Myopathy, Autophagic Vacuolar, Infantile-Onset
Description
Infantile-onset autophagic vacuolar myopathy is characterized by increased cardiac and skeletal muscle glycogen with normal acid maltase (GAA; 606800). Skeletal muscle biopsy shows characteristic intracytoplasmic vacuoles that stain for sarcolemmal proteins and complement proteins.
Similar pathologic findings are seen in Danon disease (300257), caused by mutation in the LAMP2 gene (309060) on chromosome Xq24, and X-linked myopathy with excessive autophagy (XMEA; 310440), which has been mapped to Xq28.
Clinical FeaturesAtkin et al. (1984) described fatal infantile cardiac glycogenosis without acid maltase deficiency in a male hydropic newborn.
Verloes et al. (1997) reported a boy with infantile onset of lethal hypertrophic vacuolar cardiomyopathy. The unrelated parents were unaffected. He showed severe neonatal hypotonia and died on day 41 of massive hypertrophic cardiomyopathy. Abnormal intra- and extralysosomal glycogen storage disease was demonstrated in heart and skeletal muscle. Glycogen content was twice normal in muscles and over 3-fold normal in the heart. In the heart, over 50% of the intracellular space was occupied by glycogen and possibly oligosaccharides, as demonstrated by quantitative morphometric analysis of electron micrographs. The activity of acid alpha-glucosidase was increased in the heart, skeletal muscles, and liver, but was normal in leukocytes. Verloes et al. (1997) considered their case to be different from Danon disease.
Morisawa et al. (1998) described a male infant with cardiomyopathy, generalized muscle weakness, and increased serum creatine kinase levels. Muscle biopsy revealed myopathic changes with tiny intracytoplasmic vacuoles containing PAS-positive material and high acid phosphatase activity, but normal acid maltase activity. Electron microscopy showed autophagic vacuoles without sarcolemmal indentation. Immunohistochemistry showed reactivity to complement proteins C5b-9 on the surface of abnormal muscle fibers. The patient, who required respirator support, died at 27 months of age from pneumonia and hypertrophic cardiomyopathy. There was no family history of similar disorders. Morisawa et al. (1998) suggested that this was an infantile form of Danon disease.
Yamamoto et al. (2001) further characterized the cases reported by Verloes et al. (1997) and Morisawa et al. (1998). Skeletal muscle biopsies showed scattered muscle fibers with tiny intracytoplasmic vacuoles. Immunostaining for complement proteins C5b-9 of the membrane attack complex was seen in muscle sarcolemma of 1 patient and within the cytoplasmic vacuoles of the other patient. Electron microscopy of 1 patient showed that the vacuoles contained membrane-bound glycogen particles, free glycogen particles, and cytoplasmic degradation products. Multilayered basal lamina was seen at some areas of the sarcolemma, but there were no sarcolemmal indentations. Both infants had normal LAMP2 protein in skeletal muscle tissue and no mutations in the LAMP2 gene, thus excluding Danon disease. Yamamoto et al. (2001) concluded that this infantile disease is pathogenically similar to X-linked myopathy with excessive autophagy.