Danon disease is an X-linked disorder clinically characterized by the triad of
hypertrophic cardiomyopathy,
myopathy, and
intellectual disability.
Cardiomyopathy is a severe and life-threatening problem, for which
cardiac transplantation is the only therapeutic option. The most striking finding in muscle biopsy samples is small basophilic granules scattered in myofibers, which are in fact small autophagic vacuoles surrounded by membranes with sarcolemmal features characterized by the recruitment of sarcolemmal
proteins and
acetylcholine esterase and by the presence of basal lamina on its
luminal side. The mechanism underlying the formation of these autophagic vacuoles with unique sarcolemmal features (AVSF) still remains a mystery and its origin is unknown. In heart, cardiomyocytes show dramatically increased vacuolation and degenerative features, including myofibrillar disruption and
lipofuscin accumulation. In brain, pale granular neurons and neurons with
lipofuscin-like granules may be seen.
Danon disease is caused by loss-of-function mutations in the LAMP2 gene, which encodes
lysosome-associated membrane protein 2 (LAMP-2), a single-spanned transmembrane
protein localized in the limiting membranes of lysosomes and late endosomes. Most mutations lead to splicing defects or
protein truncation, resulting in a loss of transmembrane and/or cytoplasmic domains, leading to LAMP-2
protein deficiency. LAMP-2 is required for the maturation of autophagosomes by fusion with lysosomes; therefore, LAMP-2 deficiency leads to a failure in macroautophagy. There are three LAMP-2
isoforms, LAMP-2A, -2B, and -2C. Clinical features of
Danon disease are thought to be mediated by loss of the LAMP-2B
isoform which is the major
isoform expressed in muscle. It is also known that LAMP-2 plays a role in chaperone-mediated autophagy and
RNA- and
DNA-targeting autophagy. However, the precise pathophysiological mechanism through which LAMP-2 deficiency causes
Danon disease is still not fully understood and its elucidation would promote the development of new
therapies.