A fatal case of COQ7‐associated primary coenzyme Q₁₀ deficiency

Abstract

Background Primary coenzyme Q 10 (CoQ 10 ) deficiencies are clinically and genetically heterogeneous group of disorders associated with defects of genes involved in the CoQ 10 biosynthesis pathway. COQ7 ‐associated CoQ 10 deficiency is very rare and only two cases have been reported. Methods and Results We report a patient with encephalo‐myo‐nephro‐cardiopathy, persistent lactic acidosis, and basal ganglia lesions resulting in early infantile death. Using whole exome sequencing, we identified compound heterozygous variants in the COQ7 gene consisting of a deletion insertion resulting in frameshift [c.599_600delinsTAATGCATC, p.(Lys200Ilefs*56)] and a missense substitution [c.319C>T, p.(Arg107Trp), NM_016138.4]. Skin fibroblast studies showed decreased combined complex II + III activity and reduction in CoQ 10 level. Conclusion This third patient presenting with lethal encephalo‐myo‐nephro‐cardiopathy represents the severe end of this ultra‐rare mitochondrial disease caused by biallelic COQ7 mutations. The response to CoQ 10 supplement is poor and alternative treatment strategies should be developed for a more effective management of this disorder.

A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

“…During the initial ES in 2016, the association of COQ7 and coenzyme Q 10 (CoQ 10 ) deficiency was limited as there was only one article reporting an individual with homozygous variant in 2015 46 . After reanalysis, individual U094 became the third case reported with this diagnosis, caused by compound heterozygous variants in COQ7 47 . He has clinical phenotype compatible to CoQ 10 deficiency and further skin fibroblast testing showed a reduction in CoQ 10 level and decreased combined complex II + III activity, supporting that the biallelic variants may contribute to U094's phenotype 47 .…”

“…After reanalysis, individual U094 became the third case reported with this diagnosis, caused by compound heterozygous variants in COQ7 47 . He has clinical phenotype compatible to CoQ 10 deficiency and further skin fibroblast testing showed a reduction in CoQ 10 level and decreased combined complex II + III activity, supporting that the biallelic variants may contribute to U094's phenotype 47 .…”

Human Mitochondrial Pathologies of the Respiratory Chain and ATP Synthase: Contributions from Studies of Saccharomyces cerevisiae

“…Three cases of primary CoQ 10 deficiency caused by mutations in COQ7 , responsible for the penultimate step of CoQ biosynthesis, have been reported in two children with similar phenotypes of spasticity, sensorineural hearing loss and muscle hypotonia; and a third more severe case of fatal mitochondrial encephalo-myo-nephro-cardiopathy, persistent lactic acidosis, and basal ganglia lesions [ 272 , 273 , 274 ]. In one of the patients, treatment with the unnatural biosynthesis precursor 2,4-dihydroxybenzoate (DHB), a hydroxylated variant of the native 4-hydroxybenzoic acid (4-HB) normally modified by COQ7, increased CoQ 10 levels and partially restored mitochondrial respiration [ 273 ].…”

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

“…In 2019, Kwong et al [46] reported a patient with a severe phenotype characterized by encephalomyonephrocar -diopathy, persistent lactic acidosis, and basal ganglia lesions, who died at 12 months. The patient had intrauterine growth restriction, cardiomegaly, and tricuspid regurgitation since antenatal period.…”

“…Early intervention with CoQ 10 supplementation in high doses has been shown to improve renal function [62] . However, in neonatal cases with neurological involvement, response of CoQ 10 supplementation is poor, probably due to the irreversible brain damage at the time of the diagnosis, as well as the poor bioavailability of CoQ 10 , which does not cross the blood-brain barrier [29,46,53] . New solubilized and stabilized formulations that are able to preserve CoQ 10 in its reduced form (CoQH 2 or ubiquinol) have been developed and increase bioavailability after oral dosing compared to standard ubiquinone [63] .…”