Danon disease (DD), a rare X-linked genetic illness with poor prognosis, was described in 1981 by Danon. Three main clinical features of the pathology are cardiomyopathy, skeletal myopathy, and mental retardation.^[1]DD is caused by loss-of-function mutations in the LAMP2 gene (Xq24) that encodes for lysosome-associated membrane protein-2, lower levels of which causes autophagy disrupted. The clinical presentation is more problematic in males who are hemizygous for LAMP2. Women are usually affected but tend to have a milder and more variable phenotype than males.^[2]

The prevalence of DD is unknown but is considered to be less than one case per million.^[3,4] According to the study of 50 pediatric patients with HCM, two cases of Danon disease (4%) were found.^[5] The estimated prevalence of 1%–6% in patients with unexplained left ventricular hypertrophy (LVH) was reported.^[6] The high prevalence of DD (12%) was found in young female patients with non-ischemic heart failure.^[7]

In this study, we present a detailed clinical report on familial cardiomyopathy resulting from mutation c.190_191delАС firstly identified in the LAMP2 gene. We compare cardiac phenotypes between family members and show the development of early cardiac dysfunction and hypertrophic cardiomyopathy in males. We demonstrate a critical decrease of healthy LAMP2 allele expression in the female carrier heart due to X chromosome inactivation.

a 34-year-old female patient with previous history of Caesarean section was admitted to the Scientific and Practical Center of Cardiology (Belarus) with symptoms of congestive heart failure (HF). During the last trimester of the her third pregnancy, she suffered from swelling, shortness of breath and weakness. Dilatation of the heart chambers and systolic left ventricular (LV) dysfunction were established. Her electrocardiogram (ECG) showed sinus tachycardia and pre-excitation with a positive delta wave in the inferior leads and negative T waves in the anterior leads. Chest X-ray revealed massive cardiomegaly. Transthoracic 2D-Echo study revealed global hypokinesia, severe LV systolic dysfunction and an ejection fraction of 30%. Coronary angiography was normal. Diagnosis of peripartum cardiomyopathy was made and the patient received standard heart failure treatment.

During the next few months after delivery despite the medical therapy, the patient developed progressive heart failure with symptoms consisting of decreased exercise capacity, tiredness, dyspnoea, orthopnoea, oedema, and palpitations. After 14 months, she was readmitted to the emergency department with acute heart failure, atrial and ventricular tachyarrhythmias. The patient ultimately underwent heart transplantation 5 weeks later.

The electrocardiogram showed atrial flutter, atypical left bundle branch block (LBBB) with pseudo-infarction signs of Sodi-Pollares (abnormal QS in leads I, aVL, V5-V6)(Fig. 1А) . Cardiovascular magnetic resonance imaging revealed biventricular dilatation and systolic dysfunction (15% ejection fraction of both ventricles), apex aneurysm with thrombosis, multiple areas of late enhancement with extensive diffuse mid-myocardial pattern contrasting delay and transmural fibrosis in the anterior and anterolateral LV wall (calculated myocardial mass index 127 g/m²). Expansive fibrotic changes in the dilated left ventricle are shown inFigs 1B-E .

The neuromuscular examination revealed no specific abnormalities, especially no muscle weakness. Pertinent laboratory parameters included elevated lactate dehydrogenase (420 U/l; normal range, 120–250 U/l), elevated N-terminal pro b-type natriuretic peptide (16766 pg/ml; normal range, 0–450 pg/ml), elevated aspartate transferase (279 U/l; normal range, 13–35 U/l) and elevated γ-glutamyl transpeptidase (99 U/l; normal range, 7–45 U/l). All other serum parameters were normal as well as creatine phosphokinase. Genetic evaluation and cascade screening were proposed to the proband in that the family history construction showed a sudden cardiac death of her mother at the age of 30 years.

We identified a new LAMP2 variant in a family with a history of heart failure and described disease variability and outcomes in three affected members. The variant c.190_191delАС leads to severe morbidity for male and female carriers and can be classified as pathogenic according to the criteria reported by Richards et al.^[21] In the presented case the affected woman (II-2) has only cardiac involvement manifested as phenocopy of dilated cardiomyopathy in her thirties. The search for a causal variant by NGS led to the identification of new LAMP2 mutation and correction of the initial diagnosis for Danon disease. This pathology often stays unrecognized in women due to the absence of the specific signs. Because females have two X chromosomes, they have a milder and more variable phenotype than males. The onset of DD is in late adulthood and shows a slower progression. In the observed family, the presenting phenotype in the female proband was dilated cardiomyopathy in her thirties, whereas her two sons had hypertrophic cardiomyopathy since their childhood. As is expected, the clinical picture for the sons does not promise an optimistic scenario.

Like many other X-linked diseases, the severity of DD in females depends on XCI status in affected tissues. However, the data on the impact of XCI on Danon phenotype published until today is limited (Table 2). We consider it is important to collect data about the DD onset and XCI status in women. This must have prognostic significance, especially in families where several female members carry LAMP2 mutation. In the case published by Arad et al.^[22], seven women with the pathogenic LAMP2 variant have been reported in the same family. Six of them were asymptomatic at the age of 14–49 years at the moment of publication, while one woman died from congestive heart failure at 44 years. This variability can be explained by the different degrees of the mutant X chromosome inactivation: more in asymptomatic members and less in a deceased woman. Moreover, DD cannot be excluded in young asymptomatic females in their future life. Disease development prognosis is required for such families.

We have attempted to evaluate the relationship between the XCI in muscle and cardiomyopathy onset as the main life-threatening symptom. The limited data did not allow us to demonstrate the reliable linear correlation. But these results reveal the need for further investigation of tissue-specific XCI and clinical outcomes in female DD patients.

Unfortunately, the XCI status in blood cells as the most available tissue is not appropriate for DD prognosis. The XCI pattern is specific to tissue or organ compartments where clinical features are observed – heart, skeletal muscle and brain. Since the heart tissue is often unavailable for investigation, the severity of cardiac phenotypes in women with LAMP2 mutations remain difficult to predict.

In conclusion, the 2bp-deletion c.190_191delАС in LAMP2 was identified in the family with sudden cardiac death history and three members with cardiomyopathy. Based on the strong association of truncating LAMP2 mutations with Danon disease and clinical phenotypes observed in carriers, c.190_191delАС can be classified as pathogenic. In males it led to completely lost of function LAMP2 due to a single copy of this gene. In a woman, cardiomyopathy developed because of both the LAMP2 mutation and a decrease in the expression of a healthy allele in the heart.

Author contributions

L.S. and T.V. - study design, manuscript preparation; T.V. - clinical investigations, L.S. and A.L. - NGS data and mutation analysis; N.D., O.D., and N.Z. - data interpretation and manuscript editing.

The authors have no support to report.

The authors have no funding to report.

The authors have declared that no competing interests exist.