Insight into a “new disorder”—Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)

Abstract

Citrullinemia is an autosomal recessive disease caused by a deficiency of argininosuccinate synthetase and is characterized by elevated serum and urine citrulline levels. Classic citrullinemia (CTLN1) is caused by mutations in the gene encoding argininosuccinate synthetase (ASS). Citrullinemia type II (CTLN2) is now recognized to occur in two different phenotypes: adult-onset type II citrullinemia and neonatal-onset type II citrullinemia (also known as Neonatal Intrahepatic Cholestasis Caused By Citrin Deficiency (NICCD). Both are caused by mutation in the SLC25A13 gene (gene map locus 7q21.3) (Nature Genet 1999;22:159). There have been multiple recent reports of Japanese neonates with NICCD. Affected infants presented with intrahepatic cholestasis associated with hypercitrullinemia, hypermethioninemia, or hypergalactosemia detected by a neonatal mass screening. Liver biopsy findings consisted of marked fatty changes and variable degrees of fibrosis. Without specific treatment other than feeding formula containing medium-chain triglycerides or a lactose-free formula, most patients had favorable clinical courses, with amino acid profiles and clinical signs of cholestasis normalizing within the first year. It was found that citrin deficiency causes NICCD and adult-onset CTLN2 with an epigenetic effect of genetic or environmental modifiers. Since citrin is a mitochondrial aspartate glutamate carrier, NICCD and CTLN2 are presumably related to defective aspartate export from the mitochondria to the cytosol along with defects in the malate aspartate shuttle (J Hum Genet 2002;47:333). It is commonly reported that CTLN2, both the neonatal and the adult onset forms, are found exclusively in Japanese subjects. In this issue of The Journal, Yeh et al report NICCD in Taiwanese infants. This disorder accounted for ∼15% of the infants in their clinic being evaluated for idiopathic intrahepatic cholestasis. This observation is an important milestone in the emerging history of this “new disease” and should lead to greater recognition. This disorder should also be a consideration–in any infant–when elevated amino acid profiles are detected by neonatal screening programs.