Novel LAMP-2 Mutation in a Family With Danon Disease Presenting With Hypertrophic Cardiomyopathy

Abstract

Danon disease is an X-linked dominant multisystem disorder that includes hypertrophic cardiomyopathy with skeletal myopathy, and results from mutations in the gene encoding the lysosome-associated membrane protein-2 (LAMP-2). To date, over 20 different mutations in LAMP2 have been identified. Three members of a family, a male proband (18 years old) and 2 sisters (15 and 20 years old) were studied. Their mother had been diagnosed with dilated cardiomyopathy at the age of 39 years, and died from advanced heart failure at the age of 43 years. The proband developed marked concentric hypertrophy at the age of 5 years and DNA analyses revealed a novel hemizygous frameshift mutation (c.573delA) in exon 5. The 2 affected sisters were also heterozygous for the same mutation. Functional analyses of this novel LAMP2 mutation are mandatory.

Danon disease: focusing on heart

“…2 Although apparently rare, the geographic distribution of Danon disease is wide, reported from the USA, Italy, Australia, Sweden, the UK, Japan and China. [3][4][5][6][7][8][9][10][11] The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in cardiac ( Figure 1) and skeletal muscle cells. 1, 12 The final diagnosis is based on the genetic analysis of LAMP2 gene.…”

Hypertrophic Cardiomyopathy with Unusual Extensive Scarring Pattern: Danon Disease

“…Endomyocardial biopsy and genetic analysis can confirm the diagnosis. [4][5][6][7] This report demonstrates the clinical value of CMR for the diagnostic work-up of Danon disease, with diagnostic confirmation by endomyocardial biopsy and genetic analysis.…”

Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy

“…For instance, in skeletal muscle biopsies, an accumulation of vacuolar structures are consistently found; these contain acetylcholine esterase, proteins of the sarcolemma (the muscle fiber cell membrane) and extracellular matrix proteins (typically those of the basal lamina, such as dystrophin, laminin and spectrin) (Dougu et al, 2009;Endo et al, 2015;Yang and Vatta, 2007), and are known as autophagic vacuoles with unique sarcolemmal features (AVSFs). AVSFs should be located near the peripheral sarcolemma if they are sarcolemma-derived but, because they are instead found scattered throughout the cytoplasm, it is thought that these AVSFs are generated through a poorly understood de novo biogenesis process (Endo et al, 2015).…”

“…AVSFs should be located near the peripheral sarcolemma if they are sarcolemma-derived but, because they are instead found scattered throughout the cytoplasm, it is thought that these AVSFs are generated through a poorly understood de novo biogenesis process (Endo et al, 2015). Disease-associated skeletal muscle vacuoles have also been reported to accumulate glycogen (Bertini et al, 2005;He et al, 2014;Yang and Vatta, 2007), degenerating mitochondria (Yang and Vatta, 2007), lipids (Bertini et al, 2005) and basophilic granules (implicating buildup of lysosomal organelles in the myofibers) (He et al, 2014;Sugie et al, 2005;Endo et al, 2015;Dougu et al, 2009), and to express increased levels of LC3 and ubiquitin (Endo et al, 2015).…”