Sudden Death Associated With Danon Disease in Women

Danon disease is an X-linked systemic disorder characterized by left ventricular hypertrophy, mental retardation, and skeletal myopathy affecting young men. Electrocardiogram usually displays a Wolff–Parkinson–White preexcitation pattern. Less has been reported about the phenotype in women, although later-onset cardiac symptoms have been described. The aim of this study was to expand the knowledge of the phenotype of Danon disease in women. We clinically followed and evaluated with echocardiography, cardiac magnetic resonance imaging (cMRI), and genetic testing a family affected by Danon disease in which 2 men and 6 women showed a severe arrhythmogenic phenotype. Affected family members carried a nucleotide substitution at position 294 in exon 3 (c.294 G → A) that changed a tryptophan residue to a stop codon at position W98X in the lysosome-associated membrane protein 2 (LAMP2) gene. Four women died suddenly (1 aborted) at 37 to 54 years of age. Wolff–Parkinson–White pattern with atrioventricular block was detected in 2 of 6 women. Four had successful pregnancies without symptoms of heart failure. cMRI showed late gadolinium enhancement areas in a clinically healthy woman who was a mutation carrier. Two patients underwent heart transplantation; histology of explanted hearts demonstrated severe interstitial fibrosis, hypertrophic cardiomyocytes with cytoplasmic vacuoles, and myofibrillar disarray. In conclusion, LAMP2 mutation can cause a severe arrhythmogenic phenotype in women that includes a high risk of sudden death. cMRI may be useful in women harboring LAMP2 mutations to permit early detection of cardiac involvement and guide timely considerations of implantable cardioverter–defibrillator therapy. Heart transplantation should be considered at onset of heart failure symptoms owing to rapid progression of the disease. Danon disease is an X-linked systemic disorder characterized by left ventricular hypertrophy, mental retardation, and skeletal myopathy affecting young men. Electrocardiogram usually displays a Wolff–Parkinson–White preexcitation pattern. Less has been reported about the phenotype in women, although later-onset cardiac symptoms have been described. The aim of this study was to expand the knowledge of the phenotype of Danon disease in women. We clinically followed and evaluated with echocardiography, cardiac magnetic resonance imaging (cMRI), and genetic testing a family affected by Danon disease in which 2 men and 6 women showed a severe arrhythmogenic phenotype. Affected family members carried a nucleotide substitution at position 294 in exon 3 (c.294 G → A) that changed a tryptophan residue to a stop codon at position W98X in the lysosome-associated membrane protein 2 (LAMP2) gene. Four women died suddenly (1 aborted) at 37 to 54 years of age. Wolff–Parkinson–White pattern with atrioventricular block was detected in 2 of 6 women. Four had successful pregnancies without symptoms of heart failure. cMRI showed late gadolinium enhancement areas in a clinically healthy woman who was a mutation carrier. Two patients underwent heart transplantation; histology of explanted hearts demonstrated severe interstitial fibrosis, hypertrophic cardiomyocytes with cytoplasmic vacuoles, and myofibrillar disarray. In conclusion, LAMP2 mutation can cause a severe arrhythmogenic phenotype in women that includes a high risk of sudden death. cMRI may be useful in women harboring LAMP2 mutations to permit early detection of cardiac involvement and guide timely considerations of implantable cardioverter–defibrillator therapy. Heart transplantation should be considered at onset of heart failure symptoms owing to rapid progression of the disease.