Identification of Two Novel Lamp2 Gene Mutations In Danon Disease

Abstract Background Danon disease is a rare X-linked inherited disorder characterized by massive left ventricular hypertrophy, skeletal muscle dystrophy and mental retardation. The disease is caused by mutations in the LAMP2 gene encoding for lysosome-associated membrane protein-2. Methods Two young male patients with hypertrophic cardiomyopathy, characterized by marked, concentric left ventricular hypertrophy, elevated levels of creatine kinase, and manifest limb-girdle muscular dystrophy in one case, were investigated. Genetic screening included direct sequencing of the whole coding sequence of the LAMP2 gene. Results Genetic analysis identified two novel LAMP2 gene mutations. In Family A, a G-A transition (c.962G>A) leading to a nonsense mutation at codon 321 (p.Trp321Ter); and in Family B, a one-nucleotide insertion (c.973insC) leading to a full frame-shift (p.Pro324+24X) was detected in exon 8 of the LAMP2 gene. Family screening identified eight mutation carriers, with four non-penetrant cases and three additional, probably affected family members without DNA diagnosis. The cardiac phenotype was hypertrophic cardiomyopathy in all cases, including female mutation-carriers. Five disease-related deaths occurred in the families, at an average age of 33±16 years, which was clearly lower in males than in females (28±7 vs. 42±25 years). A high prevalence of arrhythmias or conduction abnormalities was also observed. Conclusions The reported two novel LAMP2 gene mutation carrier families, one of them being one of the largest reported to date, highlight the malignant clinical course of Danon disease, characterized by a high rate of disease-related death at an early age and a high prevalence of arrhythmias or conduction abnormalities.