Danon disease: intrafamilial phenotypic variability related to a novel LAMP‐2 mutation

Abstract

Danon disease is an X-linked lysosomal disorder, characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation. We report a family with a novel mutation, in which the mother and her three sons were affected with various clinical presentations. A massive hypertrophy of the left ventricle was the predominant feature in the three male patients, with different degrees of severity of cardiac symptoms, from isolated palpitations to cardiac failure and sudden death. Muscle pain and weakness were also variable, but constantly associated with increased plasma CK levels. Finally, the male patients had variable degree of a mental retardation. The mother had an attenuated phenotype, limited to a mild hypertrophic cardiomyopathy with premature ventricular contractions diagnosed during her 40's. Microscopy examination of skeletal muscle biopsy, performed in the youngest patient, demonstrated atrophic myofibers with intracytoplasmic vacuoles suggesting lysosomal glycogen storage disease. Immunohistochemistry analyses in muscle specimen showed no detectable Lysosomal-Associated Membrane Protein-2 (LAMP-2), in keeping with the diagnosis of Danon disease. However, a very low expression of a shortened LAMP-2 protein could be evidenced by Western-blot in the patient's fibroblasts. Molecular investigations identified a novel splicing mutation (IVS6 + 1delG) in the LAMP-2 gene. This case report highlights the intrafamilial variability of Danon disease phenotype. In this case, morphological examination of muscle biopsy, showing lysosomal storage myopathy, and immunohistochemistry analyses can provide key elements for orienting etiologic investigations.

Danon disease as a cause of concentric left ventricular hypertrophy in patients who underwent endomyocardial biopsy

“…Maron et al 9 reported that six of seven Danon disease patients were boys with a median age of 14 years, and six patients were with WPW syndrome and deeply inverted T-waves at diagnosis. Furthermore, all the three patients had markedly elevated serum hepatic enzymes and CK concentrations, consistent with previous studies by Yang et al, 7 Maron et al, 9 Cottinet et al, 10 Balmer et al, 11 and Morisawa et al…”

Review: Danon disease: Review of natural history and recent advances

“…In most patients, the first symptoms were heart murmurs , chest pain , palpitations or easy fatigability . Syncopal episodes in young patients were frequent (40% of cases) .…”

“…At echocardiography, the cardiomyopathy typically manifested as a concentric LV hypertrophy , with preserved ejection fraction, especially in childhood , but later progressed to a dilated pattern. DCM occurred in 10–33% of cases .…”

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.…”