新生儿枫糖尿症5例临床特征和基因分析

Neonatal maple syrup diabetes:a report on five cases

目的:分析新生儿枫糖尿症(maple syrup urine disease,MSUD)的临床特征和基因特点。方法:选择2017年1月至2023年10月西安交通大学附属西安市儿童医院新生儿科收治的MSUD患儿临床资料进行回顾性分析。结果:共纳入MSUD患儿5例,其中男2例,女3例,起病日龄6~9 d,1例有阳性家族史。5例首发症状均为喂养困难、反应差,病情进展期出现激惹、精神萎靡、肌张力和原始反射改变、频繁抽搐发作、呼吸困难及意识障碍,5例均有枫糖样体味。5例患儿血常规、血生化、血氨、血清乳酸、C反应蛋白及降钙素原均正常,血清支链氨基酸、尿支链α-酮酸明显升高。5例头颅影像学均显示弥漫性脑水肿,以双侧基底节区改变为著。全基因组外显子测序共发现9个变异位点,其中BCKDHA基因变异位点2个,BCKDHB基因变异位点4个,DBT基因变异位点3个。入院后均予禁食、抗惊厥及对症支持治疗,4例病情进行性加重,放弃治疗后很快死亡;1例予饮食控制,补充维生素B 1、左卡尼汀,病情好转,1岁行肝移植,现生长发育同正常同龄儿。 结论:新生儿MSUD临床特征为喂养困难、反应差、肌张力改变、频繁抽搐发作、枫糖样体味及弥漫性脑水肿,血支链氨基酸、尿支链α-酮酸升高为重要诊断线索,确诊依靠基因检测,早期干预可改善预后。

Objective To study the clinical features,diagnosis,treatment,prognosis and genotypes of neonatal maple syrup urine disease(MSUD).Methods This study retrospectively analyzed five cases of neonatal MSUD admitted to Xi'an Children's Hospital from January 2017 to October 2023,including the clinical manifestations,laboratory examinations,treatments and long-term follow-up outcomes.Results In the five cases,there were two male newborns and three female nerborns.All of them were full-term infants.The onset symptoms occurred between six to nine days after birth,with only one case presenting a positive family history.The initial symptoms included feeding difficulties,poor response,abnormal crying,irritability,lethargy,alterations in muscle tone and weakening or disappearance of primitive reflexes,etc.In the progression stage,frequent convulsions,dyspnea and consciousness disturbance may occur.All five cases exhibited a maple sugar-like odor.No obvious abnormalities were found in the complete blood count,blood biochemistry,blood ammonia,lactate,C-reactive protein and procalcitonin in the five children.Liquid chromatography-tandem mass spectrometry and urine gas chromatography-mass spectrometry revealed elevated levels of branched-chain amino acids and branched-chainα-ketoacids.Brain magnetic resonance imaging and color Doppler ultrasonography indicated diffuse cerebral edema in all five cases,with bilateral basal ganglia changes.Whole genome exon sequencing showed nine mutation sites,including two BCKDHA gene mutation sites,four BCKDHB gene mutation sites,and 3 DBT gene mutation sites.After admission,all five cases received fasting,anti-convulsant and symptomatic supportive therapy.Four cases exhibited progressive deterioration and died shortly after giving up treatment.One case was managed through dietary control,vitamin B1 and L-carnitine supplementation,resulting in improvement.At the age of one year,she underwent a liver transplant and is currently thriving and progressing normally.Conclusions The clinical manifestations of neonatal MSUD include feeding difficulties,poor response,alterations in muscle tone,frequent convulsions,maple sugar-like body odor,and diffuse cerebral edema.The elevation of blood branched-chain amino acids and urine branched-chainα-ketoacids may provide important clues for diagnosis.The diagnosis depends on genetic detection,and timely intervention can improve the prognosis of children.