Background: We previously reported two brothers with X-linked congenital autophagic vacuolar myopathy (XcAVM) whose muscle biopsy showed autophagic vacuoles with sarcolemmal features, multilayered basal lamina, MAC deposition in the sarcolemma, similarly to X-linked myopathy with excessive autophagy (XMEA) which is a childhood-onset disease characterized by slowly progressive muscle weakness without other organ involvement. Recently, XMEA was shown to be caused by hypomorphic VMA21 mutations. VMA21 protein is the principal human assembly chaperone of the V-ATPase, the cell’s organelle-acidification pump complex. Objective: To clarify whether XcAVM is also due to VMA21 mutation and whether VMA21 mutation affects non-muscle organs. Patients: The two boys presented severe hypotonia and respiratory failure at birth. Seven maternal male relatives had similar symptoms and five died in infancy. Their motor development milestones were delayed. Although they could walk at age 2 years, they became wheelchair bound by age 5 years. They required nocturnal non-invasive positive pressure ventilation at age 14 years. Presently, they have severe muscle atrophy, scoliosis, and deformity of lower extremities. Results: We identified c.164-6T>G substitution in intron 2 in VMA21, indicating that XcAVM is allelic to XMEA. We evaluated the functions of non-muscle organs such as kidney, stomach, inner ear, and bone where V-ATPase is known to be expressed and thought to have physiological roles. Bone mineral density (BMD) was extremely reduced and bone turnover markers were elevated. However, urinary and gastric pH, and auditory brain-stem response (ABR) were normal. Conclusion: Not only XMEA but also XcAVM is due toVMA21 mutation and thus XcAVM is a severe congenital form of XMEA. Osteoporosis was a puzzling finding as a defect in V-ATPase would be expected to result in osteopetrosis. Peculiar bone involvement in XcAVM may not be simply explained by the dysfunction of V-ATPase in osteoclasts.

Myopathies with autophagic vacuoles with sarcolemmal features (MAVSF) are a group of skeletal muscle diseases exhibiting autophagic vacuolation of myofibers. The vacuoles have membranes of mixed sarcolemmal, lysosomal, and autophagosomal origin. They contain partially degraded cell components including proteins, glycogen, membrane whorls, and organelles.1 The two most common MAVSF are Danon disease and X-linked myopathy with excessive autophagy (XMEA). Danon disease is caused by mutations in the LAMP2B isoform of the lysosome-associated membrane protein-2 ( LAMP2 ) gene.2 LAMP2B may play a role in approaching lysosomes to merge with autophagosomes.1 The genes for XMEA and the other MAVSF are unknown. We previously mapped the XMEA gene to chromosomal band Xq28, one of the most gene-rich regions of the genome, in a 4.64 Mb locus containing over 110 genes.3 We now refine this locus to 0.58 Mb containing only six genes. XMEA is inherited recessively, affecting boys and sparing carrier females. Onset is between ages 6 and 18 years with weakness and gradual wasting of the proximal muscles of the lower extremities. Other skeletal muscle groups are progressively affected including the upper limb girdle and distal muscles. Patients are wheelchair-bound in their 50s, and lifespan appears to be shortened due to respiratory muscle involvement. Considerable variation from this clinical picture can be seen, with some patients exhibiting extremely mild and sometimes no weakness or wasting (see below). The central and …

X-linked myopathy with excessive autophagy (XMEA) (MIM 310440) is an X-linked recessive boyhood-onset disorder of skeletal muscle with a slowly progressive course toward wasting of proximal muscles of the lower extremities and wheelchair dependency by the fifth decade of life. Involvement of distal leg muscles and upper extremities is clinically evident late in the disease.1–4 Skeletal muscle pathology is characterized by a constellation of rare and unique features. Autophagic vacuoles containing cellular debris are present in the sarcoplasm, and at the sarcolemma extruding their contents to the extracellular space. Myofibers containing vacuoles have multiple layers of basement membrane. Intense calcium accumulation is seen at the myofiber periphery, in the absence of necrosis. Extensive deposition of complement membrane attack complex (MAC) is present at the myofiber surface, without resultant cell lysis. Finally, class I major histocompatibility complex is expressed, despite the absence of inflammation.1–4 Nerve conduction studies (NCS) are normal but …

Nat. Genet. 36, 339–341 (2004). In the bottom half of Figure 1b, the second EST is a mouse Mecp2B EST (BU517697; IMAGE 6515311).