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Eur Heart J. 2016 Aug 21;37(32):2552-9. doi: 10.1093/eurheartj/ehv306. Epub 2015 Jul 17.

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

Author information

1
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
2
Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne, UK.
3
Department of Neurology, Royal London Hospital, London, UK.
4
Department of Cardiology, The London Chest Hospital, London, UK.
5
Hemel Hemstead Hospital, Hertfordshire, UK.
6
East Surrey Hospital, Redhill, UK.
7
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK grainne.gorman@ncl.ac.uk.

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.

KEYWORDS:

Cardiac; Genetic autopsy; Sudden death; m.3243A>G

PMID:
26188002
PMCID:
PMC5008417
DOI:
10.1093/eurheartj/ehv306
[Indexed for MEDLINE]
Free PMC Article

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