Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and other VMA21-related disorders.

Abstract

X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disorder caused by mutations in the VMA21 gene, encoding a chaperone protein present in the endoplasmic reticulum (ER). In yeast and human, VMA21 has been shown to chaperone the assembly of the vacuolar (v)-ATPase proton pump required for the acidification of lysosomes and other organelles. In line with this, VMA21 deficiency in XMEA impairs autophagic degradation steps, which would be key in XMEA pathogenesis. Recent years have witnessed a surge of interest in VMA21, with the identification of novel mutations causing a congenital disorder of glycosylation (CDG) with liver affection, and its potent implication in cancer predisposition. With this, VMA21 deficiency has been further linked to defective glycosylation, lipid metabolism dysregulation and ER stress. Moreover, the identification of two VMA21 isoforms, namely VMA21-101 and VMA21-120, has opened novel avenues regarding the pathomechanisms leading to XMEA and VMA21-CDG. In this review, we discuss recent advances on the clinical spectrum associated with VMA21 deficiency and on the pathophysiological roles of VMA21.