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Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 393

Pathological variants produce two phenotypic syndromes: syndrome of growth retardation, aminoaciduria,
cholestasis, iron overload, and early death (GRACILE) and Bjorstand syndrome (abnormal flattening
and twisting of hair shafts and hearing problems). As with other mitochondrial diseases, there are a
range of phenotypes with variants in the BCS1L gene ranging from adults with aminoacidura, seizures,
[73]
sensorineural deafness, and learning difficulties to infants with early death .

COX or Complex IV is the terminal step of the respiratory chain involved in accepting electrons from
cytochrome c to reduce oxygen to water. COX is composed of 14 subunits; 3 are mtDNA-encoded genes
and 11 are nuclear-encoded genes. Variants in eleven subunits are associated with isolated Complex IV
deficiency: three are mtDNA-encoded, MT-CO1, MT-CO2, and MT-CO3, and eight are nuclear-encoded,
[74]
COX411, COX 412, COX5A, COX6A1, COX6B1, COX7B, COX8A, and NDUFA4 . There are at least 26
known assembly/ancillary proteins with unknown numbers of other proteins, with ten associated with
Complex IV deficiency: CEP89, COX14, COX20, COA3, COA7, COA8, PET100, PET117, TACO1, and
SURF1 . Remarkably, SURF1 pathological variants account for the most common genetic etiology of
[75]
[76]
Leigh syndrome, even though over 79 genes have been documented to cause this disorder . One patient
with variants in COX8A has been reported to induce Leigh syndrome, but why the other 24 assembly/
[77]
ancillary proteins have not been shown to produce this disease is unclear . There has been a milder-form
of Charcot-Marie-Tooth syndrome caused by COX6A1 pathological variants . The protein APOPT1/
[78]
[79]
COA8 has been recently shown to protect COX assembly from oxidation-induced degradation . Biallelic
[80]
APOPT1/COA8 variants have been shown to cause COX deficiency and cavitating leukoencephalopathy .
ATP synthase or Complex V is the final step in ETC, the phosphorylation of ADP to ATP. There are two
functional domains, F1 and Fo. The F1 domain comprises five different subunits and is situated in the
[81]
matrix. Fo domain contains six subunits, which are associated with five accessory subunits . The only two
[5]
mtDNA-encoded subunits are found in the Fo domain, ATP6 and ATP8 genes . Pathological variants in
the ATPase 6 gene have been described as inducing Leigh syndrome . ATPase 6 dysfunction encompasses
[82]
[83]
phenotypes of neuropathy, ataxia, and retinitis pigmentosa and Leigh syndrome based on heteroplasmy .
Additional related phenotypes include leukencephalopathy, seizures, and renal disease . The structural
[84]
gene, ATP5A1, has been described to induce phenotypes ranging from severe infantile encephalopathy
and early death, to a patient with polyneuropathy and mild mental retardation [81,85] . A common nuclear-
[86]
encoded variant disease is encoded by TMEM70, an assembly factor of Complex V . The TMEM70
gene produces a phenotype of neonatal onset, cardiomyopathy, facial dysmorphism, lactic acidosis, and
3-methylglutaconic aciduria. Variants in USMG5 induce loss of Complex V dimerization and loss of cristae
curvature at the apex of cristae, demonstrating dimerization and structural architecture are required for full
[87]
activity of Complex V . USMG5 encodes a small protein that is a supernumerary subunit of Complex V
that is required for Complex V dimerization and ATP synthetase activity .
[88]
One of the common mitochondrial syndromes is Leigh syndrome [Table 1]. Approximately 10% of Leigh
syndrome patients have pathological variants in Complex V, at position m. 8993A>G [89,90] . The other
genetic etiologies of Leigh syndrome represent both mtDNA-encoded and nuclear DNA-encoded genes.
Pathological variants in mtDNA-encoded genes include almost all Complex I subunits, ND1, ND2, ND3,
ND4, ND4L, ND5, and ND6; Complex IV subunit, COX III; and the mt-tRNA-encoding genes for lysine,
[64]
valine, leucine, and tryptophan . The most common nuclear-encoded gene inducing Leigh syndrome is
SURF1, which is an assembly factor for Complex IV [64,91] .

The most common mitochondrial disease in infants and children is Leigh syndrome. Onset is typically
between 3 and 12 months, but can range from birth to adulthood [89,92] . Disease presentation usually begins
in the context of a viral illness or infection, after normal early development. Presentation of feeding issues,
nystagmus, and/or optic atrophy heralds the disorder. Progression of disease is noted by ataxia, eyelid