Improved standards for prenatal diagnosis of citrullinemia
Improved standards for prenatal diagnosis of citrullinemia
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DOI：
10.1016/j.ymgme.2014.05.004
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发表时间：
2014-07-01
影响因子：
3.8
通讯作者：
Sutton, V. Reid
中科院分区：
文献类型：
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作者：
Miller, Marcus J.;Soler-Alfonso, Claudia R.;Sutton, V. Reid
I 型瓜氨酸血症是由精氨基琥珀酸合成酶 1 (ASS1) 常染色体隐性突变引起的尿素循环障碍。在这种疾病的典型形式中，新生儿期的症状表现为进行性嗜睡、喂养不良以及继发于高氨血症的中枢神经系统抑制。在涉及两个携带者父母的妊娠中，产前诊断对于生殖决策和新生儿护理的提前准备都很重要。目前产前诊断的金标准是除 DNA 突变分析之外的瓜氨酸掺入测定。在此，我们回顾了 11 年来对 41 例高危妊娠进行 I 型瓜氨酸血症产前诊断的经验。在此期间，我们通过分子和生化测试相结合，确定了 15 个受影响的胎儿。鉴于瓜氨酸掺入测定和 DNA 突变分析的既定局限性，我们探究了数据以评估羊水氨基酸水平在产前诊断中的价值。之前的出版物提出在产前诊断中使用羊水中瓜氨酸/（精氨酸+鸟氨酸）的比率；然而，我们注意到我们的队列中羊水精氨酸水平正常，并假设羊水瓜氨酸/鸟氨酸比率可能更高。事实上，我们的分析表明，在所有情况下，仅羊水瓜氨酸/鸟氨酸的比率即可正确区分受影响的胎儿和未受影响的胎儿。在建立正常参考范围的过程中，我们发现即使胎儿不受影响，与正常人群相比，高危妊娠的羊水瓜氨酸水平也显着升高。这凸显了在建立正常参考范围时使用携带者母亲的羊水的重要性。最后，我们报告了我们作为首批采用桑格测序进行瓜氨酸血症前瞻性产前诊断的中心之一的经验。虽然这在许多情况下显然是一个有用的工具，但我们遇到了一些家庭，他们的分子分析发现了未知临床意义的变异或根本没有突变。基于这些新发现，我们推荐采用 ASS1 测序和羊水瓜氨酸/鸟氨酸的组合方法来进行 I 型瓜氨酸血症的产前诊断。(C) 2014 Elsevier Inc. 保留所有权利。
Citrullinemia type I is a urea cycle disorder caused by autosomal recessive mutations in argininosuccinate synthetase 1 (ASS1). In the classical form of this disease, symptoms manifest during the neonatal period as progressive lethargy, poor feeding, and central nervous system depression secondary to hyperammonemia. In pregnancies involving two carrier parents, prenatal diagnosis is important for both reproductive decisions and advanced preparation for neonatal care. The current gold standard for prenatal diagnosis has been the citrulline incorporation assay in addition to DNA mutation analysis. Herein, we review our experience with prenatal diagnosis of citrullinemia type I over the span of 11 years in 41 at-risk pregnancies. During this time, we identified 15 affected fetuses using a combination of molecular and biochemical testing. Given the established limitations of both the citrulline incorporation assay as well DNA mutation analysis, we probed our data to assess the value of amniotic fluid amino acid levels in prenatal diagnosis. Previous publications have proposed using the amniotic fluid ratio of citrulline/(arginine + ornithine) in prenatal diagnosis; however, we noted that amniotic fluid arginine levels were normal in our cohort and hypothesized that the amniotic fluid citrulline/omithine ratio may be superior. Indeed, our analyses revealed that the ratio of amniotic fluid citrulline/ornithine alone correctly distinguished affected from unaffected fetuses in all cases. During the establishment of a normal reference range we discovered significant elevations in amniotic fluid citrulline levels in at-risk pregnancies compared to the normal population even when the fetus was unaffected. This highlights the importance of using amniotic fluid from carrier mothers when setting up a normal reference range. Finally, we report our experience as one of the first centers to adopt Sanger sequencing for prospective prenatal diagnosis of citrullinemia. While this is clearly a useful tool in many cases, we encountered families for whom molecular analysis uncovered variants of unknown clinical significance or no mutation at all. Based upon these new findings, we recommend a combinatorial approach involving ASS1 sequencing and amniotic fluid citrulline/omithine for the prenatal diagnosis of citrullinemia type I. (C) 2014 Elsevier Inc. All rights reserved.