Identification of Two Novel LAMP2 Gene Mutations in Danon Disease

Beáta Csányi, Anca Popoiu, Lidia Hategan, Z. Hegedűs, Viktória Nagy, Katalin Rácz, Márta Hogye, László Sághy, B. Iványi, M. Csanády, T. Forster, Róbert Sepp

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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.

Original languageEnglish
JournalCanadian Journal of Cardiology
DOIs
Publication statusAccepted/In press - Nov 25 2015

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Glycogen Storage Disease Type IIb
Mutation
Genes
Hypertrophic Cardiomyopathy
Left Ventricular Hypertrophy
Cardiac Arrhythmias
Lysosome-Associated Membrane Glycoproteins
Limb-Girdle Muscular Dystrophies
Nonsense Codon
Genetic Testing
Creatine Kinase
Codon
Intellectual Disability
Exons
Skeletal Muscle
Nucleotides
Phenotype
DNA

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Identification of Two Novel LAMP2 Gene Mutations in Danon Disease. / Csányi, Beáta; Popoiu, Anca; Hategan, Lidia; Hegedűs, Z.; Nagy, Viktória; Rácz, Katalin; Hogye, Márta; Sághy, László; Iványi, B.; Csanády, M.; Forster, T.; Sepp, Róbert.

In: Canadian Journal of Cardiology, 25.11.2015.

Research output: Contribution to journalArticle

Csányi, Beáta ; Popoiu, Anca ; Hategan, Lidia ; Hegedűs, Z. ; Nagy, Viktória ; Rácz, Katalin ; Hogye, Márta ; Sághy, László ; Iványi, B. ; Csanády, M. ; Forster, T. ; Sepp, Róbert. / Identification of Two Novel LAMP2 Gene Mutations in Danon Disease. In: Canadian Journal of Cardiology. 2015.
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AU - Nagy, Viktória

AU - Rácz, Katalin

AU - Hogye, Márta

AU - Sághy, László

AU - Iványi, B.

AU - Csanády, M.

AU - Forster, T.

AU - Sepp, Róbert

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AB - 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.

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