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.

Highlights

  • Mitochondrial disorders are a common cause of inherited disease, exhibiting marked phenotypic and genotypic heterogeneity

  • The phenotypes associated with the m.3243A.G mutation include clinical syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS),[5] chronic progressive external ophthalmoplegia (CPEO),[6] and maternally inherited deafness and diabetes (MIDD),[7] though the majority of patients have clinical features that do not fit any of these classifications.[8]

  • There was no gross structural cardiac abnormality found in Case 1, and there was only mild left ventricular hypertrophy identified in Case 2

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Summary

Introduction

Mitochondrial disorders are a common cause of inherited disease, exhibiting marked phenotypic and genotypic heterogeneity. The most common form of mitochondria disease is due to the pathogenic mitochondrial DNA (mtDNA) point mutation m.3243A.G in the mt-tRNA leucine gene (MTTL-1). The prevalence of this mutation in the population is 1 in 400,1,2 the reported incidence of clinically manifesting disease due to the mutation ranges from 3.5 to 16.3 per 100 000 in the adult population.[3,4]. The most common causes of death include cardiac events;[12] status epilepticus, stroke-like episodes; aspiration pneumonia or sepsis; paralytic ileus and metabolic acidosis.[13,14]

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