A Nonsense Mutation in COQ9 Causes Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q10 Deficiency: A Potentially Treatable Form of Mitochondrial Disease

Abstract

Coenzyme Q(10) is a mobile lipophilic electron carrier located in the inner mitochondrial membrane. Defects of coenzyme Q(10) biosynthesis represent one of the few treatable mitochondrial diseases. We genotyped a patient with primary coenzyme Q(10) deficiency who presented with neonatal lactic acidosis and later developed multisytem disease including intractable seizures, global developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction. Cultured skin fibroblasts from the patient had a coenzyme Q(10) biosynthetic rate of 11% of normal controls and accumulated an abnormal metabolite that we believe to be a biosynthetic intermediate. In view of the rarity of coenzyme Q(10) deficiency, we hypothesized that the disease-causing gene might lie in a region of ancestral homozygosity by descent. Data from an Illumina HumanHap550 array were analyzed with BeadStudio software. Sixteen regions of homozygosity >1.5 Mb were identified in the affected infant. Two of these regions included the loci of two of 16 candidate genes implicated in human coenzyme Q(10) biosynthesis. Sequence analysis demonstrated a homozygous stop mutation affecting a highly conserved residue of COQ9, leading to the truncation of 75 amino acids. Site-directed mutagenesis targeting the equivalent residue in the yeast Saccharomyces cerevisiae abolished respiratory growth.

Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9

“…6,11 In mice, this metabolite was identified as 6-demethoxy ubiquinone 9 . Detailed human studies are lacking so far.…”

“…The case, together with the description of Duncan et al, places COQ9 deficiency among the most severe forms of CoQ 10 metabolism disorders, comparable to descriptions in patients with defects in COQ2 or COQ4. 6,13,14 However, further clinical descriptions will be required to evaluate the specific clinical spectrum of patients with COQ9 mutations. As suggested by Duncan et al, 6 CoQ 10 treatment might be helpful in COQ9-deficient children.…”

“…6,13,14 However, further clinical descriptions will be required to evaluate the specific clinical spectrum of patients with COQ9 mutations. As suggested by Duncan et al, 6 CoQ 10 treatment might be helpful in COQ9-deficient children. Accordingly, in unclear cases of neonatal/ early childhood mitochondrial disease, an empirical medication with CoQ 10 is recommended.…”

“…Until now, just a single patient with CoQ 10 deficiency caused by a homozygous stop variant in COQ9 c.730C4T, p.Arg244*, leading to neonatal lactic acidosis, intractable seizures and global developmental delay, has been reported. 6 Using exome sequencing, we identified a new variant affecting function in COQ9 associated with neonatal encephalopathy and early death. Our report expands the clinical spectrum associated with COQ9 variants and indicates a severe pre-/neonatal-onset phenotype.…”

Mitochondrial disease—an important cause of end-stage renal failure

“…However, and importantly, Montini et al reported that pre-symptomatic treatment with high doses of coenzyme Q 10 was associated with an excellent clinical outcome in a patient with COQ2 mutations, with no progression of renal disease and no evidence of neurological dysfunction [15]. Renal tubulopathy was noted in the only patient reported with COQ9 mutation to date [16].…”