Sunday, June 28, 2020

Danon disease

Inspired by a colleague’s patient

Ntelios D, Parcharidou D, Zegkos T, et al. The multiple faces of Danon disease [published online ahead of print, 2020 Jun 15]. Hellenic J Cardiol. 2020;S1109-9666(20)30101-9. doi:10.1016/j.hjc.2020.06.004

No abstract.  From the article.

Danon disease is a rare genetic disorder characterized by cardiomyopathy accompanied by preexcitation, skeletal myopathy, retinopathy and intellectual disability. It results from mutations in the LAMP2 gene (mostly truncating mutations) and is inherited in an X-linked dominant pattern. LAMP2 encodes for lysosomal associated membrane protein-2, a type I transmembrane protein and among the most abundant proteins in lysosomes. Differential diagnosis of Danon disease can be difficult due to the non-specific or overlapping symptoms with other genetic syndromes causing cardiac hypertrophy and skeletal myopathy. Therefore, the wider implementation of genetic testing has enabled prompt recognition by the clinician of this previously underdiagnosed disease. Several studies have revealed sex-specific differences in the cardiovascular manifestations of the disease. Almost all male patients (88%) with Danon disease develop hypertrophic cardiomyopathy (HCM) (reported wall thickness up to 65mm), with progression to dilated cardiomyopathy observed in 12%. On the other hand, women present at an older age and have higher prevalence of dilated cardiomyopathy at presentation when compared to men. When Danon disease is identified, a multidisciplinary approach that includes cardiologists, neurologists and genetics professionals is key to the care of the family. However, the severity of the cardiac involvement that often requires advanced treatments such as catheter ablation, implantable devices and heart transplantation necessitates early referral to a specialized cardiomyopathy center and lifelong close monitoring.

Currently, there are no prospectively validated risk factors specific to Danon disease patients. However, a high frequency of ventricular arrhythmias has been reported in female patients. For primary prevention of sudden cardiac death (SCD) in Danon disease, HCM guidelines are followed for risk stratification. Interestingly, in one small study, ineffective ICD Shocks for ventricular tachyarrhythmias has been reported in five patients. There are no official recommendations for the use of electrophysiologic study (EPS) as a risk stratification tool for SCD in Danon disease. Additionally, EPS is currently not recommended for the identification of HCM patients who would benefit from primary prevention strategies in hypertrophic cardiomyopathy.  However, EPS can be used to rule out clinically important accessory atrioventricular pathways in Danon disease. The management of patients presenting with dilated cardiomyopathy relies upon guideline-directed therapy for heart failure. However, there are no prospective studies evaluating the efficacy of this approach.

He J, Xu J, Chen L, et al. Clinical features and cardiovascular magnetic resonance characteristics in Danon disease [published online ahead of print, 2020 Jun 1]. Clin Radiol. 2020;S0009-9260(20)30168-9. doi:10.1016/j.crad.2020.04.012


Aims: To investigate the clinical spectrum, cardiovascular magnetic resonance imaging (cMRI) characteristics, including T1 and extracellular volume fraction, and outcomes of Danon disease to facilitate further understanding of the phenotype of patients with Danon disease.

Materials and methods: The study comprised six male patients 8-23 years old recruited to the study between 2014-2019. The clinical presentation, laboratory examinations, pathology/genetic analysis, electrocardiography (ECG), echocardiography, and cCMRI characteristics were summarised.

Results: Five out of six patients suffered from hypertrophic cardiomyopathy (HCM) phenotype of Danon disease, while one patient had dilated cardiomyopathy (DCM) phenotype. Left ventricular (LV) and left atrial (LA) function were impaired at strain measurement. Diffuse and focal late gadolinium enhancement (LGE) were observed separately in the LV walls of three patients and right ventricular (RV) insertion points of the remaining three patients. Furthermore, values for the native T1 (mean 1313.3 ms) and extracellular volume fraction (ECV; mean 39.17%) of three patients were increased.

Conclusions: Both dilated and hypertrophic cardiomyopathy may be the phenotypes of Danon disease. Comprehensive cCMRI played a unique role in the diagnosis and grading severity and risk factors of Danon disease in vivo, especially by using robust quantitative strain analysis, T1 mapping, and further ECV calculation.

Novelli V, Bisignani A, Pelargonio G, et al. Clinical utility of genetic testing in the early diagnosis of Danon disease mimicking hypertrophic cardiomyopathy: a case report. BMC Cardiovasc Disord. 2020;20(1):156. Published 2020 Apr 5. doi:10.1186/s12872-020-01421-4


Background: Danon disease (OMIM 300257) is an X-linked lysosomal storage disorder, characterized by hypertrophic cardiomyopathy (HCM), skeletal myopathy, variable intellectual disability, and other minor clinical features. This condition accounts for ~ 4% of HCM patients, with a more severe and early onset phenotype in males, causing sudden cardiac death (SCD) in the first three decades of life. Genetic alterations in the LAMP2 gene are the main cause of this inherited fatal condition. Up to date, more than 100 different pathogenic variants have been reported in the literature. However, the majority of cases are misdiagnosed as HCM or have a delay in the diagnosis.

Case presentation: Here, we describe a young boy with an early diagnosis of HCM. After 2 episodes of ventricular fibrillation within 2 years, genetic testing identified a novel LAMP2 pathogenic variant. Subsequently, further clinical evaluations showing muscle weakness and mild intellectual disability confirmed the diagnosis of Danon disease.

Conclusions: This report highlights the role of genetic testing in the rapid diagnosis of Danon disease, underscoring the need to routinely consider the inclusion of LAMP2 gene in the genetic screening for HCM, since an early diagnosis of Danon disease in patients with a phenotype mimicking HCM is essential to plan appropriate treatment, ie cardiac transplantation.

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