Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes
Lucia Laugwitz, Annette Seibt, Diran Herebıan, Susana Peralta, Imke Kienzle, Rebecca Buchert, Ruth Falb, Darja Gauck, Amelie J. Müller, Mona Grimmel, Stefanie Beck-Woedel, Jan Marco Kern, Karim Daliri, Pegah Katibeh, Katharina Danhauser, Steffen Leiz, Viola Alesi, Fabian Baertling, Gessica Vasco, Robert Steinfeld, Matias Wagner, Ahmet Okay Çağlayan, Hakan Gümüş, Margit Burmeister, Ertan Mayatepek, Diego Martinelli, Parag Tamhankar, Vasundhara Tamhankar, Pascal Joset, Katharina Steindl, Anita Rauch, Penelope E. Bonnen, Tawfiq Froukh, Samuel Groeschel, Ingeborg Krägeloh‐Mann, Tobias B. Haack, Felix Distelmaier
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.