Myocardial Strain and Association With Clinical Outcomes in Danon Disease: A Model for Monitoring Progression of Genetic Cardiomyopathies

Background Myocardial strain can identify subclinical left ventricular dysfunction in various cardiac diseases, but its association with clinical outcomes in genetic cardiomyopathies remains unknown. Herein, we assessed myocardial strain in patients with Danon disease (DD), a rare X‐linked autophagic disorder that causes severe cardiac manifestations. Methods and Results Echocardiographic images were reviewed and used to calculate myocardial strain from a retrospective, international registry of patients with DD. Regression analyses were performed to evaluate for an association of global longitudinal strain (GLS) and ejection fraction with the composite outcome (death, ventricular assist device, heart transplantation, and implantable cardioverter defibrillator for secondary prevention). A total of 22 patients with DD (male 14 [63.6%], median age 16.5 years) had sufficient echocardiograms for analysis. Absolute GLS was reduced with a mean of 12.2% with an apical‐sparing pattern observed. Univariable regression for GLS and composite outcome showed an odds ratio of 1.32 (95% CI, 1.02–1.71) with P =0.03. For receiver operating characteristic analysis, the areas under the curve for GLS and ejection fraction were 0.810 ( P =0.02) and 0.605 ( P =0.44), respectively. An absolute GLS cutoff of 10.0% yielded a true positive rate of 85.7% and false positive rate of 13.3%. Conclusions In this cohort of patients with DD, GLS may be a useful assessment of myocardial function and may predict clinical outcomes. This study highlights the potential use of myocardial strain phenotyping to monitor disease progression and potentially to predict clinical outcomes in DD and other genetic cardiomyopathies.

Case Report: A Novel LAMP2 Splice-Altering Mutation Causes Cardiac-Only Danon Disease

Danon disease (DD) is a rare glycogen storage lysosomal disorder caused by mutations in the LAMP2 gene. Patients with DD are usually characterized clinically by severe multisystem syndromes. We describe a specific family with a novel pathogenic splice-altering mutation in the LAMP2 gene (c.741+2T>C) with cardiac-only symptoms (frequent ventricular tachycardia, intraventricular block, and hypertrophic cardiomyopathy). Minigene assays were used to evaluate the consequence of the splice-site mutation in the LAMP2 gene. The results showed that the c.741+2T>C mutation led to extra 6-bp preservation of intron 5 at the junction between exons 5 and 6 during transcriptional processing of the mRNA, which creates a stop codon and truncated the LAMP2 protein to 248-amino-acid residues. The mutant LAMP2 protein was predicted to have a conformational change, lacks the important transmembrane domain, and subsequent protein destabilization.

Fulminant Danon Disease in a Young Female Patient with a Novel LAMP2 Mutation

A 14-year-old female presented for congestive heart failure with biventricular hypertrophy and severely depressed LVEF. Cardiac MRI findings of extensive LGE but sparing the mid septum, genetic tests reporting a LAMP2 missense mutation and LAMP2 protein staining in the minority of cardiac myocytesat immunohistochemistry suggested a Danon Disease diagnosis.

Utility of 4-Dimensional echocardiography and left ventricular systolic strain measured by 2-dimensional speckle-tracking for Danon Disease- a case series

Background Danon disease is an X-linked multisystemic disorder characterised by skeletal myopathy, cardiomyopathy and intellectual disability. Summary of cases Herein we describe two patients affected by Danon disease from the same family, a father (patient 1) and his daughter (patient 2). In patient 1 a short PR interval with pre-excitation was evident. In patient 2, over a 24-hour period 2369 atrial premature beats and rare isolated ventricular ectopics were detected. Both patients exhibited left ventricular hypertrophy with non-compaction myocardium, and the left ventricular ejection fraction was impaired in patient 1 and normal in patient 2. In patient 2, the total left ventricular strain value was reduced, and layer-specific strain revealed that subepicardial strain impaired more than in other layers. Late gadolinium enhancement was detected both in left and right ventricles in patient 2, and cardiac fibrosis was more apparent in the subepicardium of left ventricular free wall. Four-dimensional echocardiography revealed that left atrial reservoir strain and left ventricular total longitudinal strain were induced. Discussion Novel four-dimensional echocardiography and left ventricular systolic strain may play important role in diagnosis and myocardial functional evaluation in Danon disease.