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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 27

boy with mental retardation, encephalomyopathy, and dysmorphic features who responded to CoQ
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supplementation (30 mg/kg per day of ubiquinone).

In 2015, the first five patients with point mutations in COQ4 were described. Four of them had prenatal
or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia,
bradycardia, respiratory insufficiency, and heart failure. Two sisters showed antenatal cerebellar hypoplasia,
neonatal respiratory-distress syndrome, and epileptic encephalopathy. Only one patient had a gradually
progressive condition characterized by spastic ataxic gait and seizures. Except for the solitary patient with
the progressive condition, CoQ supplementation was not administered due to fatal early onset. All these
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individuals carried homozygous or compound-heterozygous variants, clearly indicating that the disease is
inherited as autosomal-recessive trait, indicating that haploinsufficiency might not be pathogenic because the
[33]
parents, heterozygous for the nonsense variant, were unaffected .
[34]
Chung et al. described five recessive missense mutations in COQ4 segregating with disease in four families.
All patients presented with a severe multisystemic neonatal form including nervous system manifestations
such as hypotonia, encephalopathy with EEG abnormalities, neonatal seizures, and cerebellar atrophy. Other
manifestations included lactic acidosis, cardiomyopathy, and secondary breathing difficulties. Cerebellar
hypoplasia was a common finding and nephropathy was not present. Only two patients received CoQ
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supplementation, without response.

[35]
Sondheimer et al. identified novel mutations in COQ4 in an infant presenting with early onset biventricular
hypertrophic cardiomyopathy, hypotonia, hearing loss, seizures, and lactic acidosis associated with severe
muscle CoQ deficiency.
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[36]
Ling et al. showed three unrelated Chinese families presenting with the COQ4 c.370G>A (p.G124S) variant,
manifesting as either encephalopathy with intractable seizures and developmental delay or cardiomyopathy
with left ventricle hypertrophy. In the first case of this series, CoQ supplementation (600 mg/day) was
10
started at six years, which resulted in improvement in the patient’s alertness only. In the second patient,
CoQ supplementation was started at 250 mg per day; then, it was increased to 400 mg per day, 3 months
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after symptom onset with some improvement in the control of seizures and patient’s alertness. The patient
had only one further episode of epilepsy at the age of three. The third patient was not treated. The same
homozygous c.370G>A (p.G124S) COQ4 variant was reported in another Chinese patient, who presented
in the second month of life with Leigh syndrome, respiratory distress, lactic acidosis, dystonia, seizures, and
[37]
failure to thrive, without renal involvement .

A recent paper reported 11 additional southern Chinese patients, the largest cohort of COQ4 deficient
patients to date. Five had classical neonatal-onset encephalo-cardiomyopathy, while the other six had
infantile-onset characterized by different constellations of symptoms such as hypotonia, cortical visual
impairment, severe developmental delay, and seizures. Although dystonia was observed in two out of the
six patients with infantile-onset presentation, none displayed basal ganglia lesions. The patients carried the
[37]
[36]
variant c.370G>A, (p.Gly124Ser), previously reported by Ling et al. and Lu et al. , suggesting a founder
effect in the southern Chinese population. Among the 10 patients who received CoQ supplement and with
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continuous follow-up, only 3 showed stabilization of the cardiopathy or seizure control; all were homozygous
for c.370G>A, p. (Gly124Ser). Some improvement was observed in one patient with the heterozygous
missense variants c.370G>A and c.371G>T. Five patients harbored the splicing mutation c.402+1G>A,
[38]
inducing a severe early onset phenotype that was not responsive to CoQ supplementation .
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A recent report expanded the spectrum phenotype of COQ4 mutations to include childhood-onset
spinocerebellar ataxia with stroke-like episodes, associated with a homozygous variant in the COQ4