RESUMEN

Danon disease (DD) is a rare lysosomal storage disorder resulting from pathogenic variants of the lysosome-associated membrane protein type 2 (LAMP-2) gene. The disease is characterized by severe cardiomyopathy, which rapidly progresses to end-stage heart failure. This case, with DD caused by a missense variant, exhibited slow progressive cardiomyopathy and survived for an extended period despite being a male. A pathological analysis revealed that only a minority of the samples exhibited autophagic vacuoles with unique sarcolemmal features (AVSFs), which are typical of DD. Importantly, LAMP-2 expression was absent and the myocardial tissue contained a substantial amount of p62-positive aggregates.

RESUMEN

[This corrects the article DOI: 10.3389/fcvm.2023.1159576.].

RESUMEN

Introduction: Danon disease is an X-linked disorder caused by pathogenic variants in lysosome-associated membrane protein 2 (LAMP2) gene, typically characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. However, many patients may not present the typical presentation, especially in the early stage. Electrocardiogram (ECG) abnormalities can be found in almost all patients, with Wolff-Parkinson-White (WPW) syndrome being the most common. We reported the case of a 51-year-old woman who experienced multiple types of arrhythmias over three decades and was diagnosed with Danon disease late by genetic testing. Case summary: A 51-year-old woman with a 36-year history of intermittent palpitations was admitted due to hemodynamically stable ventricular tachycardia (VT). Her past medical history revealed multiple arrhythmias and ECG abnormalities in her 30s and 40s, including WPW syndrome with paroxysmal supraventricular tachycardia, paroxysmal atrial flutter, atrial fibrillation, ventricular tachycardia, and complete left bundle branch block. She denied any family history of cardiovascular disease or sudden death. Upon arrival, her vital signs were unremarkable. Cardiovascular magnetic resonance (CMR) imaging revealed left ventricular enlargement and late gadolinium enhancement (LGE) in the anterior, inferior, and lateral walls. Subsequent, whole-exome sequencing (WES) gene testing revealed a pathogenic heterozygous variant in LAMP2 gene (c.696T>A; p.Cys232Ter), which confirmed the diagnosis of Danon disease. Conclusion: Genetic testing should be considered in patients who display multiple arrhythmias with LV structural abnormalities of unknown etiology for a possible Danon disease.

RESUMEN

OBJECTIVE: Danon disease is defined by a clinical trio of cardiomyopathy, skeletal myopathy, and cognitive impairment. It results from the lysosomal-associated membrane protein-2 (LAMP2) gene variants. The aim of study is determination of genotype and phenotype of a newly diagnosed Iranian family with a unique phenotype due to a pathogenic variant of the LAMP2 gene along with a phenotypic comparison of all reported patients. MATERIALS AND METHODS: In this descriptive study, we evaluated the demographic data, clinical features, management procedures, as well as genetic analysis of both patients in this newly diagnosed family. Whole genome sequencing (WGS) and in silico structural and functional predictions were applied. A comprehensive search of the c.877C>T variant in LAMP2 was conducted using the PubMed, Google Scholar, VarSome, ClinVar, Human Gene Mutation Database (HGMD), and Franklin databases to identify any genotype-phenotype correlations. RESULTS: Nine patients were carriers of the c.877C>T variant. All patients were male, and displayed variable degrees of left ventricular hypertrophy (LVH) that ranged from mild to severe. All patients exhibited typical cardiac conduction abnormalities consistent with Danon disease. Four underwent heart transplants and survived. Skeletal muscle involvement and cognitive impairment were observed in four patients each. The mean age of onset was 14 years. The proband in this study exhibited an earlier onset of cardiac symptoms. CONCLUSION: Genetic analysis is the preferred diagnosis approach for Danon disease and can assist families in managing affected patients, identify carriers, and assist with future family planning. This study highlights the intrafamilial phenotypic variability of Danon disease. It is possible that variants of this gene may be frequent in Iran.

RESUMEN

Background and Objectives: Danon disease is a multisystemic disorder associated with variants in the LAMP2 gene, mainly affecting the cardiac muscle. Here, we report a multigenerational family from Latvia with two male patients, hemizygous for a novel splice-affecting variant c.928+3A>G. Affected patients exhibit a cardiac phenotype, moderate mental disability, and mild retinal changes. Materials and Methods: Both patients underwent either exome or hypertrophic cardiomyopathy gene panel next-generation sequencing. The pathogenic variant effect was determined using reverse transcription, Sanger sequencing, and high-resolution electrophoresis. Results: Evaluation of the splicing process revealed that approximately 80% of the transcripts exhibited a lack of the entire exon 7. This alteration was predicted to cause a shift of the reading frame, consequently introducing a premature stop codon downstream in the sequence. Conclusions: Based on our data, we propose that c.928+3A>G is a pathogenic variant associated with Danon disease.

Asunto(s)

RESUMEN

Danon disease is a rare X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2. We report a case of hypertrophic obstructive cardiomyopathy secondary to a novel mutation in the lysosome-associated membrane protein-2 gene in a 10-year-old male adolescent. We performed a modified extended Morrow procedure to minimise the risk of death and improve the patient's quality of life. The patient did not have exertional dyspnoea, and auscultation did not reveal a cardiac murmur at 1-year follow-up.

Asunto(s)

RESUMEN

Objective:To apply cardiovascular magnetic resonance (CMR) to quantitatively evaluate the morphology and tissue characteristics of thoracic skeletal muscle (TSM) in patients with Danon disease and hypertrophic cardiomyopathy (HCM), in order to provide auxiliary differential diagnostic information.Methods:A retrospective study was conducted on 15 Danon disease patients (Danon disease group) who completed CMR examination, and 15 HCM patients (HCM group) and 15 healthy volunteers (control group) who were matched by gender and age were compared. TSM (pectoralis major, pectoralis minor, erector spinae, and subscapularis) area index (TSMAi), T1 relaxation time of four groups, and extracellular volume (ECV) of skeletal muscles of two groups (pectoralis major and subscapularis) were measured for all subjects. Single factor analysis of variance and KruskalWallis test were used to compare three sets of values.Results:The total TSMAi of the Danon disease group was lower than that of the HCM group and the control group [(15.37±3.28)cm 2/m 2 vs (23.02±3.88)cm 2/m 2 vs (22.33±4.67)cm 2/m 2, P<0.001], and the TSMAi of each TSM was also lower than that of the HCM group and the control group (all P<0.05). There was no statistically significant difference in TSMAi between the HCM group and the control group (all P>0.05). The native T1 values of the pectoralis major muscle in the Danon disease group and HCM group were higher than those in the control group (all P<0.05). The ECV of the pectoralis major muscle and subscapularis muscle in the Danon disease group were higher than those in the HCM group and control group, and the enhanced T1 values were lower than those in the HCM group and control group (all P<0.05); There was no statistically significant difference in ECV and the enhanced T1 values between the HCM group and the control group ( P>0.05). Conclusions:The application of CMR can effectively evaluate the changes in TSM morphology and tissue characteristics in Danon disease patients. Compared with HCM patients, Danon disease patients showed significant atrophy of TSM with increased extracellular volume. CMR provides a quantitative reference for TSM in the differential diagnosis of the two.

RESUMEN

BACKGROUND: Danon disease (DD), in which mutations in the X-linked lysosome-associated membrane protein-2 (LAMP-2) gene result in hypertrophic cardiomyopathy, is a rare disease, reported primarily in small samples or cases. However, with the development of cardiac magnetic resonance imaging and genetic technology in recent years, the number of reports has increased. CASE SUMMARY: We report a case of DD in an adolescent male patient, confirmed by genetic testing. The patient was admitted to our hospital with complaints of a three-year history of chest tightness and shortness of breath. His preliminary clinical diagnosis is hypertrophic cardiomyopathy. Our report includes the patient's clinical course from hospital admission to death, step-by-step diagnosis, treatment course, and noninvasive imaging features. We highlight how a noninvasive diagnostic approach, based solely on clinical and imaging "red flags" for DD, can be used to achieve a diagnosis of DD with a high degree of confidence. CONCLUSION: DD is a very dangerous cardiomyopathy, and it is necessary to achieve early diagnosis and treatment.

RESUMEN

Danon disease is a rare X-linked autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that can be accompanied with extracardiac neurologic, skeletal, and ophthalmologic manifestations. It is caused by loss of function variants in the LAMP2 gene and is among the most severe and penetrant of the genetic cardiomyopathies. Most patients with Danon disease will experience symptomatic heart failure. Male individuals generally present earlier than women and die of either heart failure or arrhythmia or receive a heart transplant by the third decade of life. Herein, the authors review the differential diagnosis of Danon disease, diagnostic criteria, natural history, management recommendations, and recent advances in treatment of this increasingly recognized and extremely morbid cardiomyopathy.

Asunto(s)

RESUMEN

One of the main causes of heart failure is cardiomyopathies. Among them, the most common is hypertrophic cardiomyopathy (HCM), characterized by thickening of the left ventricular muscle. This article focuses on HCM and other cardiomyopathies with myocardial hypertrophy, including Fabry disease, Pompe disease, and Danon disease. The genetics and pathogenesis of these diseases are described, as well as current and experimental treatment options, such as pharmacological intervention and the potential of gene therapies. Although genetic approaches are promising and have the potential to become the best treatments for these diseases, further research is needed to evaluate their efficacy and safety. This article describes current knowledge and advances in the treatment of the aforementioned cardiomyopathies.

Asunto(s)

RESUMEN

Danon disease is a rare x-linked dominant multisystemic disorder with a clinical triad of severe cardiomyopathy, skeletal myopathy, and intellectual disability. It is caused by defects in the lysosome-associated membrane protein-2 (LAMP2) gene. Numerous different mutations in the LAMP2 protein have been described. Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy and heart failure. Female patients usually present with milder and variable symptoms. This report describes a 42-year-old father and his 3-year-old daughter presenting with mild manifestations of the disease. The father has normal intellectual development and normal physical activity. At the age of 13, he was diagnosed with mild ventricular pre-excitation known as Wolf-Parkinson-White syndrome (WPWs), very mild and mostly asymptomatic cardiomyopathy and left ventricular hypertrophy, and at about the age of 25 presented with visual impairment due to cone-rod dystrophy. His daughter showed normal development and very mild asymptomatic electrocardiographic WPWs abnormalities with left mild ventricular hypertrophy. Genetic testing revealed an Xq24 microdeletion encompassing the entire LAMP2 gene. Relevant literature was reviewed as a reference for the etiology, diagnosis, treatment and case management.

Asunto(s)

RESUMEN

BACKGROUND: Danon disease (DD) is an exceptionally uncommon X-linked dominant lysosomal glycogen storage disorder characterized by pronounced ventricular hypertrophy and cardiac insufficiency. The timely identification of cardiac impairment in individuals with DD holds significant clinical importance. CASE PRESENTATION: We present a case of Danon Disease in a three-generation pedigree from Anhui Province, China. Clinical features and laboratory data were collected and analyzed for a 16-year-old male proband (III-1) and two affected female family members (II-2 and II-3). The proband exhibited Wolf-Parkinson-White syndrome, hypertrophic cardiomyopathy, abnormal cognitive function, and muscle weakness. Gene sequencing confirmed a mutation (c.963G > A) in the LAMP-2 gene. CONCLUSION: Patients with DD may present both dilated and hypertrophic cardiomyopathy. Comprehensive myocardial tissue characterization by MRI plays a key role in the diagnosis of the disease.

Asunto(s)

RESUMEN

The clinical manifestations of Danon disease, which result from the primary deficiency of the lysosome-associated membrane protein 2 gene, include cardiomyopathy, skeletal myopathy, and different degrees of intellectual disability that vary greatly among patients. The present study reports on two cases of Danon disease in two patients who only presented cardiac symptoms. Cardiac symptoms usually occur in adolescence and during a patient's twenties, and most patients die from heart failure. However, the lab results from these cases suggested that other systems were involved, despite no other clinical symptoms. Significantly, the two patients had elevated serum cardiac troponin I, which often manifests in the acute cardiac phase, especially in severely affected patients with rapidly fatal outcomes. Danon disease is a multi-system involvement disease. Therefore, clinicians must be aware of its complexity when evaluating newly diagnosed patients due to its vastly different clinical course and prognosis and the importance of multidisciplinary management.

RESUMEN

Successful therapy in a cohort with early onset Danon disease (DD) highlights the potential importance of earlier disease recognition. We present experience from the largest National Pediatric Center in Russia for cardiomyopathy patients. This report focuses on identification of early clinical features of DD in the pediatric population by detailed pedigree analysis and review of medical records. RESULTS: Nine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health ("National Pediatric Center") aged birth to 16 years. At presentation/evaluation: all patients had left ventricular hypertrophy (LVH), ECG features of Wolff-Parkinson-White (WPW), and an increase in hepatic enzymes (particularly lactate dehydrogenase (LDH)); three had marked increase in NT-proBNP; two had HCM with impaired LV function; one had LVH with LV noncompaction; five had arrhythmia with paroxysmal supraventricular and/or ventricular tachycardia. Two teenagers died at ages 16-17 from refractory heart failure and two underwent heart transplantation. All patients were found to have a pathogenic/likely pathogenic variant in the LAMP2 gene, six patients had no family history and a de novo evolvement was documented in 4/6 of those available for genetic tested. Retrospective review related to family background and earlier clinical evaluations revealed a definitive or highly suspicious family history of DD in 3, early clinical presentation with cardiac abnormalities (ECG, echo) in 3, and cerebral, hepatic and/or neuromuscular symptoms in 5. Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center. CONCLUSION: The earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo.

Asunto(s)

RESUMEN

BACKGROUND: Danon disease is characterized by the failure of lysosomal biogenesis, maturation, and function due to a deficiency of lysosomal membrane structural protein (LAMP2). METHODS: The current report describes a female patient with a sudden syncope and hypertrophic cardiomyopathy phenotype. We identified the pathogenic mutations in patients by whole-exon sequencing, followed by a series of molecular biology and genetic approaches to identify and functional analysis of the mutations. RESULTS: Suggestive findings by cardiac magnetic resonance (CMR), electrocardiogram (ECG), and laboratory examination suggested Danon disease which was confirmed by genetic testing. The patient carried a novel de novo mutation, LAMP2 c.2T>C located at the initiation codon. The quantitative polymerase chain reaction (qPCR) and Western blot (WB) analysis of peripheral blood leukocytes from the patients revealed evidence of LAMP2 haploinsufficiency. Labeling of the new initiation codon predicted by the software with green fluorescent protein followed by fluorescence microscopy and Western blotting showed that the first ATG downstream from the original initiation codon became the new translational initiation codon. The three-dimensional structure of the mutated protein predicted by alphafold2 revealed that it consisted of only six amino acids and failed to form a functional polypeptide or protein. Overexpression of the mutated LAMP2 c.2T>C showed a loss of function of the protein, as assessed by the dual-fluorescence autophagy indicator system. The mutation was confirmed to be null, AR experiments and sequencing results confirmed that 28% of the mutant X chromosome remained active. CONCLUSION: We propose possible mechanisms of mutations associated with haploinsufficiency of LAMP2: (1) The inactivation X chromosome carrying the mutation was not significantly skewed. However, it decreased in the mRNA level and the expression ratio of the mutant transcripts; (2) The identified mutation is null, and the active mutant transcript fails to translate into the normal LAMP2 proteins. The presence of haploinsufficiency in LAMP2 and the X chromosome inactivation pattern were crucial factors contributing to the early onset of Danon disease in this female patient.

Asunto(s)

RESUMEN

AIMS: This study aimed to identify a novel splicing-altering LAMP2 variant associated with Danon disease. METHODS AND RESULTS: To identify the potential genetic mutation in a Chinese pedigree, whole-exome sequencing was conducted in the proband, and Sanger sequencing was performed on the proband's parents. To verify the impact of the splice-site variant, a minigene splicing assay was applied. The AlphaFold2 analysis was used to analyse the mutant protein structure. A splice-site variant (NM_013995.2:c.864+5G>A) located at intron 6 of the LAMP2 gene was identified as a potential pathogenic variant. The minigene splicing revealed that this variant causes exon 6 to be skipped, resulting in a truncated protein. The AlphaFold2 analysis showed that the mutation caused a protein twist direction change, leading to conformational abnormality. CONCLUSIONS: A novel splice-site variant (NM_013995.2:c.864+5G>A) located at intron 6 of the LAMP2 gene was identified. This discovery may enlarge the LAMP2 variant spectrum, promote accurate genetic counselling, and contribute to the diagnosis of Danon disease.

Asunto(s)

Asunto(s)

RESUMEN

Background: Danon disease (DD) is a rare X-linked disorder due to mutations in the lysosome-associated membrane protein 2 gene. It is characterized by a clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and a variable degree of intellectual disability. Case summary: In this case series, we describe a mother and her son affected by DD, highlighting consistent clinical severity despite the expected variability related to gender. The mother (Case 1) presented isolated cardiac involvement, with an arrhythmogenic phenotype that evolved into severe heart failure requiring heart transplantation (HT). Danon disease was diagnosed 1 year after this event. Her son (Case 2) showed an earlier age onset of symptoms with complete atrioventricular block and fast progression of cardiac disease. Diagnosis was established 2 years after clinical presentation. He is currently listed for HT. Discussion: In both of our patients, diagnostic delay was extremely long and could have been avoided by emphasizing the relevant clinical red flags. Patients affected by DD may present clinical heterogeneity in terms of natural history, age of onset, and cardiac and extracardiac involvement, even in the same family. Early diagnosis that phenotypic sex differences may impact is a crucial factor in managing patients with DD. Considering the rapid progression of cardiac disease and the poor prognosis, early diagnosis is important and close surveillance should be mandatory during follow-up.

RESUMEN

Background: Cardiac involvement constitutes the primary cause of mortality in patients with Danon disease (DD). This study aimed to explore the cardiac magnetic resonance (CMR) features and progressions of DD cardiomyopathies in a family with long-term follow-up. Methods: Seven patients (five females and two males), belonging to the same family and afflicted with DD, were enrolled in this study between 2017 and 2022. The cardiac structure, function, strain, tissue characteristics on CMR and their evolutions during follow-up were analyzed. Results: Three young female patients (3/7, 42.86%) exhibited normal cardiac morphology. Four patients (4/7, 57.14%) displayed left ventricle hypertrophy (LVH), and mostly with septal thickening (3/4, 75%). A single male case (1/7, 14.3%) showed decreased LV ejection fraction (LVEF). Nonetheless, the global LV strain of the four adult patients decreased in different degree. The global strain of adolescent male patients was decreased compared to the age-appropriate female patients. Five patients (5/7, 71.43%) exhibited late gadolinium enhancement (LGE), with proportion ranging from 31.6% to 59.7% (median value 42.7%). The most common LGE location was the LV free wall (5/5, 100%), followed by right ventricle insertion points (4/5, 80%) and intraventricular septum (2/5, 40%). Segmental radial strain (rs = -0.586), circumferential strain (r = 0.589), and longitudinal strain (r = 0.514) were all moderately correlated with the LGE proportions of corresponding segments (P < 0.001). T2 hyperintense and perfusion defect foci were identified, overlapping with the LGE areas. During follow-up, both the young male patients exhibited notable deterioration of their cardiac symptoms and CMR. The LVEF and strain decreased, and the extent of LGE increased year by year. One patient underwent T1 mapping examination. The native T1 value was sensitively elevated even in regions without LGE. Conclusions: Left ventricular hypertrophy, LGE with sparing or relatively less involved IVS, and LV dysfunction are prominent CMR features of Danon cardiomyopathy. Strain and T1 mapping may have advantages in detecting early-stage dysfunction and myocardial abnormalities in DD patients, respectively. Multi-parametric CMR can serve as an optimal instrument for detecting DD cardiomyopathies.

RESUMEN

A 21-year-old woman with a history of atopy, peripheral eosinophilia, Wolf-Parkinson-White syndrome, and 5 episodes of myocarditis was diagnosed with eosinophilic myocarditis. Despite adequate immunosuppressive treatment and resolution of the myocarditis episode, the patient developed dilated cardiomyopathy and presented with worsening of her functional class. Finally, genetic testing unveiled an additional diagnosis: Danon disease. (Level of Difficulty: Advanced.).