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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 385

INTRODUCTION
Mitochondria are specialized organelles found in all nucleated mammalian cells. Described initially in 1890
and named in 1894, these organelles were shown to house the machinery for oxidative phosphorylation
[1]
in the late 1940s . The advent of clinical mitochondrial disease in medicine did not occur until decades
[2]
later, when a Swedish woman was described with severe hypermetabolism, yet euthyroid . To this day, the
mechanism of her disorder remains a mystery. The seeds of mitochondrial molecular disease were planted
[3,4]
with the description of mitochondria possessing their own DNA . Within several decades, the entire
[5]
mitochondrial genome was sequenced . The genetic era of mitochondrial disease was ushered in 1988,
when pathological variants in two diseases were described. Nine patients with myopathy were proven to
have a single large deletion in mitochondrial DNA (mtDNA) and 33 patients having optic neuropathy with
[6,7]
a pathological variant in a single subunit of Complex I, ND4, in the electron transport chain (ETC) .
The description of a pathological variant in a nuclear-encoded gene followed within the next year. A
[8]
variant in pyruvate dehydrogenase E1 was described in a boy who developed lactic acidosis with exercise .
In 1995, the first pathological variants in an ETC nuclear-encoded gene succinate dehydrogenase subunit
A (SDHA) in Complex II was described in two sisters with Leigh syndrome . The identification of
[9]
mitochondrial diseases has rapidly expanded with gene discovery technological improvements over the last
two decades. Disorders of mitochondrial function are considered the most common group of inborn errors
of metabolism, with an estimated minimum disease prevalence in adults of ~12.5 per 100,000 and ~4.7 per
100,000 in children [10,11] . The difficulty in making a confirmed genetic diagnosis makes prevalence estimates
[12]
low .

DIAGNOSIS OF MITOCHONDRIAL DISEASES: HISTORICAL OVERVIEW
The field of mitochondrial medicine has grown through the improvements in biochemical analysis,
neuroimaging, gene discovery, genetic manipulation/engineering, and cell biology. Until the early 2000s, the
first mitochondrial diseases were based on clinical-biochemical-pathological correlations. Diagnosis was
based on the combination of analyte (e.g., abnormal plasma amino acid and organic acid patterns, serum
and/or lactic acid levels), nuclear magnetic resonance imaging (MRI) findings, and muscle pathological
findings (e.g., ragged red and blue fibers, paracrystalline structures, and abnormal cristae). Utilization
of these testing methods began mitochondrial disease nosology with clinical-pathological correlations
defining multiple mitochondrial syndromes, for example chronic progressive external ophthalmoplegia
(CPEO) and, when accompanied by myopathy, CPEO plus. Leigh syndrome, first described by Denis
Leigh, was defined initially by pathological findings and later by MRI changes, together with the clinical
[13]
symptoms of a rapidly progressive stepwise neurodegenerative process . This strategy led to the definition
of the initial classic mitochondrial syndromes, which have stood the test of time [Table 1].

In the early years of diagnostic investigation, the tools used to validate disease mostly involved muscle
dysfunction combined with biochemical and clinical findings-so much so that, during the decades
preceding the 2000s, primary detection and confirmation of disease was based on findings from muscle
biopsies together with clinical, biochemical, and imaging findings. Histochemical and electron microscopy
analysis of muscle, together with the enzymatic activity of ETC complexes, also known as the respiratory
[14]
chain, were folded into the diagnostic rubric of clinical, biochemical, and neuroimaging findings .
Clinicians used these data to further classify patients who did not fit one of the syndromes, into ETC
abnormalities as Complex I, II, III, IV, or V disease [15,16] . Together with the near constant involvement of the
central nervous system, this led to the term “mitochondrial encephalomyopathy” to describe mitochondrial
[17]
diseases .
Analysis and confirmation of disease during this time required clinical acumen guided by laboratory
analysis. Analyte testing alone is not sufficiently sensitive or specific to absolutely confirm the diagnosis.