Mitochondrial diseases

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Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with mitochondrial diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including mitochondrial donation, will offer a better reproductive choice for these women in the future. The treatment of patients with mitochondrial diseases remains a challenge, but guidelines are available to manage the complications of disease. Moreover, an increasing number of therapeutic options are being considered, and with the development of large cohorts of patients and biomarkers, several clinical trials are in progress.

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Figure 1: Schematic representation of oxidative phosphorylation.
Figure 2: Human mitochondrial genome.
Figure 3: Genes associated with human mitochondrial diseases and their role in mitochondrial function.
Figure 4: Clinical presentations of mitochondrial diseases.
Figure 5: Brain MRI of patients with Leigh syndrome or mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome.
Figure 6: Diagnostic algorithm for suspected mitochondrial diseases.
Figure 7: Heteroplasmy causes mitochondrial bottleneck during oogenesis.
Figure 8: Reproductive options for women with mitochondrial DNA mutations.


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Y.K. received research support from the Japan Agency for Medical Research and Development. D.R.T. receives research support from the Australian National Health and Medical Research Council Principal Research Fellowship and by the Victorian Government's Operational Infrastructure Support Program. G.S.G., R.M.F. and D.M.T. are supported by the Wellcome Trust Centre for Mitochondrial Research, Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and the Medical Research Council (MRC)), the MRC Centre for Neuromuscular Disease, the MRC Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK), the Lily Foundation, the UK National Institute for Health Research (NIHR) Biomedical Research Centre in Age and Age Related Diseases award to the Newcastle-upon-Tyne Hospitals NHS Foundation Trust and UK NHS Specialist Commissioners ‘Rare Mitochondrial Disorders of Adults and Children’ Service. A.S. received research support from the European Research Council, the Sigrid Jusélius Foundation and the Academy of Finland. M.Z. is supported by the MRC and a European Research Council advanced grant.

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Introduction (D.M.T.); Epidemiology (G.S.G. and D.R.T.); Mechanisms/pathophysiology (D.M.T., P.F.C. and M.Z.); Diagnosis, screening and prevention (G.S.G., Y.K., R.M.F. and D.R.T.); Management (S.D. and M.H.); Quality of life (D.M.T. and G.S.G.); Outlook (A.S.); Overview of Primer (G.S.G. and D.M.T.)

Correspondence to Douglass M. Turnbull.

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Gorman, G., Chinnery, P., DiMauro, S. et al. Mitochondrial diseases. Nat Rev Dis Primers 2, 16080 (2016) doi:10.1038/nrdp.2016.80

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