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Hum Mutat. 2018 Jan;39(1):69-79. doi: 10.1002/humu.23345. Epub 2017 Nov 8.

A novel inborn error of the coenzyme Q10 biosynthesis pathway: cerebellar ataxia and static encephalomyopathy due to COQ5 C-methyltransferase deficiency.

Author information

1
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, 20892, Maryland, USA.
2
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA.
3
Inova Translational Medicine Institute, Falls Church, 22042, Virginia, USA.
4
Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, 22042, Israel.
5
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel.
6
The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, 52621, Israel.
7
Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, 5621, Israel.
8
The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, 5621, Israel.
9
Joseph Sagol Neuroscience Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
10
Department of Neurology, Sheba Medical Center, Tel-Hashomer, 5621, Israel.
11
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA.
12
Department of Pathology, Sheba Medical Center, Tel-Hashomer, 52621, Israel.
13
Graduate Partnership Program (GPP), National Institute of Health (NIH), Bethesda, 20892, Maryland, USA.
14
Johns Hopkins University School of Medicine, 733 North Broadway Street, Baltimore, MD, USA.
15
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
16
Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, USA.

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.

KEYWORDS:

COQ5; CoQ10; cerebellar ataxia; encephalopathy; next-generation sequencing; personalized medicine

PMID:
29044765
PMCID:
PMC5722658
DOI:
10.1002/humu.23345
[Indexed for MEDLINE]
Free PMC Article

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