RESUMEN
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.
Asunto(s)
Vías Biosintéticas/genética , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Metiltransferasas/deficiencia , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/deficiencia , Ubiquinona/análogos & derivados , Biopsia , Ataxia Cerebelosa/dietoterapia , Ataxia Cerebelosa/metabolismo , Variaciones en el Número de Copia de ADN , Suplementos Dietéticos , Transporte de Electrón , Femenino , Fibroblastos/metabolismo , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucocitos/metabolismo , Metiltransferasas/genética , Encefalomiopatías Mitocondriales/dietoterapia , Encefalomiopatías Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Músculos/patología , Consumo de Oxígeno , Linaje , Polimorfismo de Nucleótido Simple , Hermanos , Ubiquinona/biosíntesisRESUMEN
Despite the current acceleration and increasing leadership of Chinese genetics research, genetics and its clinical application have largely been imported to China from the Occident. Neither genetics nor the scientific reductionism underpinning its clinical application is integral to the traditional Chinese worldview. Given that disease concepts and their incumbent diagnoses are historically derived and culturally meaningful, we hypothesize that the cultural expectations of genetic diagnoses and medical genetics practice differ between the Occident and China. Specifically, we suggest that an undiagnosed diseases program in China will differ from the recently established Undiagnosed Diseases Program at the United States National Institutes of Health; a culturally sensitive concept will integrate traditional Chinese understanding of disease with the scientific reductionism of Occidental medicine.