Dataset Information

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

ABSTRACT:

Aims

To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.3243A>G mutation died suddenly and unexpectedly. The m.3243A>G mutation is present in ?1 in 400 of the population, although the recognized incidence of mitochondrial DNA (mtDNA) disease is ?1 in 5000.

Methods and results

Pathological studies including histochemistry and molecular genetic analyses performed on various post-mortem samples including cardiac tissues (atrium and ventricles) showed marked respiratory chain deficiency and high levels of the m.3243A>G mutation. Systematic review of cause of death in our m.3243A>G patient cohort showed the person-time incidence rate of sudden adult death is 2.4 per 1000 person-years. A further six cases of sudden death among extended family members have been identified from interrogation of family pedigrees.

Conclusion

Our findings suggest that SADS is an important cause of death in patients with m.3243A>G and likely to be due to widespread respiratory chain deficiency in cardiac muscle. The involvement of asymptomatic relatives highlights the importance of family tracing in patients with m.3243A>G and the need for specific cardiac arrhythmia surveillance in the management of this common genetic disease. In addition, these findings have prompted the derivation of cardiac guidelines specific to patients with m.3243A>G-related mitochondrial disease. Finally, due to the prevalence of this mtDNA point mutation, we recommend inclusion of testing for m.3243A>G mutations in the genetic autopsy of all unexplained cases of SADS.

SUBMITTER: Ng YS

PROVIDER: S-EPMC5008417 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

Ng Yi Shiau YS Grady John P JP Lax Nichola Z NZ Bourke John P JP Alston Charlotte L CL Hardy Steven A SA Falkous Gavin G Schaefer Andrew G AG Radunovic Aleksandar A Mohiddin Saidi A SA Ralph Matilda M Alhakim Ali A Taylor Robert W RW McFarland Robert R Turnbull Douglass M DM Gorman Gráinne S GS

European heart journal 20150717 32

<h4>Aims</h4>To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.3243A>G mutation died suddenly and unexpectedly. The m.3243A>G mutation is present in ∼1 in 400 of the population, although the recognized incidence of mitochondrial DNA (mtDNA) disease is ∼1 i ...[more]

PMID: 26188002

Similar Datasets

Project description:BACKGROUND:Sudden cardiac death occurs in ?220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES:This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS:The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS:Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS:Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ?1% of asymptomatic adults.

Dataset Information

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

Aims

Methods and results

Conclusion

Publications

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

Similar Datasets

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