Mitochondrial disease in adults: what's old and what's new?

Patrick F Chinnery

doi:10.15252/emmm.201505079

Abstract

Ten years ago, there was an emerging view that the molecular basis for adult mitochondrial disorders was largely known and that the clinical phenotypes had been well described. Nothing could have been further from the truth. The establishment of large cohorts of patients has revealed new aspects of the clinical presentation that were not previously appreciated. Over time, this approach is starting to provide an accurate understanding of the natural history of mitochondrial disease in adults. Advances in molecular diagnostics, underpinned by next generation sequencing technology, have identified novel molecular mechanisms. Recently described mitochondrial disease phenotypes have disparate causes, and yet share common mechanistic themes. In particular, disorders of mtDNA maintenance have emerged as a major cause of mitochondrial disease in adults. Progressive mtDNA depletion and the accumulation of mtDNA mutations explain some of the clinical features, but the genetic and cellular processes responsible for the mtDNA abnormalities are not entirely clear in each instance. Unfortunately, apart from a few specific examples, treatments for adult mitochondrial disease have not been forthcoming. However, the establishment of international consortia, and the first multinational randomised controlled trial, have paved the way for major progress in the near future, underpinned by growing interest from the pharmaceutical industry. Adult mitochondrial medicine is, therefore, in its infancy, and the challenge is to harness the new understanding of its molecular and cellular basis to develop treatments of real benefit to patients.

Highlights

The year 1988 saw the first description of patients with pathogenic mutations of mitochondrial DNA (Holt et al, 1988; Wallace et al, 1988), opening the floodgates, and paving the way for the new discipline of clinical mitochondrial medicine
Review articles published a over decade ago described a molecular dichotomy between adults and children (Leonard & Schapira, 2000a,b), with mitochondrial DNA (mtDNA) defects typically presenting in adult life, and children typically having autosomal recessive disorders due to presumed defects of the nuclear DNA
One could argue that separate review articles on childhood and adult mitochondrial diseases perpetuate the old dogma

Summary

Introduction

The year 1988 saw the first description of patients with pathogenic mutations of mitochondrial DNA (mtDNA) (Holt et al, 1988; Wallace et al, 1988), opening the floodgates, and paving the way for the new discipline of clinical mitochondrial medicine. Recent exome studies have identified new, unrelated disease mechanisms for mtDNA maintenance disorders, including autosomal dominant mutations in DNA2 (Ronchi et al, 2013), which codes for the DNA replication ATP-dependent helicase/nuclease DNA2; and autosomal recessive mutations in MGME1 which cause secondary mtDNA deletions by disrupting the cleavage of single-stranded mtDNA and the processing of DNA flap substrates (Kornblum et al, 2013). When considered together, these interesting findings raise several important issues for adults with mtDNA diseases. Given recent reports that similar mtDNA mutations accumulate with ageing and may contribute to the ageing process (Payne & Chinnery, 2015), these disorders may be useful models to understand and slowdown the human ageing process itself

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Conclusions

Findings

Conflict of interest