Prenatal Diagnosis of Citrin Deficiency in a Chinese Family with a Fatal Proband
Prenatal Diagnosis of Citrin Deficiency in a Chinese Family with a Fatal Proband
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具有致命先证者的中国家庭 Citrin 缺乏症的产前诊断
DOI：
10.1620/tjem.225.273
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发表时间：
2011-12-01
影响因子：
2.2
通讯作者：
Xiao, Xiao-Min
中科院分区：
文献类型：
--
作者：
Zhao, Xin-Jing;Tang, Xiao-Mei;Xiao, Xiao-Min
Citrin缺乏症是一种常染色体隐性遗传病，其致病基因为SLC25A13，编码肝型天冬氨酸/谷氨酸载体亚型2(AGC2)的Citrin。新生儿肝内胆汁淤积症：Citrin缺乏引起的胆汁淤积症(NICCD)是儿童年龄的主要CD表型，先前已被报道为一种自限性疾病，临床表现在6个月至1岁之间消失。我们报告了一个先证者致死的NICCD先证者家族的产前诊断。先证者是一名10个月大的男性，咳嗽8天，皮肤黄褐斑1天。体格检查发现发热，巩膜和皮肤呈黑色黄褐斑，呼吸声音沙哑，肝脾肿大。实验室测试发现，胆汁淤积指数升高，氨增加，活化的部分凝血活酶时间和凝血酶原时间延长，纤维蛋白原减少。声像图显示肝硬变的特征。代谢组学分析发现尿中有大量的4-羟基苯乳酸和二羧酸盐，血液中的瓜氨酸和蛋氨酸增加。患者在13.5个月大时因肝功能衰竭去世。突变分析显示，他是SLC25A13基因外显子9的一个四碱基缺失的851del4纯合子。应第二胎父母的要求，经羊膜穿刺术和羊水培养后，用聚合酶链式反应-电泳法进行产前诊断，证实胎儿为相同突变的携带者。本报告中的死亡先证者提供了临床证据，挑战了NICCD预后的传统概念。此外，作为CD产前诊断的第一次尝试，本研究可能为CD的临床治疗开辟一个新的领域。
Citrin deficiency (CD) is an autosomal recessive disorder with SLC25A13 as causative gene that encodes citrin, the liver-type aspartate/glutamate carrier isoform 2 (AGC2). Neonatal intrahepatic: cholestasis caused by citrin deficiency (NICCD), the major CD phenotype at pediatric age, has been previously reported as a self-limiting condition with clinical presentations resolving between 6 months and 1 year of life. We report the prenatal diagnosis of CD in a family with a fatal NICCD proband. The proband was a 10-month-old male presenting cough for 8 days and jaundiced skin 1 day. Physical examination revealed fever, dark jaundiced sclera and skin, hoarse breathing sounds, and hepatosplenomegaly. Laboratory tests uncovered elevated cholestatic indices, increased ammonia, and prolonged activated partial thromboplastin time and prothrombin time, and reduced fibrinogen. Sonography showed the features of liver cirrhosis. Metabolome analysis uncovered large quantity of 4-hydroxyphenyllactate and dicarboxylates in urine and increased citrulline and methionine in blood. The patient passed away due to liver failure at his age of 13.5 months. Mutation analysis revealed him a homozygote of 851del4, a four-base deletion in exon 9 of SLC25A13 gene. On request of the parents who had a second fetus, prenatal diagnosis of CD was performed by PCR-electrophoresis following amniocentesis and amniocyte culture, and demonstrated the fetus a carrier of the same mutation. The fatal proband in the present report has provided clinical evidence challenging the traditional concept on NICCD prognosis. Moreover, as the first trial on CD prenatal diagnosis, this study might open a novel area for clinical management of CD.