摘要目的 探讨4羟基丁酸尿症患儿的临床及实验室诊断及随访.方法 收集2012年6月至2017年7月天津市儿童医院就诊的9例4羟基丁酸尿症患儿资料,根据其临床特征,应用头颅磁共振成像(MRI)、尿气相色谱-质谱法(GC/MS)半定量检测及ALDH5A1基因突变检测多层面分析.结果 9例起病年龄均＜1岁,均存在精神运动发育落后,4例癫痫发作,1例意识障碍,1例不自主运动.9例均行头颅MRI检查,4例头颅MRI示双侧对称性苍白球病变,其中1例伴中脑大脑脚对称性异常信号,1例头颅MRI示左颞叶皮质区软化灶,4例头颅MRI示脑室、脑外间隙增宽.9例尿GC/MS半定量检测示尿4羟基丁酸增高.9例行基因检测均为ALDH5A1基因突变,突变位点3例为c.1568C＞T纯合突变,1例为c.839T＞G纯合突变,余5例分别为c.691G＞ A,c.1568C ＞T;c.1383_2delA,c.1568C ＞T;c.527G＞ A,c.691G＞ A;c.904G＞ A,c.1022C＞ A;c.398_399delA、c.638G＞T复合杂合突变.9例予对症治疗,其中4例伴癫痫患儿予抗癫痫药物治疗.9例随访,1例因癫痫持续状态死亡,1例癫痫已控制5年,2例抗癫痫治疗有效.8例精神运动发育落后有不同程度好转,1例不自主运动消失,2例复查尿GC/MS半定量检测仍示尿4羟基丁酸增高.结论 4羟基丁酸尿症多在1岁内起病,以精神运动发育落后为首发表现,可有癫痫.头颅MRI以对称性苍白球异常信号为主要特征.尿GC/MS示4羟基丁酸增高,为本病生化诊断依据,其在体内蓄积主要损害中枢神经系统.ALDH5A1为致病基因,其中c.1568C ＞T位点发生突变频率高,推测此位点可能为中国患儿的热点突变.有癫痫者可能死于癫痫持续状态,可作为评判疾病严重度的一个临床指标.无特效治疗,有癫痫者予抗癫痫药物治疗,丙戊酸可加重病情,应避免使用.

abstractsObjective To study the clinical and laboratory diagnosis and follow-up of 4-hydroxy butyrate aciduria in children.Methods From June 2012 to July 2017,9 cases in Tianjin Children's Hospital were analyzed.According to their clinical features,multidimensional analysis was pedormed by using head magnetic resonance imaging (MRI),urine gas chromatography-mass spectrometry (GC/MS) semi-quantitative testing and gene mutation analysis of ALDH5A1.Results The onset age of the 9 cases was less than 1 year old,and all had psychomotor retardation,in which 4 cases with epileptic seizures,1 case with consciousness disturbance and 1 case with involuntary movement.All the cases underwent head MRI and 4 cases showed bilateral symmetry pallidal lesions,including 1 case with symmetry abnormality of the midbrain cerebral peduncle,1 case with encephalomalacia in left temporal cortex and 4 cases with widening of the ventricle and extracerebral space.By the urine GC/MS semi-quantitative testing,all 9 the cases showed increasing 4-hydroxy butyric acid and by the ALDH5A1 gene mutation analysis,all 9 the cases were detected with gene mutation (3 cases belonging to c.1568C ＞ T homozygous mutation,1 case belonging to c.839T ＞ G homozygous mutation and the other 5 cases belonging to compound heterozygous mutation,which included c.691G ＞ A,c.1568C ＞T;c.1383_2delA,c.1568C ＞ T;c.527G ＞ A,c.691G ＞ A;c.904G ＞ A,c.1022C ＞ A;c.398_399delA,c.638G ＞ T).Nine cases were given symptomatic treatment,and 4 cases with epileptic seizures were given antiepileptic drugs.During the follow-up of the above 9 cases,1 case died of status epilepticus,1 case had been under control for 5 years,and 2 cases were effectively treated.Psychomotor retardation was improved in varying degrees in 8 cases.Involuntarymovement disappeared in 1 case while 2 cases still showed increasing 4-hydroxy butyric acid by means of urine GC/MS semi-quantitative testing.Conclusions Most of 4-hydroxy butyrate aciduria occurs within 1 year old,with psychomotor development as the first manifestation,which can be associated with epilepsy.The head MRI is characterized by a symmetrical Globus pallid abnormal signal.Urine GC/MS shows an increase in 4-hydroxy butyrate,which is the basis for biochemical diagnosis of the disease.Its accumulation in the body mainly damages the central nervous system.ALDH5A1 is a disease-causing gene,in which c.1568C ＞ T site has a high mutation frequency,and it is speculated that this site may be a hot spot mutation in Chinese children.Patients with epilepsy may die from status epilepticus and may be used as a clinical indicator to judge the severity of the disease.There is no specific treatment,and the patients combined with epilepsy can be treated with anti-epileptic drugs.Valproic acid should be avoided as it can aggravate the condition.