枫糖尿症患儿13例临床、生化及基因研究

Clinical, biochemical and genetic features of 13 children with maple syrup urine disease

目的 研究枫糖尿症的临床、治疗及基因突变特点。 方法 13例患儿中男6例，女7例，仅1例为新生儿筛查发现，12例于2 d～1岁6个月发病，分别因＂呕吐、喂养困难、昏迷及智力运动发育落后＂就诊，对患儿进行血液氨基酸、血清支链氨基酸测定，并进行基因分析。 结果 13例患儿于16 d～1岁8个月时来院，其中11例为新生儿早期发病，符合经典型；1例为幼儿期发病，符合中间型；1例新生儿筛查检出的患儿于9 d时就诊，现2.5岁，无症状，发育良好，分型不明。11例经典型患儿智力运动发育落后，治疗前均伴有枫糖样体臭。患儿血清支链氨基酸（亮氨酸、异亮氨酸、缬氨酸、别异亮氨酸）。10例患儿接受了基因分析，共检出14种突变，其中BCKDHA基因突变7种（c.178G〉T、c.491T〉C、c.659C〉T、c.740A〉G、c.1214_1219dupCCAACC，c.1234G〉A及IVS6＋1delG），BCKDHB基因突变5种（c.482T〉G、c.508C〉T、c.767A〉G、c.768C〉G及IVS4,－2A〉C），DBT基因2种突变（c.1A〉G及c.1150A〉G）。3例患儿死亡，2例为死亡后诊断，1例于4岁6个月时因感染诱发代谢危象，死于呼吸衰竭。10例经治疗后病情好转，2例智力运动正常。 结论 枫糖尿症是一种罕见的致死性氨基酸代谢病，以代谢紊乱及脑损害为主要特点，若不及时干预，病死率及致残率很高。新生儿筛查、早期诊断、饮食治疗是改善预后的关键。

Objective To explore the clinical, treatment, and genetic findings of maple syrup urine disease （MSUD）. Methods Six boys and 7 girls out of 13 patients from unrelated Chinese families were enrolled. MSUD was detected in one patient by newborn screening. Twelve patients had the onset from the age of 2 days to 1 year and 6 months. They presented vomiting, feeding difficulties, lethargy, coma and psychomotor retardation. Blood amino acids were analyzed, and gene analysis was performed. Results The patients were hospitalized, age ranging from 16 days to 1 year and 8 months. Among them, 11 cases were of classical type and had very early onset. Only 1 patient with interme- diate type had relatively late onset. The girl detected by newborn screening was treated at the age of 9 days. She was healthy now with unknown MSUD type. Eleven classical MSUD children were diagnosed because of significantly elevated blood branched chain aminoacids （leucine, isoleueine, valine and alloisoleucine）. Fourteen mutations were found from 10 patients who accepted gene analysis,including 7 mutations in BCKDHA gene （ c. 178G 〉 T, c. 491T 〉 C, c. 659C 〉 T, c. 740A 〉 G, c. 1214_1219dupCCAACC, c. 1234G 〉 A and IVS6 ＋ ldelG0）, 5 mutations in BCKDHB gene （c. 482T〉G, e. 508C〉T, e. 767A〉G, e. 768C〉Gand IVS4, -2A〉C）, 2 mutations in DBTgene （c. IA〉G and c. 1150A 〉 G）. Two patients had normal development. One patient died from respiratory failure at the age of 4 years and 6 months. Conclusions MSUD is a rare life - threatening disorder which leads to metabolic crisis and brain damage with high mortality. Neonatal screening, early diagnosis and dietary treatment are crucial to improve the outcome.