Identification of LAMP2 Mutations in Early-Onset Danon Disease With Hypertrophic Cardiomyopathy by Targeted Next-Generation Sequencing

Fu, Lei; Luo, Sushan; Cai, Shuang; Hong, Wenjing; Guo, Ying; Wu, Jinjin; Liu, Tingliang; Zhao, Chongbo; Li, Fen; Huang, Huimin; Huang, Mei‐Rong; Wang, Jian

doi:10.1016/j.amjcard.2016.06.037

Cited by 32 publications

(36 citation statements)

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“…Deficiencies of LAMP2 protein with resultant intracellular vacuoles accumulation in both cardiac and skeletal myocytes were found to account for the development of the disease in our patients. Although Danon disease is considered as a rare entity with unknown prevalence in general population, but cases have been frequently reported in 4% to 33% of selected populations (Arad et al, 2005;Charron et al, 2004;Cheng et al, 2012;Fanin et al, 2006;Fu et al, 2016), in accordance with the finding of our study, suggestive of Danon disease's frequency closely related to the associated clinical phenotypes. To the best of our knowledge, this is the first study reporting the prevalence of Danon disease in patients with coexistent LVH and electrocardiographic preexcitation.…”

Section: Discussionsupporting

confidence: 91%

Prevalence and clinical characteristics of Danon disease among patients with left ventricular hypertrophy and concomitant electrocardiographic preexcitation

Liu

Chen

Wang

et al. 2019

Molec Gen & Gen Med

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Background Cardiac involvement in Danon disease typically manifests as left ventricular hypertrophy (LVH) and ventricular preexcitation. This study aimed to identify patients with Danon disease among patients with LVH and concurrent electrocardiographic preexcitation. Methods Electrocardiographic preexcitation was identified in 10 of 197 patients with unexplained LVH in whom genetic testing was performed using next‐generation sequencing. Results Three (3/10, 30%) patients with Danon disease were found in association with different mutations in the gene of lysosome‐associated membrane protein 2 ( LAMP2 ). Compared to seven patients without Danon disease, these three patients presented with distinctive clinical phenotypes, including onset at an earlier age (20 ± 2 years vs. 53 ± 9 years, p < 0.001), more neurological involvements (100% vs. 0, p = 0.008), higher electrocardiographic voltages (10 ± 1 mV vs. 5 ± 1 mV, p < 0.001), wider QRS complexes (163 ± 5 ms vs. 115 ± 20 ms, p = 0.006), less common asymmetric hypertrophy (0% vs. 86%, p = 0.033), and more frequent elevation of three serum enzymes (creatine kinase, aspartate aminotransferase, and lactate dehydrogenase). Intracellular vacuoles accumulation with deficiencies of LAMP2 protein was found in both cardiac and skeletal myocytes of patients with Danon disease. Conclusion In patients with coexistent LVH and ventricular preexcitation, Danon disease is common with distinctive clinical presentations. Comprehensive assessment of these resemble patients can provide valuable findings for early identification and clinical decision making of patients with Danon disease.

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Section: Discussionsupporting

confidence: 91%

Prevalence and clinical characteristics of Danon disease among patients with left ventricular hypertrophy and concomitant electrocardiographic preexcitation

Liu

Chen

Wang

et al. 2019

Molec Gen & Gen Med

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“…Cardiac symptoms were present in all patients with onset in infancy/childhood or adolescence. The earliest reported onset was in a 3‐month‐old boy in whom HCM was diagnosed following the detection of a heart murmur , and in a 4‐month‐old boy with hypotonia and cardiac failure . The latest onset was in a 45‐year‐old man with a mutation in exon 9b (Tables , ).…”

Section: Clinical Features In Male Patientsmentioning

confidence: 99%

“…In most patients, the first symptoms were heart murmurs , chest pain , palpitations or easy fatigability . Syncopal episodes in young patients were frequent (40% of cases) .…”

Section: Clinical Features In Male Patientsmentioning

confidence: 99%

“…Other ECG abnormalities included complete heart block, supraventricular tachycardia, fascioventricular pathways , delta waves and high precordial voltage . Heart block was present in 35–50% of cases, requiring pacemaker implantation.…”

Section: Clinical Features In Male Patientsmentioning

confidence: 99%

“…Screening of LAMP2 gene mutations by next‐generation sequencing (NGS) in selected series of patients has permitted the identification of an increasing number of DD patients (i.e. DD is more frequent than previously thought), for example, the disease frequency is estimated to be 4–6% among children with hypertrophic cardiomyopathy (HCM) , 0.7–4% among adults with HCM , 6–8% among adults with concentric HCM , 17–30% among patients with both thickened left ventricular (LV) walls and pre‐excitation on ECG , and 33% among patients with vacuolar myopathy and HCM . No DD patient was identified by NGS screening among 72 children with idiopathic dilated cardiomyopathy (DCM) .…”

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confidence: 99%

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Review: Danon disease: Review of natural history and recent advances

Cenacchi

Papa

Pegoraro

et al. 2019

Neuropathology Appl Neurobio

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Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients. The disease is inherited as an X‐linked dominant trait. The primary deficiency of lysosome‐associated membrane protein‐2 (LAMP‐2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives. An early molecular diagnosis is of crucial importance for genetic counselling and for therapeutic interventions: in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.

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LAMP2 exon‐copy number variations in Danon disease heterozygote female probands: Infrequent or underdetected?

Majer

Piherová

Řeboun

et al. 2018

American J of Med Genetics Pt A

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Danon disease (DD) is an X-linked disorder caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene (Xq24). DD is characterized by cognitive deficit, myopathy, and cardiomyopathy in male patients. The phenotype is variable and mitigated in females. The timely identification of de-novo LAMP2 mutated family members, many of whom are heterozygous females, remains critical for their treatment and family counseling. DD laboratory testing builds on minimally invasive quantification of the LAMP2 protein in white blood cells and characterization of the specific mutation. This integrative approach is particularly helpful when assessing suspect female heterozygotes. LAMP2 exon-copy number variations (eCNVs) were so far reported only in X-hemizygous male DD probands. In heterozygous female DD probands, the wild-type allele may hamper the identification of an eCNV even if it results in the complete abolition of LAMP2 transcription and/or translation. To document the likely underappreciated rate of occurrence and point out numerous potential pitfalls of detection of the LAMP2 eCNVs, we present the first two DD heterozygote female probands who harbor novel multi-exon LAMP2 deletions. Critical for counseling and recurrence prediction, we also highlight the need to search for somatic-germinal mosaicism in DD families.

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Identification of LAMP2 Mutations in Early-Onset Danon Disease With Hypertrophic Cardiomyopathy by Targeted Next-Generation Sequencing

Cited by 32 publications

References 13 publications

Prevalence and clinical characteristics of Danon disease among patients with left ventricular hypertrophy and concomitant electrocardiographic preexcitation

Prevalence and clinical characteristics of Danon disease among patients with left ventricular hypertrophy and concomitant electrocardiographic preexcitation

Review: Danon disease: Review of natural history and recent advances

LAMP2 exon‐copy number variations in Danon disease heterozygote female probands: Infrequent or underdetected?

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