Clinical spectrum in multiple families with primary COQ₁₀ deficiency

Abstract

Coenzyme Q 10/ COQ 10 , an essential cofactor in the electron-transport chain is involved in ATP production. Primary COQ 10 deficiency is clinically and genetically a heterogeneous group of mitochondrial disorders caused by defects in the COQ 10 synthesis pathway. Its mode of inheritance is autosomal recessive and it is characterized by metabolic abnormalities and multisystem involvement including neurological features. Mutations in 10 genes have been identified concerning this group of diseases, so far. Among those, variants of the COQ7 gene are very rare and confined to three patients with Asian ancestry. Here, we present the clinical features and results of whole-exome sequencing (WES) of three Iranian unrelated families affected by primary COQ 10 deficiency. Three homozygous variants in COQ2, COQ4, and COQ7 genes were identified. Candidate variants of the COQ2 and COQ4 genes were novel and associated with the cerebellar signs and multisystem involvement, whereas, the known variant in COQ7 was associated with a mild phenotype that was initially diagnosed as hereditary spastic paraplegia (HSP). This variant has already been reported in a Canadian girl with similar presentations that also originated from Iran suggesting both patients may share a common ancestor. Due to extensive heterogeneity in this group of disorders, and overlap with other mitochondrial/neurological disorders, WES may be helpful to distinguish primary coenzyme Q 10 deficiency from other similar conditions. Given that some features of primary coenzyme Q 10 deficiency may improve with exogenous COQ 10 , early diagnosis is very important.COQ2, COQ4 and COQ7 genes, hereditary spastic paraplegia (HSP), mitochondrial disease, primary COQ 10 deficiencies, whole-exome sequencing (WES) | INTRODUCTIONCoenzyme Q 10 (COQ 10 ), also named ubiquinone, is an electron carrier that contributes as a major electron transporter in the mitochondrial respiratory chain for energy production. COQ 10 structure comprises a long hydrophobic polyisoprenoid tail and a benzoquinone ring for redox activities allowing it to act as a cofactor for many enzymes and uncoupling proteins. The polyisoprenoid tail is synthesized by COQ1 corresponding protein and its length varies in different species. In humans, it consists of 10 isoprene units (COQ 10

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

“…Hashemi et al reported a case in which one of two affected siblings showed cerebellar atrophy and white matter abnormalities on T2 and FLAIR brain MRI sequences [ 24 ]. In another individual, brain MRI at the age of four months revealed bilateral increased signal intensities in the putamen and cerebral cortex (Leigh pattern) [ 25 ].…”

“…MR spectroscopy showed a lactate peak [ 41 ]. A nine-year-old girl with neurological symptoms and COQ7 deficiency referred to by Hashemi et al showed no gross abnormalities in MRI of the brain and spine [ 24 ].…”

Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy

“… 9 Responses to oral supplementation are variable and may be tissue dependent. 5 - 7 , 10 , 11 CoQ 10 treatment has not resulted in a long-term improvement in COQ7 phenotypes, 6 , 7 , 10 , 11 but advances in methods to solubilize CoQ 10 may lead to better outcomes in the future. 9 No experiments to rescue metabolic function of cultured fibroblasts from the affected siblings were performed in this study.…”

“…CoQ 10 deficiencies are frequently treated with a high-dose oral supplementation of CoQ 10 or CoQ 10 precursor molecules that bypass the relevant genetic alteration, with 2,4-dihydroxybensoic acid as a notable example for COQ7 -related CoQ 10 deficiency. 5 - 7 , 9 - 11 However, the efficacy and safety of 2,4-dihydroxybensoic acid has recently been called into question. 9 Responses to oral supplementation are variable and may be tissue dependent.…”

COQ8A-Ataxia as a Manifestation of Primary Coenzyme Q Deficiency

“…Moreover, the spectrum of symptoms of encephalopathy, intellectual disability, seizures, and muscle involvement has been described in patients with variants responsible for other primary coenzyme Q10 deficiency ( COQ2 , COQ4 , COQ6 , COQ7 , COQ9 ) as well as in patients with COQ8A -ataxia. In the case of patients who do not present the ataxia simplex phenotype, and due to similarity in laboratory findings and a wide spectrum of overlapping of other neurological symptoms, it may be hard to differentiate among primary coenzyme Q10 deficiency without genetic testing [ 4 , 72 ].…”