66 Ethnic differences in carotid intimal medial thickness and carotid-femoral pulse wave velocity are present in UK children

Abstract

<h3>Background</h3> Human coenzyme Q4 (COQ4) is essential for coenzyme Q₁₀ (CoQ₁₀) biosynthesis. Pathogenic variants in <i>COQ4</i> cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. <h3>Methods</h3> 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. <h3>Results</h3> 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 <i>COQ4</i>. 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 <i>COQ4</i> 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. <h3>Conclusion</h3> Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of <i>COQ4</i> variants. Due to the insufficient clinical response to oral CoQ₁₀ supplementation, alternative treatment strategies are warranted.