Clinical, morphological, and molecular characterization of patients with X-linked myopathy with excessive autophagy (XMEA)

X-linked myopathy with excessive autophagy (XMEA) is a slowly progressive disease affecting male patients, caused by hemizygous mutations in the VMA21 gene. We studied nine patients from six unrelated French families clinically suspected of having XMEA. Clinical charts were reviewed, and muscle biopsies underwent histological, immunohistochemical, and electron microscopy analysis. Sanger sequencing and next generation VMA21 gene panels were performed, and proteomic profiling was done on muscle extracts from two patients. Clinical onset ranged from childhood to adulthood with most showing proximal lower limb weakness and mild creatine kinase elevation. Three patients had cardiac and respiratory involvement. Muscle biopsies revealed cytoplasmic vacuoles, split fibers, internalized nuclei and variable fiber sizes. Vacuoles stained positively for sarcolemmal and autophagic proteins, as well as for complement C5b-9. Ultrastructural analysis showed basal lamina duplication, subsarcolemmal vacuoles, and extensive autophagosome extrusion. Proteomic analysis revealed complement activation, impaired proteolysis, and mitochondrial/cytoskeletal vulnerabilities. Biglycan and thrombospondin-4 were identified as potential novel diagnostic markers. Molecular studies found two known pathogenic variants (c.164-7T>G and c.163 + 4A>G) and a novel 3'UTR variant (c.*124A>G) in VMA21. This study expands the clinical spectrum of XMEA by reporting adult-onset cases, a novel mutation, and highlights the value of proteomics in understanding the pathophysiology of XMEA.