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Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes


Laugwitz, Lucia; Seibt, Annette; Herebian, Diran; Peralta, Susana; et al; Steinfeld, Robert; Joset, Pascal; Steindl, Katharina; Rauch, Anita (2022). Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes. Journal of Medical Genetics, 59(9):878-887.

Abstract

BACKGROUND

Human coenzyme Q4 (COQ4) is essential for coenzyme Q$_{10}$ (CoQ$_{10}$) 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 CoQ$_{10}$ 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 CoQ$_{10}$ supplementation, alternative treatment strategies are warranted.

Abstract

BACKGROUND

Human coenzyme Q4 (COQ4) is essential for coenzyme Q$_{10}$ (CoQ$_{10}$) 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 CoQ$_{10}$ 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 CoQ$_{10}$ supplementation, alternative treatment strategies are warranted.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 September 2022
Deposited On:21 Oct 2021 14:01
Last Modified:25 Apr 2024 01:40
Publisher:BMJ Publishing Group
ISSN:0022-2593
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1136/jmedgenet-2021-107729
PubMed ID:34656997