Clinical Profile of Cardiac Involvement in Danon Disease

Abstract

Background - The X-linked Danon disease (DD) manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease (DD) in cardiomyopathy centers throughout Europe. Methods - Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results - The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 yr. in males and 2-65 in females. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in males but not in females. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of males (who had LVEF 34±11%) and 59% of females (LVEF 28±13%). The risk of arrhythmia and heart failure (HF) were comparable among genders. The age of first HF hospitalization was lower in males (18 ± 6 vs. 28 ±17 yr., p<0.003). HF was the leading cause of death (10/17, 59%), and LV systolic dysfunction predicted an adverse outcome. Eight males and 8 females (28%) underwent heart transplantation or received a left ventricular assist device (LVAD). Our cohort suggests better prognosis of female compared to male heart transplant recipients. Conclusions - DD presents earlier in males than females and runs a malignant course in both genders, due to cardiac complications. Cardiomyopathy features: heart failure and arrhythmia, are similar among the genders. Clinical diagnosis and management is extremely challenging in females due to phenotypic diversity and absence of extracardiac manifestations.

Sex‐Related Differences in Genetic Cardiomyopathies

“…However, because of its X‐linked nature and the hemizygous male status, DD arises 1 to 2 decades earlier in men, with onset typically by adolescence. 45 , 46 , 47 Women have far less common extracardiac manifestations than men, making the clinical diagnosis challenging and often delayed in the absence of family history or genetic testing. 45 , 47 , 48 DD cardiomyopathy is typically rapidly progressive.…”

Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy

“…This patient did not have extra-cardiac findings of Danon disease at the time of the last follow-up at age 15 years. While this may reflect incomplete penetrance of extra-cardiac findings, studies have reported that extra-cardiac manifestations can be absent or delayed in those with secondary CMP, including those with Danon disease 27 . This reflects our rationale for including secondary CMP genes and also Tier 2 genes in our study since variants in these genes can contribute to the cardiac phenotype 28 , 29 .…”

Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes

“…In particular, among the 57 patients evaluated (30 males and 27 females), 53% had a heart failure hospitalization, 27% underwent heart transplantation or received an LV assist device, and 30% of patients died during follow-up. Moreover, in this cohort, SCD occurred in three female patients, and appropriate implantable cardioverter-defibrillator (ICD) interventions for ventricular tachycardia/fibrillation were evidenced in six patients, underlying the high risk of SCD in this population (98).…”

“…Heart failure and arrhythmia constitute the leading cause of morbidity and mortality in patients with Danon disease. Recently, data from a multicenter European registry have shown that Danon disease runs a malignant course in both genders, due to cardiac complications (98). In particular, among the 57 patients evaluated (30 males and 27 females), 53% had a heart failure hospitalization, 27% underwent heart transplantation or received an LV assist device, and 30% of patients died during follow-up.…”