Background Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency.
Methods Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed.
Results We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.
Conclusion Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.
- nervous system diseases
- early diagnosis
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
Statistics from Altmetric.com
Correction notice Since this article was first published, the institution Institute for Neurophysiology, University of Cologne has been added to Karim Daliri's author affiliations.
Contributors Conceptualisation: FD, LL and TBH; data curation and writing the manuscript: LL and FD; biochemical investigations: AS, DH and SP; genetic analyses: LL, TBH, SP, RF, DG, AM, MG, SB-W, MW, AR, KS, PEB, MB and TF; clinical data acquisition: JK, KD, PK, KD, SL, VA, FB, GV, RS and FD; patient evaluation: AOC, HG, DM, PMT, VT, PJ and EM; MRI analyses: IK-M, IK, SG and LL.
Funding SG and IK-M are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510.The study was supported by a grant of the German Research Foundation/Deutsche Forschungsgemeinschaft (DI 1731/2-2 to FD) and by a grant from the “Elterninitiative Kinderkrebsklinik e.V.” (Düsseldorf; #701900167).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.