TH基因变异致儿童酪氨酸羟化酶缺乏症的临床与遗传学分析  

Clinical features and genetic characteristics of children with tyrosine hydroxylase deficiency caused by TH gene variants

作　　者：代丽芳[1] 丁昌红[1] 方方[1] 张炜华[1] 刘明[1] 田小娟 任晓暾[1] 王晓慧[1] 李久伟[1] 卓秀伟[1] 张珅[1] 吕俊兰[1] 吴沪生[1] Dai Lifang;Ding Changhong;Fang Fang;Zhang Weihua;Liu Ming;Tian Xiaojuan;Ren Xiaotun;Wang Xiaohui;Li Jiuwei;Zhuo Xiuwei;Zhang Shen;Lyu Junlan;Wu Husheng(Department of Neurology,Beijing Children′s Hospital,Capital Medical University,National Center for Children′s Health,Beijing 100045,China)

机构地区：[1]国家儿童医学中心,首都医科大学附属北京儿童医院神经内科,北京100045

出　　处：《中华实用儿科临床杂志》2021年第8期574-579,共6页Chinese Journal of Applied Clinical Pediatrics

基　　金：国家重点研究发展计划(2016YFC1306203)。

摘　　要：目的总结儿童酪氨酸羟化酶缺乏症(THD)患者临床与遗传学特征,提高医师对该病的认识。方法回顾性总结分析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33例TH基因变异致THD患儿的临床表现、治疗及基因突变谱资料,并进行随访。结果33例THD患儿中,女19例,男14例;起病年龄0~6.3岁;起病诱因:感染、发热后起病13例,缺氧起病1例,无诱因起病19例。临床表现:轻型多巴反应性肌张力障碍7例,重型婴儿帕金森病伴运动发育迟缓16例,极重型进行性婴儿脑病10例。THD患儿症状呈波动性,晨轻暮重26例,感染加重22例,疲劳加重30例。THD患儿首发症状为尖足行走伴肢体僵硬7例、运动发育落后或倒退伴肢体软弱26例、震颤8例、眼睑下垂2例、肌张力障碍持续状态3例。THD患儿逐渐出现肢体僵硬23例、肢体松软27例、肢体活动减少27例、面部表情减少24例、震颤18例、尖足行走20例、马蹄内翻足7例、眼睑下垂8例、动眼危象10例、流涎21例、吞咽困难12例、构音障碍16例、呼吸困难3例、睡眠增多10例、睡眠减少5例、情绪烦躁15例、情绪淡漠2例、出汗多8例、肌张力障碍持续状态6例。THD患儿右侧肢体受累严重6例,下肢受累严重14例。THD患儿家族史阳性8例。33例THD患儿予左旋多巴治疗后症状均有不同程度缓解,但其中10例出现异动症或烦躁的不良反应。截至2020年1月末次随访时,4例THD患儿失访,余29例年龄为0.8~13.2岁,其中22例临床症状基本消失。33例THD患儿中共发现25种不同TH基因变异,5种热点变异依次为c.698G>A(13例)、c.457C>T(9例)、c.739G>A(6例)、c.1481C>T(4例)、c.694C>T(3例)。共发现13种未见文献报道的新基因变异(c.1160T>C、c.1303T>C、c.887G>A、c.1084G>A、c.1097A>T、c.734G>T、c.907C>G、c.588G>T、c.992T>G、c.755G>A、c.184-6C>T、c.1510C>T、c.910G>A),其中c.910G>A(2例)为可能的中国人群创始人变异�Objective To summarize the clinical characteristics and genetic features of tyrosine hydroxylase deficiency(THD)caused by TH gene variants for the improvement of the understanding of the disease.Methods The clinical and genetic data of 33 children with THD caused by TH gene variants were diagnosed in the Department of Neurology of Beijing Children′s Hospital,Capital Medical University from May 2011 to January 2020 and their data were retrospectively collected and analyzed.Results There were 19 females and 14 males.The age at onset was ranged from 0 to 6.3 years.13 patients developed diseases,accompanied with fever after infection,and 1 patient suffered from hypoxia,19 patients suffered from no predisposing factors.There were 7 mild TH-deficient dopa-responsive dystonia cases,16 severe TH-deficient infantile parkinsonism with motor delay cases and 10 very severe TH-deficient progressive infantile encephalopathy cases.Clinical symptoms were fluctuating,including 26 cases of diurnal fluctuation,22 cases of infection aggravation,and 30 cases of fatigue aggravation.The initial symptoms included tiptoeing and numbness in the limbs(7 cases),motor development retardation or degression(26 cases),fremitus(8 cases),ptosis(2 cases),and status dystonicus(3 cases).Other clinical features had hypermyotonia(23 cases),hypomyotonia(27 cases),decreased movement(27 cases),decreased facial expression(24 cases),fremitus(18 cases),tiptoeing(20 cases),talipes equinovarus(7 cases),ptosis(8 cases),oculogyric crisis(10 cases),salivation(21 cases),dysphagia(12 cases),dysarthria(16 cases),dyspnea(3 cases),increased sleep(10 cases),decreased sleep(5 cases),irritable mood(15 cases),apathetic mood(2 cases),profuse sweating(8 cases),and status dystonicus(6 cases).A total of 6 patients′right limbs were more severe,and 14 patients′lower limbs were more severe.Eight patients had family history,and Levodopa treatment was effective for all patients.Ten patients suffered side effects,including dyskinesia and irritability.Four patients were lost

关 键 词：酪氨酸羟化酶缺乏症 多巴反应性肌张力障碍 婴儿帕金森病伴运动发育迟缓 进行性婴儿脑病 TH基因 

分 类 号：R725.9[医药卫生—儿科]