title: Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Yi Shiau
authors.initials: YS
authors.lastname: Ng
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Grady
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Nichola Z
authors.initials: NZ
authors.lastname: Lax
authors.affiliation: Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Bourke
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Hardy
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Falkous
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Schaefer
authors.affiliation: Department of Neurology, Royal London Hospital, London, UK.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Radunovic
authors.affiliation: Department of Cardiology, The London Chest Hospital, London, UK.
authors.forename: Saidi A
authors.initials: SA
authors.lastname: Mohiddin
authors.affiliation: Hemel Hemstead Hospital, Hertfordshire, UK.
authors.forename: Matilda
authors.initials: M
authors.lastname: Ralph
authors.affiliation: East Surrey Hospital, Redhill, UK.
authors.forename: Ali
authors.initials: A
authors.lastname: Alhakim
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK grainne.gorman@ncl.ac.uk.
authors.forename: Gráinne S
authors.initials: GS
authors.lastname: Gorman
mesh_terms: D000328:Adult; D004272:DNA, Mitochondrial; D003645:Death, Sudden; D006801:Humans; D008928:Mitochondria; D028361:Mitochondrial Diseases; D009154:Mutation
chemical_list: D004272:DNA, Mitochondrial
keywords: Cardiac; Genetic autopsy; Sudden death; m.3243A>G