Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany; Division of Nephrology, Dialysis and Transplantation, Department of Internal Medicine, Ospedale Policlinico San Martino and University of Genoa, Genoa, Italy; Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy.
Rare Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland; Department of Biology and Medical Genetics, Clinical Genetics Unit, Medical University of Gdańsk, Gdańsk, Poland.
Kidney Int. 2022 Sep;102(3):592-603. doi: 10.1016/j.kint.2022.02.040. Epub 2022 Apr 26.
Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.
原发性辅酶 Q10 缺乏症是一种罕见的线粒体病，其器官受累范围广泛，包括类固醇难治性肾病综合征，主要与 COQ2、COQ6 或 COQ8B 基因的致病变异有关。我们进行了系统的文献回顾、PodoNet、mitoNET 和 CCGKDD 登记处查询和在线调查，收集了 251 名患者的全面临床和遗传数据，这些患者跨越了 173 个已发表（47 个更新）和 78 个新病例。在 COQ2、COQ6 和 COQ8B 致病变异个体中，肾脏疾病的首次诊断中位年龄分别为 1.0、1.2 和 9.8 岁。在诊断时，孤立性肾脏受累发生在 COQ2 变异个体的 34%、COQ6 变异个体的 10.8%和 COQ8B 变异个体的 70.7%。经典婴儿多器官受累占 COQ2 变异队列的 22%，其中 47%的患者在中位年龄 2.7 岁时出现神经症状。COQ6 变异与类固醇难治性肾病综合征和感觉神经性听力损失的关联被确认为 COQ6 变异的独特表型，听力损害在平均 3 岁时出现。COQ8B 变异患者中无一例出现，而 COQ2 和 COQ6 变异患者中有 50%在 5 岁前进展为肾衰竭。在成年时，所有疾病的肾脏存活率都同样较差（20-25%）。一些序列变异，包括假定的局部创始人突变，在发病年龄、肾脏和非肾脏表现以及肾脏存活率方面表现出不同的临床表现。在 COQ8B 变异队列中，双等位基因截断变异的肾脏表型较轻。因此，观察到显著的个体内和个体间表型变异性，表明疾病严重程度存在遗传和非遗传修饰因素。
