Primary Coenzyme Q10 Deficiency-7 and Pathogenic COQ4 Variants: Clinical Presentation, Biochemical Analyses, and Treatment

Abstract

Primary Coenzyme Q10 Deficiency-7 (COQ10D7) is a rare mitochondrial disorder caused by pathogenic COQ4 variants. In this review, we discuss the correlation of COQ4 genotypes, particularly the East Asian-specific c.370G > A variant, with the clinical presentations and therapeutic effectiveness of coenzyme Q10 supplementation from an exon-dependent perspective. Pathogenic COQ4 variants in exons 1–4 are associated with less life-threating presentations, late onset, responsiveness to CoQ10 therapy, and a relatively long lifespan. In contrast, pathogenic COQ4 variants in exons 5–7 are associated with early onset, unresponsiveness to CoQ10 therapy, and early death and are more fatal. Patients with the East Asian-specific c.370G > A variant displays intermediate disease severity with multi-systemic dysfunction, which is between that of the patients with variants in exons 1–4 and 5–7. The mechanism underlying this exon-dependent genotype-phenotype correlation may be associated with the structure and function of COQ4. Sex is shown unlikely to be associated with disease severity. While point-of-care high-throughput sequencing would be useful for the rapid diagnosis of pathogenic COQ4 variants, whereas biochemical analyses of the characteristic impairments in CoQ10 biosynthesis and mitochondrial respiratory chain activity, as well as the phenotypic rescue of the CoQ10 treatment, are necessary to confirm the pathogenicity of suspicious variants. In addition to CoQ10 derivatives, targeted drugs and gene therapy could be useful treatments for COQ10D7 depending on the in-depth functional investigations and the development of gene editing technologies. This review provides a fundamental reference for the sub-classification of COQ10D7 and aim to advance our knowledge of the pathogenesis, clinical diagnosis, and prognosis of this disease and possible interventions.

Ethnically unique disease burden and limitations of current expanded carrier screening panels

“…Biallelic mutations in the COQ4 gene leads to impairment in CoQ10 biosynthesis, resulting in primary coenzyme Q10 deficiency. The severe mitochondrial disorder causes life‐threatening multisystemic dysfunction, where neonatal or infantile‐onset patients often present with clinical features of lactic acidosis, cardiomyopathy, seizures, hypotonia, respiratory distress and encephalopathy 21 . The variant c.370G>A (p.Gly124Ser) in exon 4 of the COQ4 gene was previously identified as a pathogenic founder mutation in the southern Chinese population, 22 and the allele was exclusively found in four East Asians in gnomAD (gnomAD browser v3.1.2).…”

Biallelic variants in the COQ4 gene caused hereditary spastic paraplegia predominant phenotype

“…The most important role of CoQ10 is as an electron carrier, which can shuttle electrons derived from complexes I (NADH: ubiquinone oxidoreductase) and II (succinate dehydrogenase) to complex III (ubiquinone‐cytochrome c oxidoreductase). It is also reported to be involved in several other essential biological processes, such as biosynthesis of pyrimidine, antioxidant response, regulation of the mitochondrial structural stabilization, β‐oxidation of fatty acids, apoptosis, and so on 8 . So far, there are more than 10 genes directly related to biosynthesis of CoQ10 ( ADCK3 , PDSS1 , PDSS2 , COQ2 , COQ3 , COQ4 , COQ5 , COQ6 , COQ7 , COQ8A , COQ8B , COQ9 , COQ10A , and COQ10B ).…”

“…Among the primary CoQ10 deficiency‐related genes, COQ4 is relatively newly identified. To date, 62 COQ10D7 patients including 21 Chinese patients presenting various clinical phenotypes and 39 variants have been described worldwide by WES 8,16,17 …”

“…Pathogenic variants in COQ4 (MIM 612898) are the cause of autosomal recessive primary CoQ10 deficiency‐7 (COQ10D7), first identified in 2015 7 . The COQ10D7 has an extremely broad phenotypic spectrum, manifesting as lethal neonatal‐onset mitochondrial encephalopathy, developmental delay, cognitive defects, epilepsy, childhood‐onset ataxia, visual dysfunction, cardiomyopathy, and respiratory insufficiency 8 . Some of the clinical features of COQ10D7 overlap with those of HSP.…”

“…to complex III (ubiquinone-cytochrome c oxidoreductase). It is also reported to be involved in several other essential biological processes, such as biosynthesis of pyrimidine, antioxidant response, regulation of the mitochondrial structural stabilization, β-oxidation of fatty acids, apoptosis, and so on 8. So far, there are more than 10 genes directly re-…”