Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants

Abstract

Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants.

Hypermethioninemias of genetic and non‐genetic origin: A review

“…Elevations of methionine may be accompanied by elevations of galactose, citrulline, threonine, tyrosine, phenylalanaine lysine, and arginine. Table IV lists plasma methionine values reported for infants from several countries of Asia: Japan [Tamamori et al, 2004; Ohura et al, 2007], Korea [Ko et al, 2007a,b], China [Song et al, 2009a], Taiwan [Yeh et al, 2006], and the patients of various ethnicity (French‐Canadian, South‐East Asian, Han, Arabic, Pakistani, and Northern European) identified by Dimmock et al [2009]. The elevations of methionine may be only moderate, or quite severe, but are not present in all cases, either during newborn screening or later.…”

“…As of 2008, 52 mutations had been identified in SLC25A13 [Kobayashi et al, 2008]. These included not only individuals from Japan [Kobayashi et al, 1999; Yasuda et al, 2000; Yamaguchi et al, 2002; Takaya et al, 2005], but also from Taiwan [Lee et al, 2006; Tsai et al, 2006; Yeh et al, 2006; Sheng et al, 2010], Korea [Ko et al, 2007a,b], and China [Song et al, 2008, 2009a,b] so that citrin deficiency is particularly prevalent in East Asia [Kobayashi et al, 2003; Saheki et al, 2004; Lu et al, 2005; Tabata et al, 2008]. Regional specificity of the mutation types within East Asia has been noted [Kobayashi et al, 2008; Tabata et al, 2008].…”

Analysis of islet beta cell functions and their correlations with liver dysfunction in patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)

“…NICCD was diagnosed on the basis of the presence of intrahepatic cholestasis, fatty liver, failure to thrive, hyperaminoacidemia, liver dysfunction, hypoglycemia, hypoproteinemia, and/or coagulation disorders, [ 1 ] and the diagnoses were confirmed by SLC25A13 gene analysis. [ 17 ]…”

Blood glucose and insulin and correlation of SLC25A13 mutations with biochemical changes in NICCD patients

“…19 Once diagnosed with NICCD, the patients were treated with lactose (galactose)-restricted and medium-chain triacylglycerol (MCT)-supplemented formula, meropenem, gamma globulin, human serum albumin (HSA), supplementation of fat soluble vitamins and low-carbohydrate, high-protein diet.…”

“…15,16 NICCD is characterized by multiple amino acidemia, hypoglycemia, galactosemia, hypoproteinemia, cholestasis, and fatty liver. 5,10,19 Retrospective analysis of biochemical indices in 75 NICCD cases carried out by Ohura et al 20 in Japan had found 18 cases (24%) with hypoglycemia, and concluded that hypoglycemia is common among neonatalonset NICCD. By using gene knockout technology, Saheki et al 21 who established mice with SLC25A13 deficiency had shown hypoglycemia after fasting, in comparison to wild type mice.…”