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Page 394 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

ptosis with ophthalmoparesis, dystonia, respiratory problems, and gastrointestinal abnormalities become
expressed. The median time from disease onset to death is approximately 1.8 years, with over 50% of
[89]
patients dying due to respiratory complications .
The hallmark findings of bilateral symmetric lesions within the brainstem and basal ganglia structures
[13]
define Leigh syndrome . Pathologically, these lesions consist of spongiform and necrotic tissue. The
advent of MRI imaging has replicated the changes and has essentially replaced the need for pathological
[93]
confirmation . There have been strict clinical criteria for identification of Leigh syndrome involving
neuroradiological/pathological findings, intellectual and motor developmental delay, and elevated serum
[90]
or cerebrospinal fluid lactate . Although the genetic and phenotypic landscape of mitochondrial diseases
has exponentially exploded, Leigh syndrome represents one of the anchoring definitions of mitochondrial
disease expression.

Coenzyme Q10 (CoQ10) or ubiquinone is a 1,4-benzoquinone molecule located within the inner membrane
of the human mitochondrion. It functions within the ETC as an electron shuttle from Complexes I and
II to Complex III. The compound also has properties to act as an antioxidant, it controls mitochondrial
uncoupling, it is required for pyrimidine nucleoside biosynthesis, and it regulates apoptosis [94,95] . There are
15 proteins/enzymes required for CoQ10 synthesis, of which nine are associated with disease. Each of the
CoQ10 synthesis genes (COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, COQ9, PDSS1, and PDSS2) has
[96]
been shown to give rise to primary CoQ10 deficiency . There are also secondary deficiencies of CoQ10
due to variants in APTX, BRAF, and ETFDH, which create a CoQ10 deficient state not directly involved
[95]
in CoQ10 synthesis . However, extensive genetic testing has failed to uncover genetic etiologies of some
[95]
patients who have low CoQ10 levels and compatible disease . The phenotype of CoQ10 deficiency
ranges widely, but mostly involving the renal, cardiac, eye, hearing, muscle, and central nervous system.
A common abnormality is a steroid-resistant nephrotic syndrome associated with COQ2, SOQ6, COQ8B,
and PDSS2 variants. All variants have central nervous system involvement with encephalopathy and many
patients also express seizures and ataxia with comorbid myopathy. Age of onset is quite variable, from birth
to the seventh decade of life. Searching for CoQ10 deficiency is critical in patient management, as high-
dose oral supplementation can be helpful for those with primary and secondary deficiency.

Cytochrome c is a water-soluble 13 kilodalton (kDa) heme protein that shuttles electrons between Complex
III to Complex IV. It is bound to cardiolipin in the IMM. There are two genes responsible the structure
of the protein. HCCS is an X-linked gene encoding the holocytochrome c-type synthetase that covalently
binds the prosthetic heme group to apocytochrome c . There is some evidence that HCCS variants may
[97]
give rise to microphthalmia with linear skin defects syndrome associated with segmental monosomy of
the Xp22 region . The other nuclear-encoded gene involved in synthesis of cytochrome c is CYCS, which
[98]
encodes the apocytochrome c. A loss of function deletion in the CYCS gene has recently been linked to
[99]
non-syndromic thrombocytopenia in a Japanese family . To date, it remains unclear how cytochrome c is
transported into the mitochondria as no mitochondrial leader sequence has been found. Cytochrome c is
also intimately involved in the primary apoptotic pathway. When the cell detects DNA damage, metabolic
stress, or the presence of unfolded proteins, the intrinsic apoptotic pathway is triggered, and cytochrome c
is released into the cytoplasm and triggers programmed cell death [100] .

Disorders of mtDNA, replication, and maintenance
Rearrangements in mitochondrial DNA
Sporadic, mostly non-inherited group of diseases derived from a single large nucleotide deletion in
sizes from 1.3 to 7.6 kb produce three classic mitochondrial syndromes [101] . The most common deletion
is approximately 5 kb in length. The location of this deletion spans the ATPase 8 gene to the ND5 gene,
and both genes are flanked by a perfect 13-base pair-directed nucleotide repeat [102] . In a large study of