Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes. Issue 9 (16th October 2021)

• Record Type: Journal Article
• Authors: Laugwitz, Lucia; Seibt, Annette; Herebian, Diran; Peralta, Susana; Kienzle, Imke; Buchert, Rebecca; Falb, Ruth; Gauck, Darja; Müller, Amelie; Grimmel, Mona; Beck-Woedel, Stefanie; Kern, Jan; Daliri, Karim; Katibeh, Pegah; Danhauser, Katharina; Leiz, Steffen; Alesi, Viola; Baertling, Fabian; Vasco, Gessica; Steinfeld, Robert; Wagner, Matias; Caglayan, Ahmet Okay; Gumus, Hakan; Burmeister, Margit; Mayatepek, Ertan; Martinelli, Diego; Tamhankar, Parag Mohan; Tamhankar, Vasundhara; Joset, Pascal; Steindl, Katharina; Rauch, Anita; Bonnen, Penelope E; Froukh, Tawfiq; Groeschel, Samuel; Krägeloh-Mann, Ingeborg; Haack, Tobias B; Distelmaier, Felix;
• Is Part Of: Journal of medical genetics. Volume 59:Issue 9(2022)
• Page Start: 878
• Page End: 887
• Publication Date: 2021-10-16
• Subjects: nervous system diseases -- pediatrics -- epilepsy -- early diagnosis; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2021-107729
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.