Abstract
Primary coenzyme Q10 (CoQ(10) ; 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 CoQ(10) , and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ(10) 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 CoQ(10) in peripheral white blood cells of all affected individuals and reduced CoQ(10) levels in the only muscle tissue available from one affected proband. CoQ(10) supplementation led to clinical improvement and increased the concentrations of CoQ(10) in blood. This is the first report of primary CoQ(10) deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological, and molecular features, and insights regarding targeted treatment with CoQ(10) supplementation.