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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 29
[49]
In 2009, Duncan et al. described the first variant in COQ9 (c.730C>T, p.Arg244*), in a patient from an
apparently non-consanguineous Pakistani family, who presented with neonatal lactic acidosis, intractable
seizures, global developmental delay, microcephaly, dystonia, left ventricular hypertrophy, and renal tubular
[50]
dysfunction .
[51]
Danhauser et al. described another infant carrying a homozygous splice-site variant c.521+1del, p.(Ser127_
Arg202del) in COQ9, manifesting with neonatal encephalopathy with hypotonia, poor breathing, and severe
lactic acidosis with symmetrical hyperechoic signal alterations in the basal ganglia, suggestive of neonatal
Leigh-like syndrome. The patient subsequently developed seizures and recurrent episodes of apnea and
bradycardia and died at 18 days of life.

[52]
In 2018, Smith et al. reported four siblings, who presented prenatally with an unknown and an ultimately
lethal condition characterized by intrauterine growth retardation, oligohydramnios, variable dilated
cardiomyopathy, anemia, abnormal appearing kidneys, and autopsy brain findings suggestive of Leigh
disease. The patients had the variants c.521+2T>C and c.711+3G>C in COQ9, which cause in-frame deletions
(p.Ser127_Arg202del and p. Ala203_Asp237del).

In 2019, a novel frameshift c.384delG (Gly129Valfs*17) homozygous mutation was reported in a 9-month-old
girl, born from consanguineous parents of Pakistani origin, presenting with growth retardation, microcephaly,
and seizures. She was born at 38 weeks gestation, weighed 2000 g, after an uncomplicated pregnancy, and was
hospitalized for 3 days due to respiratory distress. At age 4 months, she had sustained clonic seizures. Physical
examination showed microcephaly, truncal hypotonia, and dysmorphic features. Abdominal ultrasonography
revealed cystic kidneys. Non-compaction of the left ventricle was detected in echocardiography.
Cranial MRI showed hypoplasia of the cerebellar vermis and brain stem, corpus callosum agenesis,
and cortical atrophy. CoQ supplementation (5 mg/kg/day) was started when she was 10 months old.
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Despite increasing the dose to 50 mg/kg/day after the molecular diagnosis, no neurological improvement
[53]
was observed .

DIAGNOSIS OF EARLY ONSET MULTISYSTEMIC PHENOTYPE OF PRIMARY COQ
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DEFICIENCY
Early onset primary CoQ deficiency is clinically heterogeneous, and genotype-phenotype correlation
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is based on a limited number of cases [9,10] . Four phenotypic groups can be defined: (1) SRNS, isolated or
with neurological involvement, associated with defects in PDSS2, COQ2, COQ6, or COQ8B (the latter
with later age-at-onset); (2) encephalomyopathy, hypertrophic/dilated cardiomyopathy, lactic acidosis, and
tubulopathy with defects in PDSS2, COQ2, COQ7, or COQ9; (3) neonatal cardio-encephalopathies with
COQ2, COQ4, or PDSS1; and (4) pure neurological syndromes, including isolated or combined Leigh
syndrome, ARCA, and refractory epilepsy, in association with defects in COQ2, COQ4, COQ5, COQ7, or
COQ9 [Table 1 and Figure 2] [9,10] .

In general, clinical features alone are insufficient to definitively diagnose CoQ deficiency or to distinguish
10
between primary and secondary CoQ deficiencies, or even from other mitochondrial conditions. Therefore,
10
evaluation of patients with suspected CoQ deficiency relies on genetic or biochemical studies. If the
10
clinical picture and/or family history raise the possibility of a metabolic/genetic condition, WES, including
sequencing of mitochondrial DNA, if available, should be considered the first step. However, only 35% of
[54]
Mendelian diseases are solved by WES because the majority of undiagnosed cases are subject to limitations
in variant‐calling and prioritization, as well as inability to detect intronic and regulatory pathogenic variants.
WGS enables complete coverage of the genome; however, interpretation is often hindered by difficulty in
prioritization of the vast numbers of variants detected and our incomplete understanding of the non-coding