COQ2基因变异致婴儿型肾病综合征一例临床分析并文献复习

Clinical analysis of one infantile nephrotic syndrome caused by COQ2 gene mutation and literaturereview.

目的探讨COQ2基因变异致婴儿型肾病综合征临床及基因学特征。方法回顾性分析2018年2—3月北京大学第一医院儿科诊治的1例COQ2基因致病性变异致婴儿型肾病综合征患儿的临床表现、基因变异特点及预后，并以＂COQ2 gene/primary coenzyme Q10 deficiency；nephrotic syndrome/nephropathy＂＂COQ2基因，原发性辅酶Q10缺乏症＂为关键词，检索PubMed数据库、中国知网和万方数据库建库至2018年7月的相关文献，进行相关文献复习。结果患儿，男，1岁2月龄，3个月前（11月龄时）因＂水肿、大量蛋白尿＂就诊于当地医院，不伴血尿、高血压及肾功能异常，病程中无感染及惊厥发作。1月余前予口服足量糖皮质激素治疗，尿蛋白无缓解。出生史无特殊，有轻度运动发育落后（仅能扶站）及中度语言发育落后（不会说简单话语）。该患儿为母亲第4胎第4产，其父母非近亲婚配、均体健，两个姐姐体健，有一姐姐1岁时因＂肾病＂夭折。遗传性肾脏病基因筛查：COQ2基因c.518G〉A（p.Arg173His）和c.973A〉G（p.Thr325Ala），软件预测显示上述变异均可能导致蛋白质功能受影响，不属于多态性变化，在人群中发生频率极低，均有文献报道。Sanger测序验证该复合杂合变异分别遗传自父母。予减停糖皮质激素改为辅酶Q10 100 mg/次，3次/d治疗[30 mg/（kg· d）]，3周后水肿消退，7周后尿蛋白/肌酐由22.87 mg/mg降至1.98 mg/mg，血浆白蛋白由14.2 g/L升至39.9 g/L，持续监测肝肾功能正常，运动发育较前明显进步。国外文献报道COQ2基因变异可引起肾脏、神经及肌肉等多系统受累，临床表现差异性大，是一种罕见的常染色体隐性遗传病，目前已报道14例有肾脏表现的儿童患者，起病年龄新生儿期至10岁不等（8例于婴儿期起病），主要表现为激素耐药型肾病综合征，部分患儿伴有进展性的脑病、肌病和癫痫发作，早期大量辅酶Q10治疗可改善症状。目前中国有2篇临床研究论文，均是以神经系统表现为主的成人患者，国内尚无儿童肾脏表现的病例报道。结论对婴儿期起病、初治糖皮质激素耐药的肾病综合征患儿，尤其是有发育落后等神经肌肉系统表现者，应注意COQ2基因变异等影响线粒体功能的遗传性疾病。尽早行基因检测明确病因并开始大剂量辅酶Q10治疗可能会显著改善预后。

ObjectiveTo explore the clinical and genetic characteristics of infantile nephrotic syndrome caused by COQ2 variants. MethodsThe clinical and genetic data of a patient with nephrotic syndrome caused by COQ2 variants diagnosed at pediatric department of Peking University First Hospital from February 2018 to March 2018 were retrospectively analyzed. Related literature retrieved from PubMed, CNKI and Wanfang databases were searched to date （up to July 2018） with ＂COQ2 gene＂ or ＂primary coenzyme Q10 deficiency＂ and ＂nephrotic syndrome＂ or ＂nephropathy＂ as key words. ResultsA 14-month-old male, presented to local hospital at 11 months of age with edema and severe proteinuria, without hematuria, hypertension or renal dysfunction. He did not have infection or seizure in the course of the disease. He had no response to a more than four-week full-dose prednisone treatment. He had normal birth, mild motor development retardation and moderate language retardation. He was born to non-consanguineous healthy parents. He had two unaffected older sisters and one older sister died of ＂nephropathy＂ at one year of age. Genetic testing identified compound heterozygous variants in COQ2 gene： c.518G〉A and c.973A〉G, both could be predicted by in silico tools to be deleterious in protein function. These variants are not single nucleotide polymorphism and rare in normal populations. Both variants have previously been reported as pathogenic. These missense mutations were inherited from parents in autosomal recessive manner tested by Sanger sequencing. The patient was supplemented with high-dose of coenzyme Q10, at 30 mg/（kg·day） and glucocorticoid was withdrawn. Within three weeks of high dose coenzyme Q10 treatment, the edema disappeared. After seven weeks of high dose coenzyme Q10 treatment, the patient had decreased proteinuria and improved serum albumin levels. The urine protein to creatinine ratio decreased from 22.87 mg/mg to 1.98 mg/mg; Serum albumin increased from 14.2 g/L to 39.9 g/L, with normal kidney function and improved motor development. Primary CoQ10 deficiency is reported to be a rare autosomal recessive mitochondrial disorder with heterogeneous renal, neurologic, and muscular manifestations. To date, COQ2 variants have been reported in 14 children with glomerular involvement. Their age at onset ranged from neonatal period to 10-year-old （8 patients within the first year of life）. Steroid resistant nephrotic syndrome （SRNS） is the most common phenotype. Some of these children also had progressing encephalopathy and myopathy, and seizures. Patients with COQ2 variants might show clinical improvement with early high-dose oral CoQ10 supplementation. Literature review revealed two Chinese articles, mainly about adults with neurologic symptoms. SRNS was previously not reported in Chinese pediatric patients.ConclusionsIt is necessary to carry out genetic testing for infant with SRNS. The coexistence of some degree of encephalomyopathy, such as development retardation, should raise suspicion of a mitochondrial defect caused by COQ2 variants. Timely diagnostic genetic testing and early high dose of coenzyme Q10 supplement could significantly improve their prognosis.