Identification of Two Novel LAMP2 Gene Mutations in Danon Disease

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 1 case, were investigated. Genetic screening included direct sequencing of the whole coding sequence of the LAMP2 gene. Results Genetic analysis identified 2 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 8 mutation carriers, with 4 nonpenetrant cases and 3 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 male than in female patients (28 ± 7 vs 42 ± 25 years). A high prevalence of arrhythmias or conduction abnormalities was also observed. Conclusions The reported 2 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.