以痉挛性瘫痪首诊的精氨酸血症七例临床与基因分析及二例产前诊断研究

Seven patients of argininemia with spastic tetraplegia as the first and major symptom and prenatal diagnosis of two fetuses with high risk

目的 探讨7例以痉挛性瘫痪首诊的精氨酸血症患儿的疾病特点、诊断、治疗与产前诊断方法.方法 7例患儿（男3例,女4例）因痉挛性瘫痪就诊,通过血氨、肝肾功能、血液氨基酸、尿液有机酸及ARG1基因检测确诊为精氨酸血症,给予低蛋白饮食、瓜氨酸、苯甲酸钠及对症治疗进行干预.其中2例患儿母亲于第2次妊娠中期时接受产前诊断,经羊膜腔穿刺获取羊水细胞检测,进行ARG1基因突变分析.结果 7例精氨酸血症患儿发病年龄1个月至4岁,主要表现为痉挛性瘫痪与生长发育落后,1岁10个月至12岁时被确诊为精氨酸血症.其中5例患儿伴智力障碍,3例伴癫痫.7例患儿血清精氨酸浓度增高（86.66～349.83 μmol/L,正常参考范围5～25 μmol/L）,6例患儿存在肝功能异常,5例血氨增高.脑核磁共振成像显示4例患儿存在脑萎缩.7例患儿ARG1基因被检出9种突变,其中c.703G＞A和c.32T＞C为已知突变,c.34G＞T、c.53G＞A、c.67delG、c.232dupG、c.374C＞T、c.539G＞C及c.646_649delCTCA为7种新突变.1例患儿母亲羊水细胞ARG1基因存在c.703G＞A纯合突变,提示胎儿患病,行引产手术.1例母亲羊水细胞ARG1基因未检出与先证者相同的突变（c.53G ＞A）,提示胎儿未患精氨酸血症.新生女婴出生后脐带血ARG1基因分析未检出突变,血液精氨酸浓度正常,发育良好.结论 精氨酸血症是少数可治疗的导致儿童痉挛性瘫痪的遗传性疾病之一,早期诊断及饮食与药物干预是改善预后的关键.7例精氨酸血症患儿经血液氨基酸及ARG1基因分析确诊,检出7种新突变.两例孕妇通过羊水细胞基因分析成功进行胎儿产前诊断.

Objective Argininemia is a rare disorder of urea cycle defect.The clinical manifestations of this disorder are similar to those of cerebral palsy so that the diagnosis is usually much delayed.This study aimed to investigate the phenotypes and genotypes of seven Chinese patients suffering from argininemia.Method Three boys and four girls with spastic tetraplegia were diagnosed as argininemia by blood aminoacids analysis and ARG1 gene study.Patients were given a protein-restricted diet,citrulline,sodium benzoate,and other treatment intervention.The mother of Patient 5 and 6 accepted genetic counseling and underwent prenatal diagnosis by amniocentesis.Result Seven patients presented with progressive spastic tetraplegia and poor physical growth from the age of 1 month to 4 years.Argininemia was found at the age of 1 year and 10 months to 12 years.Five patients had mental retardations.Three had seizures.Their blood arginine elevated （86.66 to 349.83 μ mol/L,normal controls 5 to 25 μmol/L）.Liver dysfunction was found in six patients.Five patients had elevated blood ammonia levels.In four patients,cerebral atrophy was observed by cranial magnetic resonance imaging.Nine mutations in the ARG1 gene were identified from 7 patients.Only two mutations,c.703G 〉 A in exon 7 and c.32T 〉 C in exon 1 had been reported.c.34G 〉 T,c.53G 〉 A,c.67delG,c.232dupG,c.374C 〉 T,c.539G 〉 C and c.646-649delCTCA,were novel mutations of ARG1.A homozygous mutation c.703G 〉 A was found in the amniocytes of Patient 5＆#39;s mother,indicating that the fetus was affected by argininemia.Induced abortion was performed.c.53G 〉 A from Patient 6 was not found in the amniocytes of her mother,indicating that the fetus was not affected by hepatocyte arginase deficiency.The result was confirmed by postnatal mutation analysis of cord blood and the normal blood arginine of the newborn.Conclusion Argininemia is one of the few treatable causes of pediatric spastic paralysis.In this study,seven Chinese patients with spastic tetraplegia were detected by blood aminoacids analysis and confirmed by molecular analysis.Seven novel mutations on ARG1 gene were identified.Prenatal diagnosis of the fetus of a family was performed by amniocytes ARG1 gene analysis.