Abstract: Objective　To summarize the clinical and genetic features of dopa-responsive dystonia due to GCH1 gene variation，in order to improve the understanding of the disease and perform diagnosis and treatment to change prognosis. Methods　The clinical and genetic data of twenty-one children with dopa-responsive dystonia due to GCH1 gene variation，diagnosed in the Department of Neurology of Beijing Children’s Hospital，Capital Medical University from May 2011 to January 2020，were retrospectively collected and analyzed. Follow-up was also made. Results　There were seventeen females and four males. The age at onset ranged from 0 to 8 years，and the course of disease at diagnosis was from 0.1 to 7.6 years. One patient developed the disease after infection and twenty without cause. There were 18 cases of typical dopa-responsive dystonia and 3 atypical cases. The initial symptoms were tiptoeing（18 cases），motor development retardation or degression with limb weakness（3 cases），ptosis（2 cases），fremitus（3 cases）. The hypermyotonia spread to trunk（3 cases）and to upper limbs（9 cases）. Other clinical features included decreased movement（5 cases），decreased facial expression（3 cases），fremitus（7 cases），tiptoeing（19 cases），talipes equinovarus（9 cases），ptosis（3 cases），oculogyric crisis（1 case），salivation（3 cases），dysphagia（2 cases），dysarthria（2 cases），profuse sweating（4 cases），sleep increase（2 cases） and apathetic mood（1 case）. Clinical symptoms were fluctuating，including diurnal fluctuation in 18 cases，infection aggravation in 7 cases and fatigue aggravation in 20 cases. Left limbs were more severe in 12 patients. Right limbs were more severe in 3 patients. Lower limbs were more severe in 18 patients. There were 4 cases of motor development retardation and one case of mental retardation before disease onset. Three patients had family history. All patients received levodopa treatment，and the symptoms disappeared or were significantly relieved. Two patients had side effects of dyskinesia. One patient was not followed up，and twenty patients were followed up between 11 months and 16 years 7 months old until January 2020. The treatment course of follow-up was from 0.1 to 8.6 years. The symptoms almost disappeared in 16 patients and improved greatly in 4 patients. Twenty-one GCH1 gene variation were found，among which ten were novel variations（c.304A＞T，c.257C＞T，c.277A＞T，c.478A＞T，c.481C＞T，exon 1 duplication，exon 2+3 deletion，c.726_727insC，c.51delG，c.151_166del）. Conclusion　Dopa-responsive dystonia due to GCH1 gene variation is a treatable inherited metabolic disorder，the onset of which is in infancy or childhood. The onset may be as early as in neonatal period. The clinical manifestations are mainly typical. Typical case can have atypical features. It is easily misdiagnosed. Early identification should be strengthened. The non-coding region variation and large deletion or duplication variation of GCH1 gene should be paid attention to in DRD patients.

Key words: dopa-responsive dystonia, guanosine triphosphate cyclohydrolase 1 deficient, levodopa, GCH1 gene

摘要： 目的　总结GCH1基因变异致儿童多巴反应性肌张力障碍（DRD）临床和遗传学特征，以提高对疾病的认识，正确诊治改变预后。方法　回顾性分析2011年5月至2020年1月首都医科大学附属北京儿童医院神经内科确诊的21例GCH1基因变异致DRD患儿的临床表现、治疗及基因突变谱，并随访。结果　女17例，男4例；起病年龄0～8岁。首次就诊时病程0.1～7.6年。起病诱因：感染后起病1例，无诱因起病20例。临床表现：经典型18例，非经典型3例；首发症状为尖足行走伴下肢僵硬18例、运动发育落后或倒退伴肢体软弱3例、眼睑下垂2例、震颤3例；部分逐渐出现躯干僵硬3例、上肢僵硬9例、肢体活动减少5例、面部表情减少3例、震颤7例、尖足行走19例、马蹄内翻足9例、眼睑下垂3例、动眼危象1例、流涎3例、吞咽困难2例、构音障碍2例、出汗多4例、睡眠增多2例、情绪淡漠1例。症状呈波动性，晨轻暮重18例，感染加重7例，疲劳加重20例。左侧肢体受累严重12例，右侧肢体受累严重3例。下肢受累严重18例，无上下肢受累优势3例。起病前运动发育落后4例，智力发育落后1例。家族史阳性3例。所有患儿均给予左旋多巴治疗后症状消失或明显缓解，2例出现异动症副反应。截止2020年1月随访，1例失访，20例随访年龄11月龄至16岁7月龄，随访时疗程0.1～8.6年，随访时16例症状基本消失，4例症状明显缓解。本组共发现21种不同的GCH1基因变异，其中10种未见文献报道的新变异（c.304A＞T，c.257C＞T，c.277A＞T，c.478A＞T，c.481C＞T，exon 1 duplication，exon 2+3 deletion，c.726_727insC，c.51delG，c.151_166del）。结论　GCH1基因变异致儿童DRD是一种可治疗的先天遗传代谢病，婴儿及儿童期均可起病，可早至新生儿起病，临床表现以经典型为主，误诊率高，经典型亦可出现非经典型表现，需加强早期识别。DRD患者需注意GCH1基因非编码区变异及大片段缺失重复变异的筛查。

关键词: 多巴反应性肌张力障碍, 三磷酸鸟苷环化水解酶1缺乏症, 左旋多巴, GCH1基因