Danon Disease: Clinical Presentation and Diagnostic Workup in a Case of a Male Patient with a Novel Mutation in the LAMP2 Gene

Background/Purpose: Danon disease (DD) is a rare X-chromosome linked disorder caused by mutations in the gene encoding lysosomal-associated membrane protein 2 (LAMP2). The main clinical manifestations in male patients are cardiomyopathy, myopathy and cognitive deficits. The phenotype in X-heterozygous females is milder and variable. Given the rare occurrence of DD, diagnosis is often established late or even retrospectively.

Methods: We describe a male patient and his deceased mother, the latter with known cardiac arrhythmia. The boy presented at an age of 4 years with developmental delay, muscle hypotonia and elevated creatine kinase. An extensive diagnostic work-up was done. After exclusion of other differential diagnoses sequence analysis of the LAMP2 gene yielded a novel point mutation. The missense character of the defect suggested a single amino acid substitution, but further analyses demonstrated introduction of a novel donor splice site and omission of 29 bases from both dominant LAMP2 mRNA isoforms (B and A). Flow cytometry demonstrated complete absence of LAMP2 protein expression in peripheral white blood cells, proving the pathogenic relevance of the mutation. Immunohistochemistry confirmed LAMP2 absence in the skeletal muscle tissue. DD was consequently established through mutation analysis also in tissue of the deceased mother.

Conclusion: It is important to consider DD in boys who present with elevated creatine kinase, (mild) myopathy, and cognitive deficit. The diagnosis can be made easily and noninvasively by flow cytometry in peripheral white blood cells. Timely DD diagnosis is essential for therapeutic interventions including cardioverter implantation or heart transplantation and also for efficient family counseling.