Novel Intronic Mutation in Causing Severe Phenotype of X-Linked Myopathy with Excessive Autophagy-Case Report

X-linked Myopathy with Excessive Autophagy (XMEA) is a rare autophagic vacuolar myopathy caused by mutations in the Vacuolar ATPase assembly factor gene; onset usually occurs during childhood and rarely occurs during adulthood. We described a 22-year-old patient with XMEA, whose onset was declared at 11 through gait disorder. He had severe four-limb proximal weakness and amyotrophy, and his proximal muscle MRC score was between 2 and 3/5 in four limbs; creatine kinase levels were elevated (1385 IU/L), and electroneuromyography and muscle MRI were suggestive of myopathy. Muscle biopsy showed abnormalities typical of autophagic vacuolar myopathy. We detected a hemizygous, unreported, intronic, single-nucleotide substitution c.164-20T>A (NM_001017980.4) in intron 2 of the gene. Fibroblasts derived from this patient displayed a reduced level of transcripts (at 40% of normal) and protein, suggesting a pathogenicity related to an alteration of the splicing efficiency associated with an intron retention. This patient with XMEA displayed a severe phenotype (rapid weakness of upper and lower limbs) due to a new intronic variant of , related to an alteration in the splicing efficiency associated with intron retention, suggesting that phenotype severity is closely related to the residual expression of the VMA21 protein.