Recommendations and guidance on the diagnosis and management of Danon disease

ABSTRACT

Introduction: Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy where phenotypic expression varies by sex. It is characterized by severe cardiomyopathy, skeletal myopathy, and cognitive impairment, but can include retinopathy, gastrointestinal, hepatic and pulmonary manifestations.

Areas covered: This review of DD will cover genetics, pathophysiologic mechanisms, clinical characteristics and diagnostics, and management, and synthesizes Danon Disease literature found In PubMed from 2000 to the present. Clinical reviews, outcomes studies, registry data, case series and mechanistic studies and chapters were reviewed.

Expert opinion: DD is caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene which is involved in autophagy. Diagnosis is aided by an x-linked hereditary pattern coupled with clinical history suggesting a cardiomyopathy with multi-organ dysfunction, neurocognitive deficits, myopathy and visual defects. Current treatment trials in DD are lacking and therapeutic decisions are extrapolated from guidelines for hypertrophic and dilated cardiomyopathies. The efficacy of these treatments as well as therapies specific to DD are important areas for research. Natural history studies that can inform therapeutic trial design as well as comparative effectiveness research specific to DD and other cardiomyopathies can bridge critical knowledge gaps in DD therapies.

KEYWORDS:

• Danon disease
• X-linked cardiomyopathies
• genetic cardiomyopathies
• disorders of autophagy

Article highlights

• Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene.

• DD is a multisystemic disorder characterized by the classical triad of severe cardiomyopathy, skeletal myopathy, and cognitive impairment, but can include retinopathy as well as gastrointestinal, hepatic and pulmonary manifestations.

• Differences in phenotypic expression and disease manifestations by gender should guide when cardiac, muscular, cogntive and ophthalmological screening begins, however, given the morbidity and mortality associated with DD, early surveillance is generally recommended.

• DD typically has an aggressive clinical course compared to its phenocopies, and timely referral for heart transplant is important to optimize outcomes.

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Declaration of interest

M Brambatti is a former consultant for Rocket Pharmaceutical. M Taylor is a principal investigator in gene therapy for Danon Disease at Rocket Pharmaceutical. E Adler has stock holdings in Rocket Pharmaceutical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.