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Watson et al. J Transl Genet Genom 2020;4:188-202 Journal of Translational
DOI: 10.20517/jtgg.2020.31 Genetics and Genomics

Review Open Access

New diagnostic pathways for mitochondrial disease

Eloise Watson , Ryan Davis 1,3,4 , Carolyn M. Sue 1,2,3,4
1,2
1 Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, NSW 2065,
Australia.
2 Department of Neurology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
3 Sydney Medical School - Northern, Faculty of Medicine and Health, University of Sydney, St Leonards, Sydney, NSW 2065,
Australia.
4 Translational Genomics, Kinghorn Centre for Clinical Genomics, Garvan Institute for Medical Research, Darlinghurst, Sydney,
NSW 2010, Australia.

Correspondence to: Prof. Carolyn M. Sue, Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital and
University of Sydney, Reserve Road, St Leonards, Sydney, NSW 2065, Australia. E-mail: carolyn.sue@sydney.edu.au

How to cite this article: Watson E, Davis R, Sue CM. New diagnostic pathways for mitochondrial disease. J Transl Genet Genom
2020;4:188-202. http://dx.doi.org/10.20517/jtgg.2020.31

Received: 15 Apr 2020 First Decision: 6 May 2020 Revised: 13 May 2020 Accepted: 18 May 2020 Published: 18 Jun 2020

Science Editor: Andrea L. Gropman Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract
Mitochondrial diseases collectively represent the most common cause of inherited metabolic disease. They are
estimated to affect at least 1 in 8,000 adults and at least 1 in 250 adults carry a disease-causing genetic mutation.
They comprise a heterogeneous group of disorders caused by mutations in either the nuclear or mitochondrial
genome, which ultimately result in dysfunction of the critical cellular energy producing mitochondrial respiratory
chain. Owing to the key role of mitochondria in energy production, mitochondrial disorders predominantly
manifest in tissues with high metabolic demand. However, they demonstrate significant phenotypic and genotypic
variability, often rendering the diagnostic process protracted and challenging. Since Luft’s first description of
mitochondrial disease nearly 60 years ago, substantial evolution in diagnostic techniques have simultaneously
improved the diagnosis and understanding of mitochondrial disease and biology, but the standard diagnostic
approach has failed to evolve at the same pace. Although sequencing technologies and analysis for the diagnosis
of mitochondrial disease continue to evolve, advances to date, our expanding understanding of mitochondrial
diseases and the increasing affordability of these new technologies justify a paradigm shift in the diagnostic
approach. We review the progression, impact and challenges of diagnosing mitochondrial diseases and propose a
minimally invasive “genetics first” approach incorporating stratification using non-invasive biomarkers, followed
by non-targeted next-generation sequencing, such as whole genome sequencing. Such an approach may improve
diagnostic yield and streamline diagnosis, leaving invasive investigations to address diagnostic challenges and
functional validation of novel variants.

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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