Danon disease presenting with dilated cardiomyopathy and a complex phenotype.

Area of Science:

• Genetics
• Cardiology
• Neurology

Background:

• X-linked dilated cardiomyopathy (XLCM) was initially linked to dystrophin gene (DMD) mutations.
• A second family (XLCM-2) with XLCM lacked identified DMD mutations, necessitating further investigation.
• Danon disease, a lysosomal glycogen storage disorder, presents with a variable phenotype.

Purpose of the Study:

• To investigate the genetic cause of XLCM in the XLCM-2 family.
• To characterize the full clinical spectrum of Danon disease in this family.
• To establish diagnostic criteria for Danon disease presenting as XLCM.

Main Methods:

• Long-term clinical follow-up of the XLCM-2 family.
• Genetic analysis of the lysosome-associated membrane protein-2 (LAMP-2) gene.
• Review of cardiac biopsy findings in affected individuals.

Main Results:

• A novel LAMP-2 gene mutation was identified in the XLCM-2 family, confirming Danon disease.
• The family exhibited a broad phenotype including dilated/hypertrophic cardiomyopathy, pre-excitation, skeletal myopathy, cognitive impairment (males), and retinopathy (females).
• Cardiac biopsy in a young male showed no vacuolization, highlighting potential diagnostic challenges.

Conclusions:

• XLCM can be the primary manifestation of Danon disease.
• Familial history of hypertrophic cardiomyopathy, pre-excitation, skeletal myopathy, or retinopathy warrants LAMP-2 gene testing.
• Absence of vacuolar myopathy in early biopsies does not rule out Danon disease.