A novel inborn error of the coenzyme Q10 biosynthesis pathway: cerebellar ataxia and static encephalomyopathy due to COQ5 C-methyltransferase deficiency.
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.
Malicdan MCV, Vilboux T, Ben-Zeev B, Guo J, Eliyahu A, Pode-Shakked B, Dori A, Kakani S, Chandrasekharappa SC, Ferreira CR, Shelestovich N, Marek-Yagel D, Pri-Chen H, Blatt I, Niederhuber JE, He L, Toro C, Taylor RW, Deeken J, Yardeni T, Wallace DC, Gahl WA, Anikster Y