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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 23

INTRODUCTION
Coenzyme Q (ubiquinone; CoQ , EC 206-147-9) is a lipid molecule widely but variably distributed among
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cellular organelles and tissues. Intracellular CoQ concentration is highest in the lysosomes and Golgi
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[1,2]
vesicles, followed by microsomes and mitochondria . This essential molecule is required for multiple
cellular functions and aspects of metabolism, including ATP synthesis via the mitochondrial respiratory
chain; antioxidant defenses; regulation of the mitochondrial permeability transition pore; activation of
uncoupling proteins; and metabolism of sulfides, proline, arginine, glycine, fatty acids, and pyrimidines [1,3,4] .
CoQ contains a long polyisoprenyl tail of ten isoprene units, which positions the molecule in the mid-plane
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of membrane bilayer, as well as a fully substituted benzoquinone ring that undergoes reversible reduction
[3,5]
and oxidation . The various functions of CoQ depend on the capacity of the benzoate ring to assume
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three different redox states: (1) oxidized (ubiquinone); (2) semioxidized (semiubiquinone); and (3) reduced
[1-4]
(ubiquinol) . Although the main ubiquinone antioxidant function is protection against lipid and protein
peroxidation, ubiquinol also regenerates other powerful antioxidants, such as α-tocopherol and ascorbate,
via electron donation, and recycles them back to their active reduced forms, thereby enhancing activities of
other antioxidant defenses [1-4,6] .

Among the non-mitochondrial enzymatic systems involved in the continuous regeneration of ubiquinol
is selenoprotein thioredoxin reductase (TrxR1), an essential antioxidant enzyme known to reduce many
[6]
compounds, as well as thioredoxin . TrxR1-mediated reduction of CoQ is dependent on its selenocysteine,
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[7,8]
which may account for the relationship between levels of ubiquinone and selenium .
Similar to most other mitochondrial disorders, primary CoQ deficiency is clinically heterogenous,
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presenting at different ages of onset, with variable, multiple organs involvement [9,10] . In the past, diagnosis of
this condition relied only on biochemical assays [10,11] . Specifically, low levels of CoQ in muscle, often, but
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not always, associated with deficiency of CoQ -dependent respiratory chain enzymes (complexes I + III
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[10]
and II + III) activities ; however, identification of pathogenic gene variants, wider use of next-generation
sequencing, and recognition of characteristic phenotypes have greatly facilitated diagnosis of this condition.
For example, the two most frequent and earliest phenotypes associated with CoQ deficiency, steroid-
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resistant nephrotic syndrome (SRNS) and cerebellar ataxia, have been linked to specific molecular defects in
CoQ biosynthetic enzymes, and specific COQ genes have been added to targeted diagnostic panels [e.g.,
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COQ8A, previously known as ADCK3, is included in ataxia gene panels because pathogenic variants in this
gene cause autosomal recessive cerebellar ataxia 2 (ARCA2)] [12,13] .

In contrast, until very recently, diagnoses of the lethal, infantile or childhood-onset multisystemic forms
were reached at late stage of disease or even postmortem, through linkage or homozygous analysis in the
family, in conjunction with biochemical diagnosis, and thus fewer patients were reported, compared to the
other two phenotypes. However, in the last few years, implementation of next generation sequencing (NGS)-
based diagnostics such as whole exome sequencing (WES) and whole genome sequencing (WGS) has caused
a dramatic shift in the diagnosis, from a biochemical approach towards a molecular one, of this phenotype
too. The unbiased genetic screening approach enables early diagnosis in infants and children with complex
[14]
multisystemic syndromes, unveiling novel phenotypes, and molecular defects ; however, it is important to
note that some gene variants of uncertain significance have been reported, without the functional studies
necessary to prove pathogenicity.

To date, 10 genes encoding CoQ biosynthetic proteins have been shown to cause primary CoQ deficiency:
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PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, and COQ9 [Figure 1]. The
presentations include: infantile multisystem disease, with variable combinations of encephalopathy,
[9]
cardiopathy, nephropathy (including SRNS), and cerebellar ataxia; SRNS; and cerebellar ataxia . In this
review, we focus on the molecular defects in CoQ biosynthetic genes that cause early-onset multisystemic
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