James J. Dowling, Steven A. Moore, Hannu Kalimo, Berge A. Minassian

Autophagic vacuolar myopathies (AVMs) are a group of disorders united by shared histopathological features on muscle biopsy that include the aberrant accumulation of autophagic vacuoles. The classic conditions that compose the AVMs include Pompe Disease, Danon Disease and X-linked myopathy with excessive autophagy (XMEA). Other disorders, including acquired myopathies like chloroquine toxicity, also have features of an autophagic myopathy. This review is focused on XMEA, a myopathy with onset of slowly progressive proximal weakness and elevated serum creatine kinase (2× to 20× normal) typically in the first decade of life. However, both late-adult onset and severe, sometimes lethal, neonatal cases also occur. Skeletal muscle pathology is characterized by numerous cytoplasmic autophagic vacuoles, complex muscle fiber splitting with internalization of capillaries, and complement C5b-9 deposition within vacuoles and along the sarcolemma. The autophagic vacuoles have sarcolemmal features. Mutations in the VMA21 gene at Xq28 cause XMEA by reducing the activity of lysosomal hydrolases. The VMA21 protein regulates the assembly of the V-ATPase required to acidify the lysosome. Increased lysosomal pH and poor degradation of cellular debris may secondarily induce autophagy, the net effect being accumulation of autophagolysosomes. The relationship of XMEA to other lysosomal disorders of muscle and potential therapeutic interventions for XMEA are discussed.