. Electrodiagnostic studies demonstrated a proximal-predominant myopathy without evidence of neuropathy, and muscle histopathology revealed rimmed vacuoles and myofibrillar protein aggregates. Whole exome sequencing identified a de novo frameshift variant in the C-terminal region of HSPB8 (c.577_580dupGTCA, p.Thr194Serfs*23). This case demonstrates that HSPB8-related disorders can present with early onset limb-girdle myopathy without associated neuropathy.