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

Gurka, Jiří; Piherová, Lenka; Majer, Filip; Chaloupka, Anna; Žáková, Daniela; Pelák, Ondřej; Krebsová, Alice; Peichl, Petr; Krejčí, Jan; Freiberger, Tomáš; Melenovský, Vojtěch; Kautzner, Josef; Kalina, Tomáš; Sikora, Jakub; Kubánek, Miloš

doi:10.1002/ehf2.12823

Cited by 9 publications

(7 citation statements)

References 30 publications

(91 reference statements)

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“…As an X-linked gene, most female carriers of DMD mutations are asymptomatic although some may develop mild disease or cardiomyopathy, and it was unclear if the PPCM, in this case, was related to her carrier status. However, similar case reports of PPCM amongst DMD and LAMP2 X-linked mutation carriers have been described [ 19 , 20 , 21 ]. LAMP2 mutations cause Danon disease, a form of cardiomyopathy and skeletal myopathy, through impairment of macroautophagy [ 22 ], while DMD mutations cause muscular dystrophy and/or DCM through the loss of the stabilising protein dystrophin, leaving myocytes vulnerable to oxidative stress and calcium overload [ 23 ].…”

Section: The Role Of Familial Cardiomyopathy Genes In Ppcmmentioning

confidence: 60%

Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

Spracklen

Chakafana

Schwartz

et al. 2021

Genes

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Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately 20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation, with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional areas of future investigation may include the delineation of genotype-phenotype correlations and the screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these findings suggest that the construction of a family history may be advised in the management of PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM holds the potential to improve treatment, prognosis, and family management.

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Section: The Role Of Familial Cardiomyopathy Genes In Ppcmmentioning

confidence: 60%

Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

Spracklen

Chakafana

Schwartz

et al. 2021

Genes

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“…A variety of mutations in LAMP-2 have been reported in patients with Danon disease. Most of these mutations are nonsense or frameshift mutations, which result in truncated protein products ( Brambatti et al, 2019 ; Gurka et al, 2020 ). Lack of the transmembrane and cytoplasmic domains at the C-terminal tail abolishes its function as a lysosomal membrane protein ( D’Souza et al, 2014 ).…”

Section: Pathological Role Of Autophagy In Muscle Disordersmentioning

confidence: 99%

The Role of Autophagy in Skeletal Muscle Diseases

Xia

Huang

et al. 2021

Front. Physiol.

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Skeletal muscle is the most abundant type of tissue in human body, being involved in diverse activities and maintaining a finely tuned metabolic balance. Autophagy, characterized by the autophagosome–lysosome system with the involvement of evolutionarily conserved autophagy-related genes, is an important catabolic process and plays an essential role in energy generation and consumption, as well as substance turnover processes in skeletal muscles. Autophagy in skeletal muscles is finely tuned under the tight regulation of diverse signaling pathways, and the autophagy pathway has cross-talk with other pathways to form feedback loops under physiological conditions and metabolic stress. Altered autophagy activity characterized by either increased formation of autophagosomes or inhibition of lysosome-autophagosome fusion can lead to pathological cascades, and mutations in autophagy genes and deregulation of autophagy pathways have been identified as one of the major causes for a variety of skeleton muscle disorders. The advancement of multi-omics techniques enables further understanding of the molecular and biochemical mechanisms underlying the role of autophagy in skeletal muscle disorders, which may yield novel therapeutic targets for these disorders.

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“…The chest X-ray revealed mild cardiomegaly. Echo showed LV hypertrophy with speckles in the myocardium and good contractility (calculated indexed mass was 159 g/m 2 , maximum septal thickness 17 Bottillo et al [14] 5 50 in left ventricle 51 (DCM) 54 c.864+1G>A, p.Val248_Val288del RT-qPCR Sivitskaya et al [15] 6 70 in WBCs Asymptomatic at the age of 38 -c.808dupG, p.Ala270Glyfs*3 HUMARA Chen et al [16] 7 57 in WBCs 25 (DCM) 28 c.445_449delGACCT, p.Asp149Phefs*2 HUMARA Gurka et al [7] 8 46 in WBCs 23 (DCM) 24 c.418delC, p.Leu139Phefs*8 HUMARA Gurka et al [7] 9 40 in WBCs 12 (HCD) 21 Deletion of exons 4-8 g.17916_29069del11154 HUMARA Majer et al [17] 10 30 in WBCs 11 (HCD) -Deletion of exons 4-9C g.19925_45401del25477 HUMARA Majer et al [17] 11…”

Section: Males With C190_191delac Show Early Cardiac Phenotypesmentioning

confidence: 99%

“…Majer et al [18] 12 20 in WBCs 16 (HCD) 27 c.718C>T, p.Gln240* HUMARA Gurka et al [7] 13 18 in WBCs Asymptomatic at the age of 60 -c.277G>A, p.Gly93Arg HUMARA Xu et al [19] DCM: dilated cardiomyopathy; HCM: hypertrophic cardiomyopathy; HT: heart transplantation; HUMARA: human androgen receptor assay; WBCs: white blood cells. mm).…”

Section: Humaramentioning

confidence: 99%

“…[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.…”

Section: Introductionmentioning

confidence: 99%

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New deletion in LAMP2 causing familial Danon disease. Effect of the X-chromosome inactivation

Sivitskaya¹,

Vaikhanskaya²,

Даниленко³

et al. 2022

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Danon disease (DD), a rare X-linked genetic illness with a poor prognosis, is caused by a mutation in the lysosome-associated membrane protein 2 gene (LAMP2). Three main clinical features of this pathology are cardiomyopathy, skeletal myopathy, and mental retardation. Most Danon disease mutations create premature stop codons resulting in the decrease or absence of LAMP2 protein. The present case reports the frameshift variant c.190_191delАС in the LAMP2 in the family with sudden cardiac death history and three members with cardiomyopathy. The presenting phenotype in a female proband with c.190_191delАС was isolated dilated cardiomyopathy in her thirties whereas in two males, DD presented as hypertrophic cardiomyopathy and mild skeletal myopathy since childhood. To examine the contribution of X-inactivation to cardiomyopathy onset we estimated the X-inactivation status in the heart tissue of the affected female. We observed the random pattern (66:34) with the proportion of cardiomyocytes expressing healthy LAMP2 allele reduced to 34%. Deletion c.190_191delАС has led to a complete loss of function LAMP2 due to a single copy of this gene in males. In a woman, cardiomyopathy developed because of both the LAMP2 mutation and a decrease in the expression of a healthy allele in the heart. Based on the strong association of truncating LAMP2 mutations with DD and phenotypes in affected members, the variant c.190_191delАС was classified as pathogenic.

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

Cited by 9 publications

References 30 publications

Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

The Role of Autophagy in Skeletal Muscle Diseases

New deletion in LAMP2 causing familial Danon disease. Effect of the X-chromosome inactivation

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