A novel inborn error of the Coenzyme Q10 biosynthesis pathway: Cerebellar ataxia and static encephalomyopathy due to COQ5 C-Methyltransferase deficiency

Abstract

Primary coenzyme Q10 (CoQ₁₀; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ₁₀, and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ₁₀ synthetic pathway, have not been implicated in human disease.

Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures and cognitive disability. Whole exome and subsequent whole genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ₁₀ in peripheral white blood cells of all affected individuals and reduced CoQ₁₀ levels in the only muscle tissue available from one affected proband. CoQ₁₀ supplementation led to clinical improvement and increased the concentrations of CoQ₁₀ in blood.

This is the first report of primary CoQ₁₀ deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological and molecular features, and insights regarding targeted treatment with CoQ₁₀ supplementation.

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