新生儿期发病的经典型异戊酸血症四例分析

Analysis of four Chinese patients with neonatal-onset isovaleric acidemia

目的探讨新生儿期发病的经典型异戊酸血症的临床特点、治疗及分子诊断，及1例家系的产前诊断。方法4例患儿中男1例，女3例，于生后1～4d发病，均于2004年1月1日至2015年1月31日在北京大学第一医院儿科就诊和随访。经尿液有机酸、血液酯酰肉碱谱及异戊酰辅酶A脱氢酶（isovaleryl—CoA dehydrogenase，IVD）基因分析诊断异戊酸血症。3例存活的患儿接受了治疗，以左卡尼汀、甘氨酸、低蛋白饮食、祛除亮氨酸的特殊配方奶粉为主。结果4例患儿初诊年龄25d～4岁，主要表现为顽固性呕吐、嗜睡、昏迷、汗脚样体臭、代谢性酸中毒，其中3例伴外周血白细胞减少症或全血细胞减少症，3例血氨增高。4例患儿血液异戊酰肉碱显著增高（3．2～20．7斗mol／L，正常参考值〈0．5μmol／L），尿液异戊酰甘氨酸浓度显著增高（258．30～2535．76mmol／mmol肌酐，正常参考值〈0．4mmol／mmol肌酐）。4例患儿IVD基因共检出7种杂合突变，其中已知突变4种（c．158G〉A、c．1183C〉T、c．1193G〉A、c．1208A〉G），未检索到的新突变3种（c．145C〉T、c．611A〉G、c．676—677insA）。3例经治疗后逐渐好转，目前年龄3～14岁，其中2例发育正常，1例智力运动轻度落后。1例为死亡后诊断。死亡患儿之母于第2次妊娠19周时接受羊膜腔穿刺，羊水有机酸正常，羊水细胞IVD基因分析显示胎儿为c．158G〉A杂合突变携带者，未患异戊酸血症，新生儿生后尿液有机酸、血液酯酰肉碱谱分析结果正常，脐带血白细胞与羊水细胞IVD基因分析结果相同，验证了产前诊断结果。结论异戊酸血症新生儿接受合理的饮食与药物干预可获得良好的疗效。在先证者基因诊断明确的基础上，羊水细胞基因分析及羊水代谢物分析是产前诊断的可靠方法。

Objective To present the clinical and biochemical features, treatment, outcome and molecular findings of four Chinese patients with neonatal-onset isovaleric acidemia, and prenatal diagnosis of one case. Methods One boy and three girls with onset of isovaleric acidemia from the age of one to four days of life, who were diagnosed and followed-up at the Depantment of Pediatrics of Peking University First Hospital, were evaluated. Isovalerie acidemia was diagnosed by analysis of urinary organic acids, blood acylearnitines and an isovaleryl-CoA dehydrogenase （IVD） gene study. Three survivors were treated with L-carnitine, glycine, low-leucine formula and a protein-restricted diet. Results Four patients were admitted at the age of 25 days to 4 years presented with recurrent vomiting, unconsciousness and coma. A characteristic smell of ＂dirty socks＂ and severe metabolic acidosis were noted. Three patients had leukopenia or pancytopenia and three had hyperammonemia. Highly elevated blood isovalerylcarnitine of 3.2 to 20.7 Ix mol/L （normal value 〈 0.5 ix mol/L） and urine isovalerylglycine of 258.30 to 2 535.76 mmol/mmol Crea （normal value 〈 0.4 mmol/mmol Crea） were found in all patients. Seven mutations in the 1VD gene were found in the four patients, among which four mutations （c.158G 〉 A, c.1183C 〉 T, c.1193G 〉 A and c.1208A 〉 G） had been reported and three mutations （c.145C 〉 T, c.611A 〉 G and c.676-677insA） were novel. Progressive improvement was observed in three patients after treatment. Two of the three patients were normal at four and 14 years old at follow-up and third one was three years old with mild psychomotor retardation at follow-up. One of the four cases was diagnosed by postmortem study whose mother underwent amniocentesis at the gestational age of 19 weeks during her second pregnancy for prenatal diagnosis. Organic acids in the amniotic fluid were normal. In cultured amniocytes, only one heterozygous mutation, c.158G 〉 A, was found in the IVD gene. These results showed that the fetus was not affected by isovaleric acidemia. Postnatal urinary organic acids, blood acylcarnitines and IVD gene analysis of the cord blood cells confirmed the prenatal diagnosis. Conclusions For patients with onset isovaleric acidemia, appropriate dietary treatment and symptomatic treatment may lead to a good outcome. Amniotic fluid disease-specific metabolites and amniocyte gene analysis are reliable for the prenatal diagnosis of isovaleric acidemia.