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Page 30 Berardo et al. J Transl Genet Genom 2020;4:22-35 I https://doi.org/10.20517/jtgg.2020.02

sequences. Consequently, the diagnostic yield with WGS is only modestly increased to just over 40% [55-57] . In
parallel with NGS, laboratory analyses should include routine tests such as blood lactate and urine organic
acids, although normal values do not exclude CoQ deficiency.
10
If genetic analysis shows pathogenic homozygous or compound heterozygous variants in any of the
previously reported genes involved in CoQ synthesis with a compatible clinical picture, definitive
10
diagnosis of primary CoQ can be established without further analyses. In presence of variants of uncertain
10
significance, functional and/or complementary studies are needed. Blood mononuclear cells represent a
readily accessible sample, which is often suitable as an alternative to muscle for the measurement of CoQ ,
10
by high performance liquid chromatography or mass spectrometry [11,58] . In contrast, plasma levels of CoQ
10
are influenced by the amount of plasma lipoproteins (carriers of CoQ in circulation), dietary intake,
10
or supplementation, therefore cannot be used for diagnostic purpose. In addition, COQ levels can be
10
measured in other tissues, such as lymphoblastoid cell lines or primary fibroblasts, although normal values
in these tissues do not exclude the diagnosis of CoQ deficiency, as some patients with genetically confirmed
10
CoQ biosynthetic defects have had normal CoQ levels in fibroblasts. As mentioned above, reduced activity
10
10
[10]
of complexes I + III and II + III (and I + III) is highly suggestive of CoQ deficiency .
10
TREATMENT OF EARLY ONSET MULTISYSTEMIC PHENOTYPE OF PRIMARY COQ
10
DEFICIENCY
Current treatments
Humans
Varying doses of CoQ have been used for the treatment of primary CoQ deficiencies, ranging from 5 to
10
10
50 mg/kg/day for both adults and children [10,17] . We cannot compare the effects of different dosages because
[10]
formulations and durations of treatment also varied . We recommend high doses of CoQ supplementation
10
(> 30 mg/kg), because inadequate dosage and duration of intake have often constrained uptake of exogenous
[10]
CoQ 10 [59-61] , with few mild reported side effects .
[62]
Early intervention with CoQ supplementation in high doses has been shown to improve renal function .
10
However, in neonatal cases with neurological involvement, response of CoQ supplementation is poor,
10
probably due to the irreversible brain damage at the time of the diagnosis, as well as the poor bioavailability
of CoQ , which does not cross the blood-brain barrier [29,46,53] . New solubilized and stabilized formulations
10
that are able to preserve CoQ in its reduced form (CoQH or ubiquinol) have been developed and increase
2
10
[63]
bioavailability after oral dosing compared to standard ubiquinone . Experience in patients with primary
CoQ deficiency is limited and there are no clear indications about the dose‐equivalence of ubiquinone and
10
ubiquinol. Short-tail Q analogs, such as idebenone (IDB), are more bioavailable than CoQ but are not
10
10
[64]
effective in patients with primary CoQ deficiency .
10
In vitro and in vivo studies
In vitro studies in human fibroblasts show that short-tail Q analogs, such as CoQ and IDB, are not effective
10
2
[65]
in primary CoQ deficiency because they do not correct the respiratory chain defects .
10
Studies in Pdss2 mutant mice, a mouse model of CoQ-deficient NS, show that CoQ supplementation
10
prevents renal failure through rescue of sulfides metabolism and oxidative stress. In contrast, IDB treatment
was ineffective and comparable to placebo [66,67] .
In a mouse model of CoQ deficiency and encephalomyopathy due to Coq9 dysfunction, the water-soluble
10
[68]
formulation of ubiquinol was shown to be more effective than ubiquinone in rescuing brain abnormalities .