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
Abstract
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
Abstract
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.