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

Lookup NU author(s): Dr Charlotte Alston, Marie Appleton, Dr Yi NgORCiD, Professor Grainne Gorman, Professor Bobby McFarlandORCiD, Professor Robert Taylor

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.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.

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Author(s): Cotta A, Alston CL, Baptista-Junior S, Paim JF, Carvalho E, Navarro MM, Appleton M, Ng YS, Valicek J, da-Cunha-Junior AL, Lima MI, de la Rocque Ferreira A, Takata RI, Hargreaves IP, Gorman GS, McFarland R, Pierre G, Taylor RW

Publication type: Article

Publication status: Published

Journal: JIMD Reports

Year: 2020

Volume: 54

Issue: 1

Pages: 45-53

Print publication date: 01/07/2020

Online publication date: 02/06/2020

Acceptance date: 11/02/2020

Date deposited: 15/02/2021

ISSN (print): 2192-8304

ISSN (electronic): 2192-8312

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1002/jmd2.12107

DOI: 10.1002/jmd2.12107

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