Clinical phenotype, in silico and biomedical analyses, and intervention for an East Asian population-specific c.370G>A (p.G124S) COQ4 mutation in a Chinese family with CoQ10 deficiency-associated Leigh syndrome

Abstract

COQ4 mutations have recently been shown to cause a broad spectrum of mitochondrial disorders in association with CoQ10 deficiency. Herein, we report the clinical phenotype, in silico and biochemical analyses, and intervention for a novel c.370 G > A (p.G124S) COQ4 mutation in a Chinese family. This mutation is exclusively present in the East Asian population (allele frequency of~0.001). The homozygous mutation caused CoQ10 deficiency-associated Leigh syndrome with an onset at 1-2 months of age, presenting as respiratory distress, lactic acidosis, dystonia, seizures, failure to thrive, and detectable lesions in the midbrain and basal ganglia. No renal impairment was involved. The levels of CoQ10 and mitochondrial respiratory chain complex (C) II + III activity were clearly lower in cultured fibroblasts derived from the patient than in those from unaffected carriers; the decreased CII + III activity could be increased by CoQ10 treatment. Follow-up studies suggested that our patient benefitted from the oral supplementation of CoQ10, which allowed her to maintain a relatively stable health status. Based on the genetic testing, preimplantation and prenatal diagnoses were performed, confirming that the next offspring of this family was unaffected. Our cases expand the phenotypic spectrum of COQ4 mutations and the genotypic spectrum of Leigh syndrome.

Redefining infantile-onset multisystem phenotypes of coenzyme Q10-deficiency in the next-generation sequencing era

“…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 failure to thrive, without renal involvement [37] .…”

“…Although dystonia was observed in two out of the six patients with infantile-onset presentation, none displayed basal ganglia lesions. The patients carried the variant c.370G>A, (p.Gly124Ser), previously reported by Ling et al [36] and Lu et al [37] , suggesting a founder effect in the southern Chinese population. Among the 10 patients who received CoQ 10 supplement and with continuous follow-up, only 3 showed stabilization of the cardiopathy or seizure control; all were homozygous for c.370G>A, p. (Gly124Ser).…”

“…COQ4 is responsible for the stabilization of CoQ multienzyme biosynthetic supercomplex [ Figure 1] [31] . Mutations in COQ4 have emerged lately as common causes of primary CoQ 10 deficiency manifesting with a variety of phenotypes [ Table 1 and Figure 2], dominated by cardiopathy and/or encephalopmyopathy, without renal involvement [32][33][34][35][36][37][38][39][40] .…”

Delineation of molecular findings by whole exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population

“…COQ4 is associated with primary coenzyme Q10 de ciency type 7. 14Subsequent to the rst Chinese study published in 2019 by Lu et al (15), which described a pair of siblings with Leigh syndrome caused by homozygous COQ4 c.370G>A, p.(Gly124Ser), our team published the largest COQ4 cases series with 11 Chinese patients from nine families (including patients 1 to 4 in this study) in collaboration with a Taiwanese group. (16) Our collaborative study proved that CoQ10 de ciency could occur in neonates, infants, or children with variable phenotypes, which altered the original notion that CoQ10 de ciency shows only neonatal onset.…”

Delineation of molecular findings by whole-exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population

“…COQ4 is associated with primary coenzyme Q10 deficiency type 7 [14]. Subsequent to the first Chinese study published in 2019 by Lu et al [15], which described a pair of siblings with Leigh syndrome caused by homozygous COQ4 c.370G>A, p.(Gly124Ser), our team published the largest COQ4 cases series with 11 Chinese patients from nine families (including patients 1 to 4 in this study) in collaboration with a Taiwanese group [16]. Our collaborative study proved that CoQ10 deficiency could occur in neonates, infants, or children with variable phenotypes, which altered the original notion that CoQ10 deficiency shows only neonatal onset [14,17].…”