A family segregating lethal neonatal coenzyme Q₁₀ deficiency caused by mutations in COQ9

Abstract

Primary CoQ deficiency is a clinically and genetically heterogeneous, autosomal recessive disorder resulting from mutations in genes involved in the synthesis of coenzyme Q (CoQ). To date, mutations in nine proteins required for the biosynthesis of CoQ cause CoQ deficiency with varying clinical presentations. In 2009 the first patient with mutations in COQ9 was reported in an infant with a neonatal-onset, primary CoQ deficiency with multi-system disease. Here we describe four siblings with a previously undiagnosed lethal disorder characterized by oligohydramnios and intrauterine growth restriction, variable cardiomyopathy, anemia, and renal anomalies. The first and third pregnancy resulted in live born babies with abnormal tone who developed severe, treatment unresponsive lactic acidosis after birth and died hours later. Autopsy on one of the siblings demonstrated brain changes suggestive of the subacute necrotizing encephalopathy of Leigh disease. Whole-exome sequencing (WES) revealed the siblings shared compound heterozygous mutations in the COQ9 gene with both variants predicted to affect splicing. RT-PCR on RNA from patient fibroblasts revealed that the c.521 + 2 T > C variant resulted in splicing out of exons 4-5 and the c.711 + 3G > C variant spliced out exon 6, resulting in undetectable levels of COQ9 protein in patient fibroblasts. The biochemical profile of patient fibroblasts demonstrated a drastic reduction in CoQ levels. An additional peak on the chromatogram may represent accumulation of demethoxy coenzyme Q (DMQ), which was shown previously to accumulate as a result of a defect in COQ9. This family expands our understanding of this rare metabolic disease and highlights the prenatal onset, clinical variability, severity, and biochemical profile associated with COQ9-related CoQ deficiencies.

β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9 R239X mice

“…Those differences may reflect the diverse structure and functionality of the mitochondria in different organisms, tissues, and cell types (Vafai & Mootha, 2012). Thus, our study points out the importance of the DMQ 9 /CoQ 9 ratio in the disease phenotype, a fact that is further supported by several evidences: (i) The Coq9 Q95X mouse model has low levels of DMQ 9 and higher levels of CoQ biosynthetic proteins (compared to the Coq9 R239X muse model), and the lifespan is not compromised; (ii) the treatment with ubiquinol-10 in Coq9 R239X mice does not change the DMQ 9 levels and its therapeutic effects are significantly lower than those after b-RA treatment; (iii) the reduction in the DMQ 9 levels in the Coq7 conditional KO mice after b-RA therapy may also contribute to the increased survival observed in this mouse model, although the phenotype of this mouse model is not clear (Wang et al, 2015); and (iv) patients with high levels of DMQ 10 in the samples used for the diagnostic (muscle and/or skin fibroblasts) are associated to severe clinical presentations (Duncan et al, 2009;Freyer et al, 2015;Danhauser et al, 2016;Wang et al, 2017;Smith et al, 2018).…”

“…The therapeutic results are greater than those obtained by the classical oral CoQ supplementation because of the decrease of the DMQ/CoQ ratio. Therefore, b-RA should be preferentially considered for the treatment of human CoQ 10 deficiency with accumulation of DMQ 10 , as it has been reported in patients with mutations in COQ9, COQ7, or COQ4 (Duncan et al, 2009;Freyer et al, 2015;Danhauser et al, 2016;Herebian et al, 2017b;Wang et al, 2017;Smith et al, 2018) but also in cells under siRNA knockdown of COQ3, COQ5 and COQ6 (Herebian et al, 2017b). Similar principles could be applied for 3,4-hydroxybenzoic acid, vanillic acid, 2-methyl-4-hydroxybenzoic acid, or 2,3-dimethoxy-4hydroxybenzoic acid in the cases of mutations in COQ6, COQ5, or COQ3 (Heeringa et al, 2011;Yoo et al, 2012;Ribas et al, 2014;Gigante et al, 2017;Herebian et al, 2017a;Pierrel, 2017), respectively.…”

“…The resulting dysfunctional COQ9 protein causes a profound reduction in the levels of COQ7 protein and disruption of the multiprotein complex for CoQ biosynthesis (Complex Q), resulting in a severe CoQ deficiency with accumulation of demethoxyubiquinone (DMQ = 2-polyprenyl-6-methoxy-3-methyl-1,4-benzoquinone), brain mitochondrial dysfunction, oxidative damage, disruption of sulfide metabolism, reactive astrogliosis, spongiform degeneration, hypotension, and premature death (Garcia-Corzo et al, 2013;Luna-Sanchez et al, 2017). These pathological features are similar to those described in patients with mutations in COQ7 and COQ9, who presented a severe early-onset multisystemic disease dominated by encephalopathy, the phenotype associated with CoQ deficiency with the most limited response to oral CoQ 10 supplementation (Lopez et al, 2006;Duncan et al, 2009;Emmanuele et al, 2012;Danhauser et al, 2016;Smith et al, 2018).…”

Mitochondrial disease in children

“…Although I have started with congenital lactic acidosis as the earliest onset mitochondrial disease, antenatal mitochondrial disease presentations are increasingly recognized. For example, prenatal presentation has been reported in some of the early‐onset CoQ 10 biosynthesis deficiency syndromes [12,13], defects of mitochondrial ribosomal proteins [14,15] and even in POLG disease [16].…”

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

“…In 2018, Smith et al [52] 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).…”