FINE-MAPPING THE GENE FOR X-LINKED MYOPATHY WITH EXCESSIVE AUTOPHAGY

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 …