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Berardo et al. J Transl Genet Genom 2020;4:22-35 I https://doi.org/10.20517/jtgg.2020.02 Page 31

Investigational treatments
Administration of metabolic intermediates able to “bypass” the enzymatic block and to enable endogenous
synthesis of CoQ has been attempted in experimental in vitro and in vivo models of primary CoQ
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[69]
deficiency, as an alternative to CoQ supplementation , whose therapeutic effects are hampered by its poor
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bioavailability.
In vitro studies
Treatment with 2,4-dihydroxybenzoic acid (DHB, β‐resorcylic acid, β‐RA) was shown to be effective in
human fibroblasts carrying COQ7 pathogenic variants [44,45] and in COQ2-deficient cell lines, increasing the
[70]
levels of CoQ as well as increasing the viability of mutant cells growth in galactose medium .
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[71]
Luna-Sánchez et al. also investigated the effect of DHB in mouse embryonic fibroblasts from two different
mouse models of COQ9 dysfunction (Coq9 R239X/R239X and Coq9 Q95X/Q95X ) showing similar results to those
obtained in COQ2 and COQ7 mutant cells, with different response to treatment based on the severity of the
biochemical defect and the residual levels of COQ7.

Treatment with vanillic acid (VA) recovered CoQ biosynthesis, ATP production, and reduced levels of
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[72]
reactive oxygen species in a human cell line lacking functional COQ6 , a FAD-dependent monooxygenase
[73]
responsible for the addition of the hydroxyl group in position C5 of the quinone ring . Mutations in COQ6
[74]
cause SRNS associated with sensorineural deafness and a variable degree of encephalopathy .
In vivo studies
The first studies to show in vivo efficacy of hydroxylated CoQ precursor compounds 3,4-dihydroxybenzoic
acid, DHB, and VA to rescue endogenous CoQ biosynthesis were performed in yeast models of COQ6 and
COQ7 deficiencies [75,76] .

[77]
More recent studies showed that DHB ameliorated survival and phenotype in Coq7 knock-out mice , while
vanillic acid ameliorated proteinuria and prevented focal segmental glomerulosclerosis in podocyte-specific
[78]
Coq6 knockout mice (Coq6 podKO ), prolonging their survival .
DHB was found to rescue not only the clinical phenotype but also morphological and histopathological signs
of encephalopathy in the Coq9 R239X mouse. The therapeutic effect of DHB was not attributed to the increase
of CoQ levels, but rather to the reduction of DMQ , an intermediated metabolite that may be toxic for
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mitochondrial function when accumulated in the organelle. Thus, the authors proposed that DHB should
be preferentially considered for the treatment of human CoQ deficiency with accumulation of DMQ , as
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10
[79]
mutations in COQ4, COQ7, and COQ9 .
Although all these experimental data suggest that biosynthesis intermediates might be a promising
alternative, further studies are needed to assess therapeutic response, safety, and bioavailability and to
understand their mechanism of action before their translation to the clinical practice.

CONCLUSION
Multisystemic forms of primary CoQ deficiency are usually devastating conditions manifesting in prenatal,
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neonatal, or infantile period of life. Clinical symptoms include variable combinations of encephalomyo-
cardionephropathy syndromes. Although the diagnosis of these primary CoQ deficiency syndromes
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is usually not straightforward, renal involvement, particularly SRNS, can be a clinical clue. In the severe
multisystemic forms, WES is often the first step in the diagnostic workup. Nevertheless, detection of novel
genetic variants of uncertain significance should be followed by biochemical assays and/or functional studies
in patient cells to prove pathogenicity. Eventually, comprehensive characterization of the clinical spectrum of