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. 2004 Aug;90(8):842-6.
doi: 10.1136/hrt.2003.029504.

Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey

P Charron  1 , E Villard, P Sébillon, P Laforêt, T Maisonobe, L Duboscq-Bidot, N Romero, V Drouin-Garraud, T Frébourg, P Richard, B Eymard, M Komajda
Affiliations

Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey

P Charron et al. Heart. 2004 Aug.

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric genes. However, extensive genetic screening failed to identify a mutation in about a third of cases. One possible explanation is that other diseases, caused by other genes, may mimic HCM.

Objective: To investigate the possible involvement of Danon's disease, an X linked lysosomal disease, in a large population of patients with HCM.

Methods: A population of 197 index cases was considered; 124 were subsequently excluded because of a mutation in sarcomeric genes and 23 because of autosomal dominant inheritance. Fifty index cases were therefore included in molecular analysis (direct sequencing) of the lysosome associated membrane protein 2 (LAMP2) gene responsible for Danon's disease.

Results: Two new mutations leading to premature stop codons were identified in patients who evolved towards severe heart failure (< 25 years old): 657C>T and 173_179del. The prevalence was therefore 1% of the total population (two of 197) or 4% of enrolled index cases (two of 50). Interestingly, Danon's disease was responsible for half of the cases (two of four) with HCM and clinical skeletal myopathy but was not involved in isolated HCM (none of 41).

Conclusions: Danon's disease may be involved in patients with previously diagnosed as HCM. A diagnosis strategy is proposed. To distinguish HCM from Danon's disease is important because the clinical evolution, prognosis, mode of inheritance, and therefore genetic counselling are very different.

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Figures

Figure 1
Figure 1
Population evaluated in the study. HCM, hypertrophic cardiomyopathy.
Figure 2
Figure 2
Results of genetic sequencing with two mutations identified in the lysosome associated membrane protein 2 (LAMP2) gene. Sequence electrophoregrams representative of a control DNA sample (wild type allele) or of patient 1, a C>T substitution in exon 4 at position 657 of the gene creating a premature stop codon (TAA, boxed); or of patient 2, a 7 bp deletion (boxed sequence) at position 173_179del in exon 1 leading to a change in reading frame and a premature stop codon.
Figure 3
Figure 3
Pedigrees of families A and B. Black symbol, affected subject; white symbol, unaffected subject; shaded symbol, borderline status; slashed symbol, deceased member; 0 absence of a mutation; mut. + presence of a mutation; NA data not available.
Figure 4
Figure 4
Skeletal muscle biopsy. (A, C, E) Normal sections; and (B, D, F) sections from the patient. All sections were analysed with a 60× oil objective lens, except image B, with 40×. (A, B) Light microscopy (Gomori trichrome stain). Presence of multiple small vacuoles in some fibres. (C, D) Immunohistochemistry with LAMP2 antibodies. (E, F) Immunohistochemistry with dystrophin antibodies.
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