芳香族L-氨基酸脱羧酶缺乏症4例临床和实验室特点分析

Clinical features and laboratory characteristics of 4 cases of aromatic L-amino acid decarboxylase deficiency

目的探讨芳香族L-氨基酸脱羧酶缺乏症(AADCD)的临床特征、实验室特点及基因诊断,提高对该病的认识。方法收集2016年8月至2020年6月首都医科大学附属北京儿童医院神经内科确诊的4例AADCD患儿,对其临床表现、实验室及影像学资料、基因检测结果进行回顾性分析。结果4例患儿均在婴儿早期起病,首发症状为喂养困难,分别于2~4月龄余出现伴眼动危象的阵发性运动障碍,并出现运动倒退,肌张力低下,发育迟缓,睡眠障碍和自主神经症状如上睑下垂、出汗过多、鼻塞等。4例患儿为来自2个家庭的兄妹,他们的父母均身体健康。例1、例2的二羟基苯丙氨酸脱羧酶(DDC)基因突变分别来自母亲的错义突变c.1040G>A(p.Arg347Gln)和来自父亲的11和12号外显子的全部缺失。例3的DDC基因突变分别来自母亲的突变c.419G>A(p.G140E)和来自父亲的突变c.1375C>T(p.H459Y);例4未进行基因检测。对3例患儿进行血氨基酸和酰基肉碱谱、尿有机酸分析,均未见特异性异常;对例3用血干滤纸片筛查3-O-甲基多巴,结果明显增高;脑脊液神经递质检测结果示3-甲氧基4-羟基苯二醇、高香草酸和5-羟基吲哚乙酸浓度明显降低,5-羟色氨酸和3-O-甲基多巴水平升高;血芳香族L-氨基酸脱羧酶(AADC)活性明显降低。对例1、例3、例4进行头颅磁共振成像(MRI)和脑电图检查,其中例1头颅MRI正常,例3、例4头颅MRI提示髓鞘化稍落后,3例患儿脑电图检查均正常。例1、例2在1岁10个月时因肺炎、呼吸衰竭死亡。例3在4月龄确诊后口服氯硝西泮、盐酸苯海索片、维生素B6片,后加用盐酸司来吉兰片、盐酸普拉克索片治疗,1岁6月龄随访时眼动危象、运动障碍的发作频率减少,睡眠改善,自主神经症状减轻,但发育迟缓无改善。例4诊断脑瘫和癫痫,多种抗癫痫药物和康复训练治疗无效,于10岁时因心脏衰竭、肾脏衰竭夭折。结论AADCD临床表现复杂,误诊率高。对早发性肌张力低下、发育落后、眼动危象、运动障碍的婴儿应尽早进行干滤纸片筛查3-O-甲基多巴水平,对可疑病例进行脑脊液神经递质检测、血浆AADC活性测定和基因检查以明确诊断。早期确诊AADCD患儿及基因变异携带者,可指导治疗及提供遗传咨询,降低后代的发病率。

Objective To investigate the clinical characteristics,laboratory characteristics and genetic diagnosis of aromatic L-amino acid decarboxylase deficiency(AADCD),and to improve the understanding of this disease.Methods Four children diagnosed with AADCD from the Department of Neurology,Beijing Children′s Hospital Affiliated to Capital Medical University from August 2016 to June 2020 were collected,and their clinical manifestations,laboratory and imaging data,and genetic test results were retrospectively analyzed.Results All the 4 cases were diagnosed in early infancy,with the first symptom of feeding difficulties.They developed paroxysmal dyspraxia accompanied by eye movement crisis,movement regression,hypotonia,growth retardation,sleep disorders and autonomic nervous symptoms such as ptosis,excessive sweating and nasal congestion at the age of 2-4 months,respectively.The 4 children were siblings from 2 families with healthy parents.The dihydroxyphenylalanine decarboxylase(DDC)gene mutations in cases 1 and 2 were derived from the maternal missense mutation c.1040G>A(P.RG347gln),and from the paternal deletion of exons 11 and 12,respectively.The DDC gene mutation in case 3 was derived from the maternal mutation c.419G>A(p.G140E)and the paternal mutation c.1375C>T(p.H459Y),respectively.Case 4 did not undergo genetic testing.Blood amino acid and acylcarnitine profiles and urine organic acid analyses were performed in 3 cases,and no specific abnormalities were found.In case 3,the results of 3-O-methyldopa(3-OMD)screening by blood dry filter paper increased significantly.Cerebrospinal fluid neurotransmitter detection results showed that the concentrations of 3-methoxy-4-hydroxyphenyldiol,vanillic acid and 5-hydroxyindoleacetic acid were significantly decreased,while the levels of 5-hydroxytryptophan and 3-OMD were increased in case 3.Blood aromatic L-amino acid decarboxylase(AADC)activity decreased significantly in case 3.Cranial magnetic resonance imaging(MRI)and electroencephalogram(EEG)examinations were performed in cases 1,3,and 4,among which the cranial MRI in case 1 was normal,while the cranial MRI in cases 3 and 4 suggested that myelination was slightly backward.The EEG was normal in all the 3 cases.Cases 1 and 2 died of pneumonia and respiratory failure at the age of 1 year and 10 months.Case 3 was given clonazepam,benxel hydrochloride tablets and vitamin B6 tablets orally after diagnosis at the age of 4 months,and then treated with selegiline hydrochloride tablets and pramexol hydrochloride tablets.At the follow-up of 1 year and 6 months,the frequency of eye movement crisis and movement disorder was reduced,sleep was improved and autonomic nervous symptoms were alleviated,but there was no improvement in developmental delay.Case 4 was diagnosed with cerebral palsy and epilepsy,but failed various antiepileptic drugs and rehabilitation training,and died at the age of 10 due to heart failure and kidney failure.Conclusions The clinical manifestations of AADCD are complicated and the misdiagnosis rate is high.Infants with early-onset hypotonia,developmental retardation,eye movement crisis,and movement disorders should be screened with dry filter paper as soon as possible for 3-OMD level,and suspicious cases should be diagnosed by cerebrospinal fluid neurotransmitter detection,plasma AADC activity determination,and gene examination.Early diagnosis of AADCD in children and gene mutation carriers can guide treatment and provide genetic counseling to reduce the incidence of the offspring.