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Page 26 Berardo et al. J Transl Genet Genom 2020;4:22-35 I https://doi.org/10.20517/jtgg.2020.02

Figure 2. Phenotypes associated with CoQ 10 biosynthesis defects

and stroke-like lesions in the left cingulate cortex and subcortical area. His sister presented only with SRNS
at 12 months but was treated before she developed significant neurological manifestations [23,24] .

[28]
In 2007, Diomedi-Camassei et al. described two other patients with early-onset glomerular lesions.
The first patient presented with SRNS at the age of 18 months due to collapsing glomerulopathy, with
no extrarenal symptoms. He had compound heterozygous COQ2 variants c.590G>A (p.Arg197His)
and c.683A>G (p.Asn228Ser). The second patient presented at 5 days of life with oliguria, with severe
extracapillary proliferation on renal biopsy. He rapidly developed end-stage renal disease and died at the age
of 6 months after a course complicated by progressive epileptic encephalopathy. He harbored a homozygous
[29]
c.437G>A (p.Ser146Asn) variant. In 2018, Eroglu et al. reported four patients from two different families
with SRNS and three with insulin dependent neonatal diabetes were described. Despite initial response to
CoQ supplementation in three, all patients developed neurological features, including intractable seizures
10
that did not improve with oral CoQ treatment.
10
[25]
In contrast to the original cases with COQ2 defects and encephalonephropathies, Desbats et al. described a
neonatal case with severe lactic acidosis, proteinuria, dicarboxylic aciduria, hepatic insufficiency, hypokinetic,
and dilated left ventricle on echocardiography, although without clinical signs of cardiomyopathy, who died
[27]
within the first 24 h of life. Scalais et al. described a patient without renal involvement, who presented
at 3 weeks of age with myoclonic epilepsy and hypertrophic cardiomyopathy. Serial brain MRIs performed
at 4 months showed bilateral and symmetrical increased signal intensities within the posterior putamen
and temporal areas and in the rolandic and parasagittal cerebral regions as well as cerebral atrophy and
[26]
increased CSF lactate. Jakobs et al. described dizygotic twins from consanguineous Turkish parents born
prematurely who died at the ages of five and 6 months, respectively, after fluctuating disease courses with
apneas, seizures, feeding problems, and generalized edema. Again, in these patients, there was no evidence of
renal involvement. The patients carried a novel homozygous mutation in COQ2 (c.905C>T, p.Ala302Val).

COQ4 (MIM 616227)
[31]
COQ4 is responsible for the stabilization of CoQ multienzyme biosynthetic supercomplex [Figure 1] .
Mutations in COQ4 have emerged lately as common causes of primary CoQ deficiency manifesting with
10
a variety of phenotypes [Table 1 and Figure 2], dominated by cardiopathy and/or encephalopmyopathy,
without renal involvement [32-40] .

[32]
The initial evidence of COQ4 dysfunction as cause of encephalomyopathy was the report of Salviati et al. ,
who, in 2012, reported a 3.9-Mb deletion of chromosome 9q34.13 encompassing COQ4 in a 3-year-old