TY - JOUR T1 - Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes JF - Journal of Medical Genetics JO - J Med Genet SP - 878 LP - 887 DO - 10.1136/jmedgenet-2021-107729 VL - 59 IS - 9 AU - Lucia Laugwitz AU - Annette Seibt AU - Diran Herebian AU - Susana Peralta AU - Imke Kienzle AU - Rebecca Buchert AU - Ruth Falb AU - Darja Gauck AU - Amelie Müller AU - Mona Grimmel AU - Stefanie Beck-Woedel AU - Jan Kern AU - Karim Daliri AU - Pegah Katibeh AU - Katharina Danhauser AU - Steffen Leiz AU - Viola Alesi AU - Fabian Baertling AU - Gessica Vasco AU - Robert Steinfeld AU - Matias Wagner AU - Ahmet Okay Caglayan AU - Hakan Gumus AU - Margit Burmeister AU - Ertan Mayatepek AU - Diego Martinelli AU - Parag Mohan Tamhankar AU - Vasundhara Tamhankar AU - Pascal Joset AU - Katharina Steindl AU - Anita Rauch AU - Penelope E Bonnen AU - Tawfiq Froukh AU - Samuel Groeschel AU - Ingeborg Krägeloh-Mann AU - Tobias B Haack AU - Felix Distelmaier Y1 - 2022/09/01 UR - http://jmg.bmj.com/content/59/9/878.abstract N2 - 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.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. ER -