Page 26 - Read Online

Berardo et al. J Transl Genet Genom 2020;4:22-35 I https://doi.org/10.20517/jtgg.2020.02 Page 25

Table 1. Clinical features associated with specific defects in CoQ biosynthesis
Gene Clinical features
PDSS1 (MIM607429) Deafness, encephaloneuropathy, obesity, livedo reticularis, cardiopathy developmental delay, nephrotic
syndrome, failure to thrive, Leigh syndrome
PDSS2 (MIM610564) SRNS, neurological involvement (ataxia, dystonia, amyotrophia), Leigh syndrome, retinitis pigmentosa,
sensorineural deafness, cardiopathy, lactic acidosis, failure to thrive, optic atrophy
COQ2 (MIM609825) SRNS, encephalopathy (including stroke-like episodes), Multiple-System Atrophy, retinopathy, seizures,
hypotonia, psychomotor delay, nystagmus and optic atrophy
COQ4 (MIM 616227) Cardiopathy, encephalomyopathy, hypotonia, cortical visual impairment, severe developmental delay, seizures
COQ5 (MIM616359) Cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures, cognitive disability
COQ7 (MIM616733) Cardiopathy, neonatal lung hypoplasia, contractures, renal dysfunction (including kidney dysplasia), spastic
paraplegia, cognitive impairment, deafness, encephalopathy, Leigh syndrome, lactic acidosis
COQ9 (MIM614654) Cardiopathy, lactic acidosis, seizures, developmental delay, microcephaly, dystonia, renal tubular dysfunction,
Leigh-like syndrome
SRNS: steroid resistant nephrotic syndrome

Quinzii and Loos reported another infant, with PDSS2 pathogenic variants, who presented at age 2 months
with severe global developmental delay and failure to thrive. Later evaluations showed bilateral optic atrophy,
severe hypotonia, lactic acidosis, renal glomerular dysfunction, Leigh syndrome, and hypertrophy of the
left ventricle. At 8 months oral therapy with l-carnitine (50 mg/kg/day), CoQ (10 mg/kg/day), riboflavin
10
(100 mg/day), and thiamine (50 mg/day) was started without clinical response. The proband developed
generalized status epilepticus; his neurological status deteriorated and he died at 19 months. Postmortem
sequencing identified two novel heterozygous missense mutations: c.590 C>A, p. Ala197Glu and c.932 T>C,
[19]
p. Phe311Ser .

More recently, two novel mutations in PDSS2 were reported in a 7-month-old infant with nephrotic
syndrome, along with encephalomyopathy, hypertrophic cardiomyopathy, deafness, retinitis pigmentosa, and
elevated serum lactate level. Clinical exome sequencing revealed a heterozygous missense variant c.485A>G
(p.His162Arg) and a heterozygous 2923-bp deletion (c.1042_1148-2816del), which causes a 107-base-long
[20]
deletion of exon 8. The patient died at 8 months of age, despite CoQ supplementation (20 mg/kg/day) .
10
[21]
Pathogenic variants in PDSS2 were also reported in two patients with isolated SRNS .
COQ2 (MIM609825)
COQ2 encodes 4-para-hydroxybenzoate:polyprenyl transferase, the second enzyme in the biosynthetic
[22]
pathway of CoQ that condenses the benzoquinone ring with the decaprenyl side chain [Figure 1] .
10
Mutations in the COQ2 gene have been associated with a wide spectrum of phenotypes [Table 1 and
Figure 2], which ranges from a rapidly fatal, neonatal-onset, multisystemic disease [15,23-28] , to a milder form
characterized by SRNS in isolation or associated with encephalopathy [23,28,29] . Mutations in COQ2 have also
been reported in a patient with Multiple-System Atrophy with retinopathy .
[30]

The combination of neurological symptoms with SRNS are the hallmark of the neonatal multisystemic
presentation of mutations in COQ2. SRNS may be the first and predominating feature within the first year of
life, followed by later onset of other manifestations such as refractory seizures, hypotonia, psychomotor delay,
nystagmus, and optic atrophy [15,25,26] . Nevertheless, a few exceptional cases have lacked renal involvement [26,27] .

[24]
In 2006, Quinzii et al. reported the first genetic cause of primary CoQ deficiency, a homozygous c.890
10
A>G (p.Tyr297Cys) variant in COQ2, in a 33-month-old boy . The clinical picture was dominated by
[23]
nephro-encephalopathy with SRNS (proteinuria 4.3 g/day), psychomotor regression, optic atrophy, tremor,
and acute-onset status epilepticus with focal electroencephalogram abnormalities predominantly in the left
occipital region. Brain magnetic resonance imaging showed cerebellar atrophy, mild diffuse cerebral atrophy,