磷酸吡哆醇（胺）氧化酶缺乏症2例的临床特征及基因突变分析

Clinical characteristics and genetic analysis of 2 children with pyridox （am） ine - 5＇ - phosphate oxidase deficiency

目的分析2例磷酸吡哆醇（胺）氧化酶（PNPO）缺乏症患儿的临床特征及PNPO基因突变特征。方法患儿为2016年2月于北京大学第一医院儿科确诊的同卵双生兄弟，对其临床表现、诊治过程、血液生化、代谢筛查、脑电图、头颅磁共振成像（MRI）、癫痫相关基因（包括PNPO基因）检测结果等进行分析。结果2例患儿为35^＋5周早产，有出生窒息史。均于出生24h内出现癫痫发作，多种抗癫痫药效不佳。EEG显示不典型高度失律或多灶性癫痫样放电；MRI均显示非特异性异常。病程中曾应用维生素瞰单药或添加多种抗癫痫药物治疗，维生素吃单药治疗过程中最长1个月未出现发作。5岁左右时，在发作仍持续存在过程中逐渐停用所有抗癫痫药物，近1年仅口服维生素耽治疗，至6岁4个月时仍均有发作。血代谢筛查示精氨酸、天门冬氨酸、蛋氨酸水平降低；尿代谢筛查示香草酸水平明显升高，2例分别为正常值的49．78倍、36．60倍。患儿基因分析证实均携带PNPD基因复合杂合变异：C．445_448del（P．P150RfsX27）和c．481C〉T（P．R161C），均为国际上尚未报道的位点。确诊后，换用磷酸吡哆醛（PLP）治疗，短暂随访中，发作先略增多，后逐渐减少至完全控制。智力运动发育情况均为重度落后。结论2例患儿均以新生儿期难治性癫痫起病，维生素B6对癫痫发作有一定疗效。血、尿代谢筛查提示了PNPO缺乏症的可能，最终经基因检测首次在国内确诊了此症，应用PLP单药治疗后发作控制。

Objective To analyze the clinical characteristics and pyridox （am）ine -5＇ -phosphate oxidase （PNPO） gene mutations in 2 patients with PNPO deficiency. Methods The identical twin brothers were diagnosed at the Department of Pediatrics of Peking University First Hospital in February 2016. The clinical presentations, course of treatment, blood biochemistry, metabolic screening, EEG, brain magnetic resonance imaging （MRI） and epilepsy - related genes detection （including PNPO gene） of them were analyzed. Results These 2 patients were born at 35＋5 weeks gestation and had asphyxia after birth. The seizures started within the first day, which was uncontrolled by various antiepileptic drugs. EEG showed atypical hypsarrhythmia or multifocal epileptiform discharges. MRI showed nonspecific abnormality. Pyridoxine was used as monotherapy or combination with various antiepileptic drugs during the treatment. Seizures had ever been controlled by pyridoxine alone for up to 1 month. Antiepileptic drugs were withdrawn gradually under the circumstances of seizures persisting when they became 5 years old. During the past year, pyridoxine was used alone. They still had seizures at their age of 6 years and 4 months. Blood metabolic screening showed that the level of arginine,asparaginic acid and methionine decreased. Urinary metabolic screening showed vanillic acid elevating prominently in both patients ,49.78 and 36.60 times beyond normal, respectively. Genetic analysis showed compound heterozygous variants of PNPO gene in both patients ： c. 445_448del （ p. P150RfsX27 ） and c. 481C 〉 T （ p. R161C）. These 2 variants were not reported previously. After definite diagnosis was made, pyridoxine was replaced by pyridoxal -5＇ - phosphate （PLP） immediately. Seizures increased slightly at the initial treating with PLP,then reduced gradually and were controlled eventually. Psychomotor development was severely delayed in 2 patients. Conclusions Infantile onset intractable seizures in these 2 patients responded to pyridoxine. The results of blood and urinary metabolic screening suggest the possibility of PNPO deficiency. This is the first time to report patients with PNPO deficiency diagnosed by PNPO gene mutations in China. Seizures could be controlled by PLP monotherapy eventually.