新生儿起病的鸟氨酸转氨甲酰基酶缺乏症一家系的临床与生化及基因分析

Analysis of clinical features, biochemical analysis and gene mutations in one Chinese pedigree with neonatal-onset ornithine transcarbamylase deficiency

目的 通过对1例新生儿期急性起病的鸟氨酸转氨甲酰基酶缺乏症（OTCD）患儿家系从临床、生化和鸟氨酸转氨甲酰基酶基因（OTC）进行分析,初步探讨OTC在产前诊断中的意义.方法 分析患儿的临床、生化等特点,利用质谱技术检测患儿、患儿父母及第2胎新生儿血、尿氨基酸和有机酸代谢产物,同时应用聚合酶链反应与DNA测序的方法对患儿、患儿父母血样、第2胎胎儿羊水细胞及出生后血样进行OTC基因突变检测.结果 患儿出生后3 d起病.表现为反应差,喂养困难,新生儿感染,生化检测发现高血氨,轻度代谢性酸中毒,符合尿素循环代谢障碍的临床诊断标准.患儿于出生后第9天死亡.2次血质谱检测均显示瓜氨酸浓度明显下降,分别为0.86 μm和1.06μm,尿质谱有机酸检测发现乳清酸升高（124μm/M肌酐）,并伴乳酸明显升高.父母及第2胎新生儿血尿瓜氨酸和乳清酸等均正常.基因分析显示患儿9号外显子存在无义突变（C.958 C＞T）,使编码精氨酸的密码变成终止密码.其母亲为杂合携带者;在患儿和母亲的9号和5号内含子分别存在插入和杂合突变,分别为C.1005＋132 InsT和C.542＋134 G＞G/A;而父亲血样和第2胎胎儿羊水细胞及出生后血样DNA分析均正常.结论 OTC基因C.958 C＞T的突变可引起新生儿期急性起病.该突变如发生于男性患儿,出生后不久即可出现症状,起病迅速,如未及时抢救,极易导致死亡,而C.1005＋132 InsT和C.542＋134 G＞G/A是否与新生儿起病的OTCD有关,还需进一步的分析研究.OTC基因分析可应用于产前诊断.

Objective This study aimed at understanding clinical features, biochemistry and gene mutation in one Chinese pedigree which had a neonatal-onset ornithine transcarbamylase deficiency （ OTCD ）boy, and exploring the significance of ornithine transcarbamylase analysis in prenatal diagnosis.Method The clinical and biochemical data of one case were analyzed.The amino acids in blood and organic acids in urine were analyzed by mass spectrum technology.The OTC gene mutation was detected using polymerase chain reaction （PCR） and DNA direct sequencing for the case, his parents and the fetus amniocyte and her blood after birth.Result The age of onset was 3 days after birth, he began to have poor reaction, difficulty to feed, high blood ammonia, infection, slight metabolic acidosis, which were consistent with the clinical diagnosis of urea cycle disorders.The boy died at the age of 9 days.Citrulline of blood was detected twice,and were 0.86 μm and 1.06 μm, respectively.The orotic acid was elevated （ 124 μm/M Creatinine）, and urine lactic acid was significantly elevated.The citrulline and orotic acid in his parents and their second baby were normal in DBS and urine.One nonsense mutation in the OTC gene was found at the exon 9 （ C.958 C ＞ T） and his mother was the heterozygote, which caused an arginine to terminate the code at position 320 of the protein （R320X）.Two other mutations were also detected at intron 9 （ C.1005 ＋ 132 InsT） and intron 5 （C.542 ＋ 134 G ＞ G/A）.But the analysis of his father＇s DNA, the fetus amniocyte and her bloodwas normal.Conclusion The mutation of C.958 C ＞ T in OTC gene may occur during neonatal period.This mutation would result in a very severe symptom, even die suddenly several days after birth, if it was a boy.It needs more researches to discuss whether the C.1005 ＋ 132 InsT in intron 9 and C.542 ＋ 134 G ＞G/A in intron 5 were associated with the neonatal-onset OTCD.The DNA analysis of OTC gene could be utilized for the prenatal diagnosis.