Dataset Information

Cardiac arrest in kearns-sayre syndrome.

ABSTRACT: The prognosis of progressive ophthalmoplegia in patients with large-scale mitochondrial DNA deletions is highly variable and almost unpredictable. The risk to develop cardiac involvement and sudden cardiac death is strikingly high, especially in patients with Kearns-Sayre syndrome (KSS). The most typical cardiac complications of the disease are conduction defects, which usually begin with left anterior fascicular block with or without right bundle branch block (RBBB), progressing sometimes rapidly to complete atrioventricular block. Other cardiac manifestations reported are first or second degree of AV block, QT prolongation, torsades de pointes ventricular tachycardia, and rarely dilated cardiomyopathy. Most frequently syncope, sometimes even sudden cardiac death, is the first clinical sign of the cardiac disease in KSS. Due to these life-threatening cardiac conditions, patients should be carefully monitored for cardiac signs and symptoms and pacemaker implantation should be suggested early to avoid sudden cardiac arrest in KSS.Here, we present two cases of KSS with life-threatening syncope due to complete atrioventricular block. To emphasize the importance of an early pacemaker implantation, we review the literature on cardiac complications in KSS in the last 20 years. In almost all of the reviewed cases, ophthalmoplegia or ptosis was present before the cardiac manifestations. In most of the cases, syncope was the first symptom of the cardiac involvement. There was no correlation between the age of the onset of the disease and the onset of cardiac manifestations.With our current report, we increase awareness for life-threatening cardiac complications in patients with KSS.

SUBMITTER: van Beynum I

PROVIDER: S-EPMC3509832 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cardiac arrest in kearns-sayre syndrome.

van Beynum Ingrid I Morava Eva E Taher Marjan M Rodenburg Richard J RJ Karteszi Judit J Toth Kalman K Szabados Eszter E

JIMD reports 20110906

The prognosis of progressive ophthalmoplegia in patients with large-scale mitochondrial DNA deletions is highly variable and almost unpredictable. The risk to develop cardiac involvement and sudden cardiac death is strikingly high, especially in patients with Kearns-Sayre syndrome (KSS). The most typical cardiac complications of the disease are conduction defects, which usually begin with left anterior fascicular block with or without right bundle branch block (RBBB), progressing sometimes rapid ...[more]

PMID: 23430846

Similar Datasets

Project description:Kearns Sayre syndrome (KSS) is mitochondrial multisystem disorder with no proven effective treatment. The underlying cause for multisystem involvement is the energy deficit resulting from the load of mutant mitochondrial DNA (mtDNA), which manifests as loss of cells and tissue dysfunction. Therefore, functional organ or cellular replacement provides a promising avenue as a therapeutic option. Patient-specific induced pluripotent stem cells (iPSC) have become a handy tool to create personalized cell -based therapies. iPSC are capable of self-renewal, differentiation into all types of body cells including cardiomyocytes (CM) and neural progenitor cells (NPC). In KSS patients, mutations in mtDNA are largely found in the muscle tissue and are predominantly absent in the blood cells. Therefore, we conceptualized that peripheral blood mononuclear cells (PBMNC) from KSS patients can be reprogrammed to generate mutation free, patient specific iPSC lines that can be used as isogenic source of cell replacement therapies to treat affected organs. In the current study we generated iPSC lines from two female patients with clinical diagnosis of classic KSS. Our data demonstrate that iPSC from these KSS patients showed normal differentiation potential toward CM, NPC and fibroblasts without any mtDNA deletions over passages. Next, we also found that functional studies including ATP production, reactive oxygen species generation, lactate accumulation and mitochondrial membrane potential in iPSC, CM, NPC and fibroblasts of these KSS patients were not different from respective cells from healthy controls. PBMNCs from these KSS patients in the current study did not reproduce mtDNA mutations which were present in muscle biopsies. Furthermore, we demonstrate for the first time that this phenomenon provides opportunities to create isogenic mutation free iPSC with absent or very low level of expression of mtDNA deletion which can be banked for future cell replacement therapies in these patients as the disease progresses.

Project description:Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband's fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.

Dataset Information

Cardiac arrest in kearns-sayre syndrome.

Publications

Cardiac arrest in kearns-sayre syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets