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.
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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.
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