Early-onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion.

Autor: Cotta A; Department of Pathology SARAH Network of Rehabilitation Hospitals Belo Horizonte Brazil., Alston CL; Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne UK.; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Royal Victoria Infirmary Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK., Baptista-Junior S; Department of Pathology SARAH Network of Rehabilitation Hospitals Belo Horizonte Brazil., Paim JF; Department of Pathology SARAH Network of Rehabilitation Hospitals Belo Horizonte Brazil., Carvalho E; Department of Neurophysiology SARAH Network of Rehabilitation Hospitals Belo Horizonte Brazil., Navarro MM; Department of Pediatrics and Genetics SARAH Network of Rehabilitation Hospitals Belo Horizonte Brazil., Appleton M; Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK., Ng YS; Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne UK.; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Royal Victoria Infirmary Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK., Valicek J; Department of Neurophysiology SARAH Network of Rehabilitation Hospitals Belo Horizonte Brazil., da-Cunha-Junior AL; Department of Radiology SARAH Network of Rehabilitation Hospitals Belo Horizonte Brazil., Lima MI; Department of Electron Microscopy SARAH Network of Rehabilitation Hospitals Brasília Brazil., de la Rocque Ferreira A; Department of Molecular Biology SARAH Network of Rehabilitation Hospitals Brasília Brazil., Takata RI; Department of Molecular Biology SARAH Network of Rehabilitation Hospitals Brasília Brazil., Hargreaves IP; Neurometabolic Unit National Hospital for Neurology and Neurosurgery London UK.; School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University Liverpool UK., Gorman GS; Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne UK.; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Royal Victoria Infirmary Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK., McFarland R; Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne UK.; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Royal Victoria Infirmary Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK., Pierre G; South West Regional Metabolic Department Bristol Royal Hospital for Children Bristol UK., Taylor RW; Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne UK.; NHS Highly Specialised Services for Rare Mitochondrial Disorders, Royal Victoria Infirmary Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK.
Jazyk: angličtina
Zdroj: JIMD reports [JIMD Rep] 2020 Jun 02; Vol. 54 (1), pp. 45-53. Date of Electronic Publication: 2020 Jun 02 (Print Publication: 2020).
DOI: 10.1002/jmd2.12107
Abstrakt: Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous subtype of mitochondrial disease. We report two girls with ataxia and mitochondrial respiratory chain deficiency who were shown to have primary CoQ10 deficiency. Muscle histochemistry displayed signs of mitochondrial dysfunction-ragged red fibers, mitochondrial paracrystalline inclusions, and lipid deposits while biochemical analyses revealed complex II+III respiratory chain deficiencies. MRI brain demonstrated cerebral and cerebellar atrophy. Targeted molecular analysis identified a homozygous c.1015G>A, p.(Ala339Thr) COQ8A variant in subject 1, while subject 2 was found to harbor a single heterozygous c.1029_1030delinsCA variant predicting a p.Gln343_Val344delinsHisMet amino acid substitution. Subsequent investigations identified a large-scale COQ8A deletion in trans to the c.1029_1030delinsCA allele. A skin biopsy facilitated cDNA studies that confirmed exon skipping in the fibroblast derived COQ8A mRNA transcript. This report expands the molecular genetic spectrum associated with COQ8A -related mitochondrial disease and highlights the importance of thorough investigation of candidate pathogenic variants to establish phase. Rapid diagnosis is of the utmost importance as patients may benefit from therapeutic CoQ10 supplementation.
Competing Interests: The authors have no conflicts of interest to disclose. All authors have read and approved the submitted manuscript.
(© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
Databáze: MEDLINE
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