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Saneto. J Transl Genet Genom 2020;4:384-428 Journal of Translational
DOI: 10.20517/jtgg.2020.40 Genetics and Genomics

Review Open Access

Mitochondrial diseases: expanding the diagnosis in
the era of genetic testing

Russell P. Saneto 1,2

1 Center for Integrative Brain Research, Neuroscience Institute, Seattle, WA 98101, USA.
2 Department of Neurology/Division of Pediatric Neurology, Seattle Children’s Hospital/University of Washington, Seattle, WA
98105, USA.

Correspondence to: Dr. Russell P. Saneto, Department of Neurology/Division of Pediatric Neurology, Seattle Children’s Hospital/
University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA. E-mail: russ.saneto@seattlechildrens.org
How to cite this article: Saneto RP. Mitochondrial diseases: expanding the diagnosis in the era of genetic testing. J Transl Genet
Genom 2020;4:348-428. http://dx.doi.org/10.20517/jtgg.2020.40
Received: 29 Jun 2020 First Decision: 27 Jul 2020 Revised: 15 Aug 2020 Accepted: 21 Aug 2020 Available online: 29 Sep 2020

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

Abstract
Mitochondrial diseases are clinically and genetically heterogeneous. These diseases were initially described a
little over three decades ago. Limited diagnostic tools created disease descriptions based on clinical, biochemical
analytes, neuroimaging, and muscle biopsy findings. This diagnostic mechanism continued to evolve detection
of inherited oxidative phosphorylation disorders and expanded discovery of mitochondrial physiology over
the next two decades. Limited genetic testing hampered the definitive diagnostic identification and breadth of
diseases. Over the last decade, the development and incorporation of massive parallel sequencing has identified
approximately 300 genes involved in mitochondrial disease. Gene testing has enlarged our understanding of
how genetic defects lead to cellular dysfunction and disease. These findings have expanded the understanding of
how mechanisms of mitochondrial physiology can induce dysfunction and disease, but the complete collection
of disease-causing gene variants remains incomplete. This article reviews the developments in disease gene
discovery and the incorporation of gene findings with mitochondrial physiology. This understanding is critical to
the development of targeted therapies.

Keywords: Mitochondria, oxidative phosphorylation, electron transport chain, genetic pathological variants,
phenotype, genotype

© 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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