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steadily grew, albeit slowly. To this day, the classic syndromes remain steadfast in phenotype [Table 1], but the
range of clinical presentation suggests a wider complement of genetic etiologies. The rise of commercially
available massive parallel sequencing platforms has transformed the diagnosis and demonstrated an
expansive and diverse group of inherited diseases [Tables 3 and 4]. The increasing range of genetic variants
demonstrating mitochondrial dysfunction is pushing the boundaries of the older nosology of diseases,
genes involved directly in OXPHOS function, and those modulating other mitochondrial physiologies.
There is a trend towards a physiologically based genetic classification. I have tried to use such a scheme in
writing this review.

The lack of a precise definition of primary mitochondrial disease has created diagnostic dilemmas in both
patient identification and inappropriate phenotypes being classified as mitochondrial disease based on
biochemical and/or muscle findings [362] . Isolated genetic findings have shown that unvalidated variants
[29]
once thought to give rise to primary mitochondrial disease are found in healthy individuals . Others have
thought that primary disease is based solely on genetic variants encoding OXPHOS proteins directly or
affecting OXPHOS function by impacting production of the complex machinery needed to run the OXHOS
process [363] . However, the complete ascertainment of mitochondrial physiological functioning is unknown at
present. The advent of widespread genetic testing and validation testing will solidify primary mitochondrial
disease diagnosis and, in time, expand those non-primary diseases that have overlapping phenotypes and
mitochondrial insults. The understanding of these secondary or environmental mitochondrial insults will
help providers to forge better target therapies for inflammation, myopathy, diabetes, neurodegeneration,
and ecogenetic variants altering disease [364] .

The development of effective treatments for mitochondrial diseases represents an enormous challenge. The
extensive range of altered mitochondrial physiology makes clinical management of affected individuals
challenging. In fact, the most recent Cochrane review found there are no reliable and reproducible
treatments for mitochondrial diseases [365] . The advent of expanded genetic testing has identified genetic
abnormalities with altered cofactor availability, which can be amenable to vitamin and/or cofactor
supplementation for disease treatment [366] . Although small in number, these disorders should not be missed
as they represent treatable conditions.

Genetic treatment of disease has recently entered the clinical realm as the Federal Drug Agency (FDA)
approved the use of a single dose of intravenous adeno-associated virus serotype 9 carrying human
survival motor neuron gene (SMN) complementary DNA for patients with spinal motor atrophy [367] .
However, genetic treatment is currently very limited in scope, only used in several diseases, and has not
been FDA approved in mitochondrial disease. Without available treatments, genetic diseases have relied
on counseling, prenatal testing, preimplantation genetic diagnosis, and using surrogate donor or adoption
for family decision making. However, in nuclear diseases, the rare occurrence makes these options only
available once a previous sibling has been identified or strong family history. The unique inheritance of
mtDNA variants has introduced a possible alternative to predictive prenatal counseling, but it relies on
precise genetic testing and biological validation. All mtDNA passed on into oocytes occurs after conception
[53]
within the woman and is sorted by a process named bottleneck . This creates random amounts of mutated
mtDNA in different oocytes, and therefore the result of any pregnancy is uncertain. Prenatal testing is only
viable for those women with low risk of mtDNA transmission and who would consider termination. In
2015, the House of Lords in the United Kingdom enabled mitochondrial replacement [368] . Mitochondrial
replacement or donation involves the removal of the nuclear DNA from a mother with pathological
mtDNA into an oocyte (metaphase II spindle transfer) or zygote (pronuclear transfer) to a donor woman’s
oocyte with normal mtDNA [368] . Currently, this process is only legally supported in the United Kingdom,
whereas, in the rest of the world, it is either not allowed or there is a lack of legal regulation. The long-term
safety of this technique remains uncertain and approval for use is still awaiting confirmation.