myopathy with excessive autophagy, X-linked

myopathy with excessive autophagy, X-linked

An X-linked recessive disorder (OMIM:310440) of childhood onset characterised by progressive vacuolisation and atrophy of the proximal muscles of the legs, progressing slowly to involve other skeletal muscles over time. The phenotype is due to an increase of lysosomal pH from 4.7 to 5.2, which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids, upregulating the mTOR pathway and mTOR-dependent macroautophagy, resulting in proliferation of large and ineffective autolysosomes that engulf cytoplasm, merge, and cause cytoplasmic vacuolisation. 

Molecular pathology
Caused by defects of VMA21, which encodes a chaperone required for the assembly of lysosomal vacuolar ATPase.