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Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey
P Charron1, E Villard, P Sébillon
1Département de Génétique, Batiment Babinski, Hôpital Pitié-Salpêtrière, 47 Blvd de l'Hôpital, 75856 Cedex 13, Paris, France. pcharron@infobiogen.fr
Insights
Danon disease, an X-linked condition, may mimic hypertrophic cardiomyopathy (HCM). Genetic analysis identified LAMP2 gene mutations in 1% of HCM patients, particularly those with muscle issues, highlighting the need for differential diagnosis.
Area of Science:
- Cardiology
- Genetics
- Rare Diseases
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart condition often caused by sarcomeric gene mutations.
- A significant portion of HCM cases remain genetically unexplained, suggesting other genetic disorders may present similarly.
- Danon disease, an X-linked lysosomal disorder, is a potential mimic of HCM.
Purpose of the Study:
- To investigate the prevalence and diagnostic significance of Danon disease in patients with suspected HCM.
- To differentiate Danon disease from other causes of HCM through genetic analysis.
Main Methods:
- Molecular analysis, specifically direct sequencing of the lysosome associated membrane protein 2 (LAMP2) gene, was performed.
- Fifty index cases with unexplained HCM underwent LAMP2 gene sequencing.
- Patients were screened for mutations in sarcomeric genes and assessed for autosomal dominant inheritance patterns.
Main Results:
- Two novel LAMP2 gene mutations (657C>T and 173_179del) were identified in patients with severe heart failure before age 25.
- Danon disease accounted for 1% of the total HCM population studied (2/197) and 4% of the genetically analyzed cohort (2/50).
- Danon disease was implicated in HCM cases with co-occurring skeletal myopathy but not in isolated HCM.
Conclusions:
- Danon disease should be considered in the differential diagnosis of patients presenting with HCM.
- Distinguishing Danon disease from HCM is crucial due to differences in clinical course, prognosis, inheritance patterns, and genetic counseling.
- A diagnostic strategy incorporating LAMP2 gene analysis is proposed for specific HCM patient subgroups.
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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