Autophagic vacuolar myopathy (AVM) is an entity defined by the presence of autophagic vacuoles on muscle pathology. There are two emerging categories in AVM in addition to the best characterized
Pompe disease. One is
Danon disease and its related disorders, which are characterized by autophagic vacuoles with unique sarcolemmal features (AVSF). AVSF express virtually all sarcolemmal
proteins, in addition to
acetylcholinesterase, on their vacuolar membranes.
Danon disease is caused by primary deficiency of a
lysosomal membrane protein, LAMP-2. Interestingly, in this disease, the number of AVSF increases as the patients age. Other AVSF
myopathies include
X-linked myopathy with excessive autophagy which is now known to be caused by VMA21 mutations. The other AVM is typified by the presence of rimmed vacuoles, which are actually clusters of autophagic vacuoles on electron microscopy. One of the well known diseases in this group is
distal myopathy with rimmed vacuoles (DMRV), also called
hereditary inclusion body myopathy (HIBM). DMRV is caused by mutations in GNE gene that encode a rate-limiting
enzyme in the
sialic acid biosynthetic pathway. Interestingly, in DMRV model mice,
sialic acid supplementation almost completely precluded the disease phenotype, indicating that decreased
sialic acid is the cause of myopathic phenotype and
sialic acid supplementation can prevent the disease process. Interestingly, both genetically diagnosable AVSF
myopathies are primarily due to lysosomal dysfunctions. In contrast, rimmed vacuoles are secondarily caused by extra-lysosomal defects, such as hyposialylation in DMRV/HIBM, and are formed at later stages of the disease.