Prevalence and clinical characteristics of Danon disease among patients with left ventricular hypertrophy and concomitant electrocardiographic preexcitation

Abstract

Background Cardiac involvement in Danon disease typically manifests as left ventricular hypertrophy (LVH) and ventricular preexcitation. This study aimed to identify patients with Danon disease among patients with LVH and concurrent electrocardiographic preexcitation. Methods Electrocardiographic preexcitation was identified in 10 of 197 patients with unexplained LVH in whom genetic testing was performed using next‐generation sequencing. Results Three (3/10, 30%) patients with Danon disease were found in association with different mutations in the gene of lysosome‐associated membrane protein 2 ( LAMP2 ). Compared to seven patients without Danon disease, these three patients presented with distinctive clinical phenotypes, including onset at an earlier age (20 ± 2 years vs. 53 ± 9 years, p < 0.001), more neurological involvements (100% vs. 0, p = 0.008), higher electrocardiographic voltages (10 ± 1 mV vs. 5 ± 1 mV, p < 0.001), wider QRS complexes (163 ± 5 ms vs. 115 ± 20 ms, p = 0.006), less common asymmetric hypertrophy (0% vs. 86%, p = 0.033), and more frequent elevation of three serum enzymes (creatine kinase, aspartate aminotransferase, and lactate dehydrogenase). Intracellular vacuoles accumulation with deficiencies of LAMP2 protein was found in both cardiac and skeletal myocytes of patients with Danon disease. Conclusion In patients with coexistent LVH and ventricular preexcitation, Danon disease is common with distinctive clinical presentations. Comprehensive assessment of these resemble patients can provide valuable findings for early identification and clinical decision making of patients with Danon disease.

Review: Danon disease: Review of natural history and recent advances

“…Elevated serum troponin T levels were found during the acute cardiac phase , especially in severely affected patients with rapidly fatal outcomes , similar to what occurs in ischemic heart disease.…”

“…WPW is a feature common to other ‘metabolic’ cardiomyopathies (Pompe disease, PRKAG2 ‐related), whereas it is rare in cardiomyopathies due to mutations in genes encoding cytoskeletal/sarcomeric proteins. The origin of the pre‐excitation caused by the presence of accessory pathways could be disruption of the annulus fibrosus (which normally insulates the ventricles from inappropriate excitation by the atria) by glycogen‐filled myocytes . These anomalous microscopic atrioventricular (AV) connections, rather than morphologically distinct bypass tracts, appear to provide the anatomical substrate for ventricular pre‐excitation .…”

“…Many patients had hepatomegaly (36% of cases) , overt hepatopathy or increased liver enzyme levels from childhood .…”

“…Common histopathological features seen in endomyocardial biopsy or on explanted heart examination were hypertrophic cardiomyocytes with enlarged/pyknotic nuclei, cytoplasmic vacuoles, myofibrillar disarray , collections of macrophages, necrotic/degenerative changes, PAS‐positive inclusions and strong acid phosphatase staining . Increased levels of LC3 and ubiquitin suggest that the maturation and clearance of autophagosomes was stunted .…”

“…Screening of LAMP2 gene mutations by next‐generation sequencing (NGS) in selected series of patients has permitted the identification of an increasing number of DD patients (i.e. DD is more frequent than previously thought), for example, the disease frequency is estimated to be 4–6% among children with hypertrophic cardiomyopathy (HCM) , 0.7–4% among adults with HCM , 6–8% among adults with concentric HCM , 17–30% among patients with both thickened left ventricular (LV) walls and pre‐excitation on ECG , and 33% among patients with vacuolar myopathy and HCM . No DD patient was identified by NGS screening among 72 children with idiopathic dilated cardiomyopathy (DCM) .…”