Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease)

"Lysosomal glycogen storage disease with normal acid maltase'', which was o riginally described by Danon et al.(1), is characterized clinically by card iomyopathy, myopathy and variable mental retardation. The pathological hall mark of the disease is intracytoplasmic vacuoles containing autophagic mate rial and glycogen in skeletal and cardiac muscle cells. Sarcolemmal protein s and basal lamina are associated with the vacuolar membranes(2,3). Here we report ten unrelated patients, including one of the patients from the orig inal case report(1), who have primary deficiencies of LAMP-2, a principal l ysosomal membrane protein. From these results and the finding that LAMP-2-d eficient mice manifest a similar vacuolar cardioskeletal myopathy, we concl ude that primary LAMP-2 deficiency is the cause of Danon disease(4). To our knowledge this is the first example of human cardiopathymyopathy that is c aused by mutations in a lysosomal structural protein rather than an enzymat ic protein.