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Page 28 Berardo et al. J Transl Genet Genom 2020;4:22-35 I https://doi.org/10.20517/jtgg.2020.02

gene c.230C>T (p.Thr77Ile), reported in two siblings. After the diagnosis at ages 11 and 13 years, CoQ
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supplementation (1000 mg/day) was initiated for both siblings. Although motor outcomes were stable for the
[39]
first year of treatment, one of the patients developed a second stroke-like episode at age 14 .
Finally, a homozygous mutation c.164G>T, p.Gly55Val in COQ4 was reported in two siblings with a
combination of slowly progressive ataxia, spasticity, and seizures, constituting an autosomal recessive
cerebellar ataxia (ARCA) syndrome. The more severely affected patient received high-dose CoQ
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(2000 mg/day) and showed clinically significant improvement; he was originally wheelchair-bound, unable to
walk with support or standing unaided. With treatment, he became able to ambulate with a walker and stand
[40]
without support. After this response, the other patient was also treated, with some improvement as well .
COQ5 (MIM616359)
[41]
COQ5 catalyzes the only C-methylation in the biosynthesis of CoQ [Figure 1] . Mutations in COQ5 have
10
been reported in only three sisters of non-consanguineous Iraqi-Jewish descent. They had varying degrees of
cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, and cognitive disability, with childhood
onset and slow progression [Table 1 and Figure 2]. Neither WES nor WGS was able to identify a potential
pathogenic variant, whereas a SNP array study, performed on the parents and all siblings, identified a tandem
[42]
duplication affecting the last four exons of the gene, confirmed by Sanger analysis .

COQ7 (MIM616733)
[43]
COQ7 is required for one of the three hydroxylations of CoQ benzoquinone ring [Figure 1] . In 2015,
[44]
Freyer et al. described a 9-year-old boy with COQ7 pathogenic variants with complex clinical multiple
organ involvement. The child had a history of neonatal lung hypoplasia, joint contractures, early infantile
hypertension, and left ventricular cardiac hypertrophy, likely secondary to his prenatal kidney dysplasia with
renal dysfunction resulting in oligohydramniosis. Although renal dysfunction normalized during the first
year of life, he progressively developed mental retardation, axono-demyelinating neuropathy, hypotonia,
and hearing loss. The homozygous c.422T>A (p.Val141Glu) variant in COQ7 was identified through WES.
Additional functional studies in the patient fibroblasts confirmed the pathogenicity of the variant.

A second report described a patient carrying the combination of a novel homozygous mutation
(p.Leu111Pro) in COQ7, with the mitochondrial DNA m.1555A>G mutation, commonly associated with
deafness. The phenotype was characterized by a mild form of spastic paraparesia and cognitive impairment
as well as hearing loss. No functional studies were performed to define the cause of the deafness. The authors
hypothesized that the combination of CoQ deficiency and the m.1555A>G mutation leads to synergistic
10
inhibition of mitochondrial function, causing irreversible damages and/or cell death and finally the clinical
[45]
manifestation of hearing loss .
[46]
In 2019, Kwong et al. reported a patient with a severe phenotype characterized by encephalomyonephrocar
-diopathy, persistent lactic acidosis, and basal ganglia lesions, who died at 12 months. The patient had
intrauterine growth restriction, cardiomegaly, and tricuspid regurgitation since antenatal period. WES
identified two compound heterozygous variants in the COQ7 gene: a deletion insertion resulting in
frameshift c.599_600delinsTAATGCATC, p.(Lys200Ilefs*56) and a missense substitution c.319C>T,
p.(Arg107Trp). The proband started CoQ supplementation at 2 months of life; the initial dose
10
is unknown, but it was increased to 20 mg/kg/day at 12 months of life. Nevertheless, the patient
cardiorespiratory manifestations deteriorated and the patient died of sepsis. Skin fibroblast studies supported
pathogenicity by revealing decreased combined complex II + III activity and reduction in CoQ level.
10
COQ9 (MIM614654)
COQ9 is required for the stability and function of COQ7 [Figure 1] [47,48] . Mutations in COQ9 have
been reported in few patients, presenting with the similar lethal neonatal phenotypes characterized by
encephalomyopathy and kidney involvement, including tubulopathy [Table 1 and Figure 2].