Endovascular treatment in Danon disease: a case report.

BACKGROUND: Danon disease is a lysosomal storage disorder with X-linked inheritance. The classic triad is severe hypertrophic cardiomyopathy, myopathy, and intellectual disability, with different phenotypes between both genders. Ischemic stroke is an uncommon complication, mostly cardioembolic, related to intraventricular thrombus or atrial fibrillation, among others. CASE REPORT: We report the case of a 14-year-old Caucasian male patient with Danon disease who suffered from an acute ischemic stroke due to occlusion in the M1 segment of the middle cerebral artery. He underwent mechanical thrombectomy, resulting in successful revascularization with satisfactory clinical outcome. We objectified the intraventricular thrombus in the absence of arrhythmic events. CONCLUSION: To our knowledge, we report the first case of ischemic stroke related to Danon disease treated with endovascular treatment.

Paediatric hypertrophic cardiomyopathy secondary to Danon disease.

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.

International Consensus on Differential Diagnosis and Management of Patients With Danon Disease: JACC State-of-the-Art Review.

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.

A rare and fatal cause of hypertrophic cardiomyopathy: Danon disease.

Danon disease is a rare and fatal disease caused by a mutation in the lysosome-associated membrane protein 2 gene. Impaired intracellular autophagy causes lysosomal vacuoles to accumulate mainly in myocardial and skeletal muscle cells, leading to hypertrophic cardiomyopathy, skeletal myopathy, and varying degrees of intellectual disability. Two distinct childhood presentations of Danon disease are described in this report.

[Clinical characteristics of Danon disease].

Objective: To review the clinical data of 7 patients with Danon disease and analyze their clinical characteristics. Methods: The medical records of 7 patients with Danon disease, who were hospitalized in Peking Union Medical College Hospital of Chinese Academy of Medical Sciences from April 2008 to July 2021, were reviewed and summarized, of which 6 cases were diagnosed as Danon disease by lysosomal-associated membrane protein-2 (LAMP-2) gene mutation detection and 1 case was diagnosed by clinicopathological features. Clinical manifestations, biochemical indexes, electrocardiogram, echocardiography, skeletal muscle and myocardial biopsy and gene detection results were analyzed, and patients received clinical follow-up after discharge. Results: Six patients were male and average age was (15.4±3.5) years and the average follow-up time was (27.7±17.0) months. The main clinical manifestations were myocardial hypertrophy (6/7), decreased myodynamia (2/7) and poor academic performance (3/7). Electrocardiogram features included pre-excitation syndrome (6/7) and left ventricular hypertrophy (7/7). Echocardiography examination evidenced myocardial hypertrophy (6/7), and left ventricular dilatation and systolic dysfunction during the disease course (1/7). The results of skeletal muscle biopsy in 6 patients were consistent with autophagy vacuolar myopathy. Subendocardial myocardial biopsy was performed in 3 patients, and a large amount of glycogen deposition with autophagosome formation was found in cardiomyocytes. LAMP-2 gene was detected in 6 patients, and missense mutations were found in all these patients. During the follow-up period, implantable cardioverter defibrillator implantation was performed in 1 patient because of high atrioventricular block 4 years after diagnosis, and there was no death or hospitalization for cardiovascular events in the other patients. Conclusion: The main clinical manifestations of Danon disease are cardiomyopathy, myopathy and mental retardation. Pre-excitation syndrome is a common electrocardiographic manifestation. Autophagy vacuoles can be seen in skeletal muscle and myocardial pathological biopsies. LAMP-2 gene mutation analysis is helpful in the diagnose of this disease.

A Frequent Observation of Wolff-Parkinson-White Syndrome and Fasciculoventricular Pathways in Patients With Danon Disease.

BACKGROUND: Danon disease is typically associated with cardiomyopathy and ventricular pre-excitation. The study aimed to characterize the clinical profile of Danon disease, analyze electrocardiographic (ECG) and electrophysiologic features, and investigate their association with Wolff-Parkinson-White (WPW) syndrome and fasciculoventricular pathways (FVPs).Methods and Results:Clinical course, family history, ECG and electrophysiological data were collected from 16 patients with Danon disease. Over 0.4-8 years of follow up, 1 female patient died suddenly, and 5 male patients died of progressive heart failure by age 13-20 years. Family history analysis revealed that 3 mothers experienced hospitalization or death for heart failure at age 28-41 years. There was 100% penetrance for ECG abnormalities in 13 patients with original ECGs. Short PR intervals and delta waves were present in 9 and 8 patients, respectively. There were significant age-associated increases in the QRS complex width (r=0.556, P=0.048) and the number of leads with notched QRS (r=0.575, P=0.04). Four patients who underwent electrophysiological studies all had FVPs, and 2 of them still had left-side atrioventricular pathways. CONCLUSIONS: Danon disease causes a malignant clinical course characterized by early death caused by heart failure in both genders and progressive ECG changes as patients age. The pre-excited ECG pattern is related to FVPs and WPW, which is suggestive of extensive cardiac involvement.

Fasciculoventricular and atrioventricular accessory pathways in patients with Danon disease and preexcitation: A multicenter experience.

BACKGROUND: Studies have suggested that a fasciculoventricular pathway (FVP) may be the cause of preexcitation in patients with Danon disease, a rare X-linked dominant genetic disorder of hypertrophic cardiomyopathy. OBJECTIVE: The purpose of this study was to describe the prevalence of ventricular preexcitation on resting 12-lead electrocardiogram (ECG) in patients with Danon disease and the electrophysiological study (EPS) results of those with preexcitation. METHODS: Patients with confirmed Danon disease diagnosed with preexcitation (PR ≤120 ms, delta wave, QRS >110 ms) on ECG were included from a multicenter registry. The incidence of arrhythmias, implantable cardioverter-defibrillator (ICD) procedures, ICD shocks, and EPS results were collected. RESULTS: Thirteen of 40 patients (32.5%) with Danon disease were found to have preexcitation (mean age 17.3 years; 38% women). EPS performed in 9 of 13 patients (69%) demonstrated FVP only in 2 (22.2%), extranodal pathway without exclusion of FVP in 2 (22.2%), and both FVP and extranodal pathway in 5 (55.6%). Two patients had malignant accessory pathway (AP) properties. Over median follow-up of 842 days (interquartile range 138-1678), 11 patients (85%) had ICD placement, and 6 (46.1%) underwent heart transplantation. No patients required therapy for ventricular tachycardia, and 2 patients (15%) had paroxysmal atrial fibrillation. CONCLUSION: In a large multicenter cohort of patients with Danon disease, there was a high prevalence of FVP and extranodal pathways diagnosed on EPS in those with preexcitation. These findings suggest patients with preexcitation and Danon disease should undergo EPS to assess for FVP and potentially malignant extranodal AP.

Pigmentary retinopathy can indicate the presence of pathogenic LAMP2 variants even in somatic mosaic carriers with no additional signs of Danon disease.

PURPOSE: Danon disease (DD) is a rare X-linked disorder caused by pathogenic variants in LAMP2. DD primarily manifests as a severe cardiomyopathy. An early diagnosis is crucial for patient survival. The aim of the study was to determine the usefulness of ocular examination for identification of DD. METHODS: Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45-year-old asymptomatic female somatic mosaic carrier of a LAMP2 disease-causing variant. RESULTS: All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (<0.63) in 8 (40%) out of 20 eyes. The severity of retinal pathology increased with age, resulting in marked cone-rod involvement overtime. Spectral-domain optical coherence tomography in younger patients revealed focal loss of photoreceptors, disruption and deposition at the retinal pigment epithelium/Bruch's membrane layer (corresponding to areas of marked increased autofluorescence), and hyperreflective foci in the outer nuclear layer. Cystoid macular oedema was seen in one eye. In the asymptomatic female with somatic mosaicism, the BCVA was 1.0 bilaterally. An abnormal autofluorescence pattern in the left eye was present; while full-field electroretinography was normal. CONCLUSIONS: Detailed ocular examination may represent a sensitive and quick screening tool for the identification of carriers of LAMP2 pathogenic variants, even in somatic mosaicism. Hence, further investigation should be undertaken in all patients with pigmentary retinal dystrophy as it may be a sign of a life-threatening disease.

Long-Term Follow-Up of Peripheral Pigmentary Retinopathy in Asian Patients with Danon Disease.

BACKGROUND: Peripheral pigmentary changes are common amongst women with Danon disease; however, there is currently a lack of longitudinal observational studies of the retinal changes in this condition, and the long-term visual prognosis is not well understood. METHODS AND RESULTS: In this report, we present long-term follow-up data (12 years of follow-up) regarding peripheral retinopathy in an Asian woman and her mother who were both diagnosed with Danon disease. Both patients showed a novel nonsense mutation of the LAMP2 gene (c.123 of exon 2). During the follow-up period, no evident extension of peripheral pigmented lesions or visual field progression was observed. CONCLUSIONS: We report, for the first time, the long-term longitudinal follow-up of Danon disease-related retinopathy in an Asian patient featuring an indolent macular-sparing peripheral lesion.

A case report of delayed diagnosis of danon disease: Caused by a newly recognized mutation in the lysosome-associated membrane protein-2 gene.

INTRODUCTION: Danon disease is a rare X-linked dominant genetic disorder caused by defects in the lysosome-associated membrane protein 2 (LAMP2) gene. Unless treated, cardiogenic death is the main cause of mortality. This case report describes a 19-year-old man who was diagnosed with Danon disease and survived for 3 years from symptom onset to death. The mutation in his LAMP2 gene (p.Gly221Ilefs*19) had not been previously reported. PATIENT CONCERNS: A 19-year-old man patient was hospitalized for intermittent palpitations. He had no family history of cardiomyopathy, arrhythmia, or sudden cardiac death, but his sister had died of cirrhosis at age 12 years, but the exact cause of cirrhosis was unknown. DIAGNOSIS: Exome sequencing and Sanger sequencing identified a novel missense mutation (p.Gly221Ilefs*19) in the LAMP2 gene of the proband. This mutation was also detected in his mother, confirming the diagnosis of Danon disease. INTERVENTIONS: The patient experienced various types of arrhythmia throughout the clinical process, including Wolff-Parkinson-White syndrome, non-sustained atrial tachycardia, atrial flutter, and third-degree atrioventricular block. He was therefore treated with cardiac ablation procedures and cardiac resynchronization therapy. OUTCOMES: The period from the onset of symptoms to the onset of heart failure was 2 years. The patient died of cardiogenic death during the third year, at age 22 years. LESSONS: Danon disease is a rare disease that is difficult to recognize because of its hidden early manifestations. Early identification of its clinical symptoms can lead to early diagnosis and treatment.

Danon disease is an underdiagnosed cause of advanced heart failure in young female patients: a LAMP2 flow cytometric study.

AIMS: Danon disease (DD) is a rare X-linked disorder caused by mutations in the lysosomal-associated membrane protein type 2 gene (LAMP2). DD is difficult to distinguish from other causes of dilated or hypertrophic cardiomyopathy (HCM) in female patients. As DD female patients regularly progress into advanced heart failure (AHF) aged 20-40 years, their early identification is critical to improve patient survival and facilitate genetic counselling. In this study, we evaluated the prevalence of DD among female patients with non-ischemic cardiomyopathy, who reached AHF and were younger than 40 years. METHODS AND RESULTS: The study cohort comprised 60 female patients: 47 (78%) heart transplant recipients, 2 (3%) patients treated with ventricular assist device, and 11 (18%) patients undergoing pre-transplant assessment. Aetiology of the cardiomyopathy was known in 15 patients (including two DD patients). LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients. Whole exome sequencing was used as an alternative independent testing method to FC. Five additional female DD patients (two with different novel LAMP2 mutations) were identified by FC. The total prevalence of DD in this cohort was 12%. HCM phenotype (57% vs. 9%, * P = 0.022) and delta waves identified by electrocardiography (43% vs. 0%, ** P = 0.002) were significantly more frequent in DD female patients. CONCLUSIONS: Danon disease is an underdiagnosed cause of AHF in young female patients. LAMP2 expression testing in peripheral WBCs by FC can be used as an effective screening/diagnostic tool to identify DD in this patient population.

Thrombotic microangiopathy following heart transplant in pediatric Danon disease.

This case describes an uncommon acute complication of diffuse thrombotic angiopathy and associated aHUS/TTP in an 11-year-old girl with Danon disease who underwent orthotopic heart transplant. Shortly after transplant, despite an uncomplicated operative course, the patient developed severe kidney injury and progressive altered mental status, culminating in cerebral edema, brain herniation, and death. She had received a single dose of tacrolimus (FK506) and a single dose of antithymocyte globulin. Sources of progressive somnolence, including oversedation from impaired renal clearance of opiates, and severe myopathy as has been previously described in Danon disease, were ruled out, and the patient continued to decline. Initial brain CT scan early after transplant showed no signs of cerebral edema, but repeat CT indicated severe cerebral edema. Based on autopsy, diffuse thrombotic angiopathy, with signs of hemolytic anemia with schistocytes, was likely responsible for her deterioration in the broader condition of aHUS/TTP.

Retinal dystrophy associated with Danon disease and pathogenic mechanism through LAMP2-mutated retinal pigment epithelium.

INTRODUCTION: Lysosome-associated membrane protein 2 plays an important role in autophagy and lysosomal function and its mutation is responsible for pathogenesis of Danon disease, which can cause retinopathy, though its pathophysiological contribution to retinal dysfunction remains unclear. The purpose of our research is to report the first case of Japanese Danon disease retinopathy and to understand how LAMP2 dysfunction contributes to pathogenesis of retinopathy. METHODS: One case underwent ophthalmic examination including slit-lamp exam, fundus imaging, visual field testing, and electroretinogram. In molecular biological study, relative messenger RNA expression levels of three splicing variants of Lamp2 or LAMP2 in wild type mouse retina and retinal pigment epithelium, human retinal pigment epithelium cell line adult retinal pigment epithelium-19 were quantified. LAMP2 was knocked down by small interfering RNA in adult retinal pigment epithelium-19 and its effect to LC3, an autophagy marker, was assessed by Western blotting. Intracellular localization of LAMP2 and LC3 in untreated and LAMP2-knocked-down adult retinal pigment epithelium-19 was analyzed by confocal microscopy. RESULTS: Our case manifested cone dystrophy in both eyes. In mice, expression of Lamp2a and Lamp2b was significantly higher in retinal pigment epithelium than that in neural retina. Expression of Lamp2a and Lamp2b were significantly higher than that of Lamp2c in mouse retinal pigment epithelium. Adult retinal pigment epithelium-19 cells showed similar LAMP2 expression pattern to mouse retinal pigment epithelium. LAMP2 knockdown in adult retinal pigment epithelium-19 reduced LC3-II amount and the number and size of autophagosome. DISCUSSION: We report a Japanese case of Danon disease retinopathy, and our study implies that LAMP2 plays an important role in autophagosome formation in retinal pigment epithelium.

A novel LAMP2 p.G93R mutation associated with mild Danon disease presenting with familial hypertrophic cardiomyopathy.

BACKGROUND: Danon disease (DD) is an X-linked dominant multisystem disorder that is associated with cardiomyopathy, skeletal myopathy, and varying degrees of intellectual disability. It results from mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. METHODS: Herein, a proband with a mild DD case presenting with a familial hypertrophic cardiomyopathy (HCM) phenotype and additional family members were evaluated. Exome sequencing and Sanger sequencing were performed to explore the genetic basis of DD in the proband. Segregation, in silico, and functional analyses were carried out to explore potential pathogenicity in the candidate mutation. RESULTS: Exome sequencing and Sanger sequencing identified one novel missense mutation (p.G93R) in the LAMP2 gene in the proband, and this mutation was also identified in three other family members. In silico analysis of LAMP2 predicted that the mutation causes a conformational change and subsequent protein destabilization. Furthermore, functional examination showed that mutation carriers have a significant reduction in LAMP2 expression, which supports that the mutation is pathogenic. Moreover, skewed X chromosome inactivation (XCI) was identified in one female mutation carrier, thus suggesting that skewed XCI may be the reason why this individual escaped the pathogenic influence of the mutation. CONCLUSION: These findings will aid in diagnosing DD patients carrying this LAMP2 mutation that presents with a HCM phenotype. Furthermore, this study illustrates the importance of utilizing a molecular diagnostic approach in HCM patients and is the first study to report a LAMP2 p.G93R mutation associated with mild DD and identify that XCI serves a protective role in DD etiology.

Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene.

Purpose: To describe the phenotype and genotype in a young woman with Danon disease. Methods: The patient underwent an ophthalmic examination including best corrected visual acuity (BCVA), fundus photography and fundus autofluorescence (FAF), full-field electroretinography (full-field ERG), multifocal ERG, optical coherence tomography (OCT) and SAP-Humphrey 30-2 at the ages of 20 and 25. Electrooculography, fluorescein angiography (FA), indocyanine angiography and OCT angiography were performed only once. Genetic testing using a Next-Generation Sequencing panel and immunohistochemical analysis of LAMP2 protein expression were performed in the patient's explanted heart, and the patient's cardiologic and ophthalmologic records were retrospectively reviewed. Results: A de novo, novel, mosaic mutation, c.135dupA; p.(Trp46Metfs*10) was identified in exon 2 of the LAMP2 gene. Immunohistochemical investigation of the myocardium in the explanted heart revealed pronounced deficiency of LAMP2 protein in cardiomyocytes. The color photographs, FAF images and FA revealed more extensive peripheral pigmentary retinal dystrophy (PPRD) at the 5-year follow-up examination. No changes were observed in BCVA, OCT, SAP-Humphrey 30-2 or multifocal ERG findings at follow-up. Full-field ERG showed an asymmetric interocular reduction in ERG response at follow-up: the b-wave amplitude of the rod response had decreased by 29% in the right eye, but by only 6 % in the left eye. The a-wave amplitude of single-flash response had decreased by 9 % in the left eye, while it had increased by 3% in the right eye. Conclusions: Although PPRD progressed slowly, it was an important clue in the diagnosis of the life-threatening condition of Danon disease.

Arrhythmias and fasciculoventricular pathways in patients with Danon disease: A single center experience.

BACKGROUND: Danon disease is a rare X-linked storage disorder characterized by hypertrophic cardiomyopathy leading to arrhythmias and heart failure. A preexcitation pattern on electrocardiogram (ECG) has been described in these patients, however, invasive studies to distinguish between Wolff-Parkinson-White syndrome syndrome and fasciculoventricular pathways (FVP) are limited. OBJECTIVES: The purpose of this study was to delineate the electrophysiological cardiac abnormalities in patients with Danon disease and to describe the presence of FVP in this population. METHODS: We performed a retrospective study of all patients with a confirmed diagnosis of Danon disease presenting to a single center from May 2005 to May 2018. Baseline demographics, clinical characteristics, ECG findings, and electrophysiology study (EPS) results were collected. RESULTS: Ten patients with Danon disease (30% male, average age 17.4 years) were identified. Seven patients (70%) had tachyarrhythmias including five with atrial arrhythmias and six with nonsustained ventricular tachycardia. Preexcitation pattern on ECG was found in four (40%) patients. Of these, two underwent an EPS which confirmed the presence of an FVP. One patient underwent an adenosine challenge which supported a FVP. Implantable cardioverter defibrillator was placed in five patients for primary prevention with no patients receiving an appropriate discharge. Over a follow-up of 5.3 years, five underwent heart transplantation. CONCLUSIONS: This study reports a high incidence of FVP in patients with Danon disease and preexcitation. It underscores an alternate etiology of preexcitation in this population which can potentially be diagnosed without invasive EPS testing. Future multicenter studies are needed to expand this experience.

Danon disease: Gender differences in presentation and outcomes.

BACKGROUND: Danon disease (DD) is a rare X-linked autophagic vacuolar myopathy, characterized by high penetrance and severe cardiomyopathy. Because of its rarity, the natural history (NH) is uncertain. OBJECTIVES: We aimed to describe disease variability and outcomes through a systematic review of all published DD cases. METHODS: Among 83 manuscripts in MEDLINE and EMBASE on DD cases published until October 2017, we identified 146 patients with positive genetic testing for DD or positive muscle biopsy in a relative of a genetically diagnosed proband. RESULTS: 56 females and 90 males were identified. 92.5% of patients had cardiac abnormalities. Females presented with either hypertrophic cardiomyopathy (HCM, 70.3%) or dilated cardiomyopathy (DCM, 29.3%) whereas males presented with HCM 96.2% of the time. The composite outcome of death, heart transplant or ventricular assist devices occurred equally in both sexes (32% of females and 37% of males, p = 0.60) but later in females (median age 38 years) than in males (median age 21 years, p < 0.001). Whereas women present with isolated cardiac disease 73% of the time, in males DD was frequently multisystemic and presented as a triad of cognitive impairment, skeletal myopathy, and HCM in 42% of patients. CONCLUSIONS: In this first systematic review of DD, we confirmed the severe morbidity and mortality associated with disease in both sexes. Women presented with both HCM and DCM and generally with isolated cardiac disease, whereas in men DD usually presented as HCM and was frequently multi-systemic. Further prospective NH studies will be required to confirm these findings.