Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, Tübingen, Germany.
J Med Genet. 2022 Sep;59(9):878-887. doi: 10.1136/jmedgenet-2021-107729. Epub 2021 Oct 16.
Human coenzyme Q4 (COQ4) is essential for coenzyme Q (CoQ) biosynthesis. Pathogenic variants in cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency.
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.
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 . 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 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.
Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of variants. Due to the insufficient clinical response to oral CoQ supplementation, alternative treatment strategies are warranted.
人类辅酶 Q4（COQ4）是辅酶 Q（CoQ）生物合成所必需的。 致病变体在导致儿童期发病的神经退行性变。我们旨在描绘 COQ4 缺乏症的临床谱和细胞后果。
分析了大量 COQ4 缺乏症儿科患者的临床病程和神经影像学发现。在患者来源的细胞系中进行了功能研究。
我们描述了 36 个 COQ4 缺乏症家族的 44 名个体（16 名新描述）。共鉴定出 23 种不同的变体，包括 中的 4 种新变体。对临床和神经影像学发现的相关性分析显示出三种疾病模式：1 型：具有新生儿脑异常和癫痫性脑病的早发型表型；2 型：具有独特中风样病变的中间型；3 型：具有非特异性脑病理学和稳定病程的中度表型。使用源自患者的成纤维细胞系进行的体外研究支持 变体的功能相关性。实验显示 COQ4 蛋白水平显着降低，细胞 CoQ 水平降低，代谢中间产物 6-去甲氧基泛醌水平升高。
我们的研究描述了 COQ4 缺乏症的异质临床表现，并确定了表型亚型。基于细胞的研究支持 变体的致病性特征。由于口服 CoQ 补充的临床反应不足，需要替代治疗策略。
