The coexistence of dynamin 2 mutation and multiple mitochondrial DNA (mtDNA) deletions in the background of severe cardiomyopathy and centronuclear myopathy

Gál, Anikó; Inczédy-Farkas, Gabriella; Pál, Endre; Remenyi, Viktoria; Bereznai, Benjámin; Gellér, László; Szelid, Zsolt; Merkely, Béla; Molnár, Mária Judit

doi:10.5414/np300789

Cited by 10 publications

(10 citation statements)

References 7 publications

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“…In terms of genotype-phenotype relationship, we found that two genetically confirmed patients had additional heterozygous variants of other recessive myopathies. The coexistence of two causative genes in one patient has rarely been reported (23,24). These additional variants probably serve as a modifier for explaining the genotype-phenotype mismatching, although we did not find an add-on effect in this study.…”

Section: Discussioncontrasting

confidence: 65%

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Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders

et al. 2016

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Inherited muscular disorders (IMDs) are clinically and genetically heterogeneous genetic disorders. We investigated the mutational spectrum and genotype-phenotype correlations in Korean patients with IMD. We developed a targeted panel of 69 known IMD genes and recruited a total of 209 Korean patients with IMD. Targeted capture sequencing identified 994 different variants. Among them, 98 variants were classified as pathogenic/likely pathogenic variants; 38 were novel variations. A total of 39 patients had the pathogenic/likely pathogenic variants. Among them, 75 (36%) patients were genetically confirmed, and 18 (9%) patients had one heterozygous variant of recessive myopathy. However, two genetically confirmed patients had an additional heterozygous variant of another recessive myopathy. Four patients with one heterozygous variant of a recessive myopathy showed different phenotypes, compared with the known phenotype of the identified gene. The major causative genes of Korean patients with IMDs were DMD (19 patients), COL6A1 (9), DYSF (9), GNE (7), LMNA (7), CAPN3 (6), and RYR1 (5). This study showed the mutational and clinical spectra in Korean patients with IMD and confirmed the usefulness of strategies utilizing targeted sequencing.

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Section: Discussioncontrasting

confidence: 65%

“…The coexistence of two causative genes in one patient has rarely been reported (23,24). The coexistence of two causative genes in one patient has rarely been reported (23,24).…”

Section: Discussionmentioning

confidence: 98%

Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders

et al. 2016

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“… 93) A patient with centronuclear myopathy due to a dynamin-2 mutation was also diagnosed with CMP. 94) At age 40, this patient subsequently developed left bundle-branch-block (LBBB), three years after which a pacemaker was implanted. 94) Early-onset dCMP in centronuclear myopathy may require HTX.…”

Section: Resultsmentioning

confidence: 99%

Heart Disease in Disorders of Muscle, Neuromuscular Transmission, and the Nerves

Finsterer

Stöllberger

2016

Korean Circ J

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Little is known regarding cardiac involvement (CI) by neuromuscular disorders (NMDs). The purpose of this review is to summarise and discuss the major findings concerning the types, frequency, and severity of cardiac disorders in NMDs as well as their diagnosis, treatment, and overall outcome. CI in NMDs is characterized by pathologic involvement of the myocardium or cardiac conduction system. Less commonly, additional critical anatomic structures, such as the valves, coronary arteries, endocardium, pericardium, and even the aortic root may be involved. Involvement of the myocardium manifests most frequently as hypertrophic or dilated cardiomyopathy and less frequently as restrictive cardiomyopathy, non-compaction, arrhythmogenic right-ventricular dysplasia, or Takotsubo-syndrome. Cardiac conduction defects and supraventricular and ventricular arrhythmias are common cardiac manifestations of NMDs. Arrhythmias may evolve into life-threatening ventricular tachycardias, asystole, or even sudden cardiac death. CI is common and carries great prognostic significance on the outcome of dystrophinopathies, laminopathies, desminopathies, nemaline myopathy, myotonias, metabolic myopathies, Danon disease, and Barth-syndrome. The diagnosis and treatment of CI in NMDs follows established guidelines for the management of cardiac disease, but cardiotoxic medications should be avoided. CI in NMDs is relatively common and requires complete work-up following the establishment of a neurological diagnosis. Appropriate cardiac treatment significantly improves the overall long-term outcome of NMDs.

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“…Since there were no significant abnormalities in the staining patterns of sarcolemmal proteins, muscular dystrophy was discounted; however, to our knowledge, the existence of CNM was not tested. Recent reports of human cases of CNM coexisting with cardiomyopathy ( Ceyhan-Birsoy et al, 2013 ; Agrawal et al, 2014 ; Gal et al, 2015 ) further highlight the importance of assessing the existence of CNM in skeletal muscles from patients with cardiomyopathy arising from PLN mutations.…”

Section: Discussionmentioning

confidence: 99%

Phospholamban overexpression in mice causes a centronuclear myopathy-like phenotype

Fajardo

Bombardier

McMillan

et al. 2015

Disease Models &Amp; Mechanisms

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Centronuclear myopathy (CNM) is a congenital myopathy that is histopathologically characterized by centrally located nuclei, central aggregation of oxidative activity, and type I fiber predominance and hypotrophy. Here, we obtained commercially available mice overexpressing phospholamban (PlnOE), a well-known inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs), in their slow-twitch type I skeletal muscle fibers to determine the effects on SERCA function. As expected with a 6- to 7-fold overexpression of phospholamban, SERCA dysfunction was evident in PlnOE muscles, with marked reductions in rates of Ca2+ uptake, maximal ATPase activity and the apparent affinity of SERCA for Ca2+. However, our most significant discovery was that the soleus and gluteus minimus muscles from the PlnOE mice displayed overt signs of myopathy: they histopathologically resembled human CNM, with centrally located nuclei, central aggregation of oxidative activity, type I fiber predominance and hypotrophy, progressive fibrosis and muscle weakness. This phenotype is associated with significant upregulation of muscle sarcolipin and dynamin 2, increased Ca2+-activated proteolysis, oxidative stress and protein nitrosylation. Moreover, in our assessment of muscle biopsies from three human CNM patients, we found a significant 53% reduction in SERCA activity and increases in both total and monomeric PLN content compared with five healthy subjects, thereby justifying future studies with more CNM patients. Altogether, our results suggest that the commercially available PlnOE mouse phenotypically resembles human CNM and could be used as a model to test potential mechanisms and therapeutic strategies. To date, there is no cure for CNM and our results suggest that targeting SERCA function, which has already been shown to be an effective therapeutic target for murine muscular dystrophy and human cardiomyopathy, might represent a novel therapeutic strategy to combat CNM.

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The coexistence of dynamin 2 mutation and multiple mitochondrial DNA (mtDNA) deletions in the background of severe cardiomyopathy and centronuclear myopathy

Cited by 10 publications

References 7 publications

Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders

Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders

Heart Disease in Disorders of Muscle, Neuromuscular Transmission, and the Nerves

Phospholamban overexpression in mice causes a centronuclear myopathy-like phenotype

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