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Improved standards for prenatal diagnosis of citrullinemia.

Abstract：

: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/ornithine 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/ornithine for the prenatal diagnosis of citrullinemia type I.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Miller MJ,Soler-Alfonso CR,Grund JE,Fang P,Sun Q,Elsea SH,Sutton VR

doi

10.1016/j.ymgme.2014.05.004

subject

Has Abstract

pub_date

2014-07-01 00:00:00

pages

205-9

issue

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(14)00158-9

journal_volume

112

pub_type

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Improved standards for prenatal diagnosis of citrullinemia.