Paneeya Pienvichit

Genetic polymorphisms in Thai neonates with hyperbilirubinemia.

Aim:  Polymorphisms of the UGT1A1 gene, SLCO1B1 gene and GST gene have been associated with significant hyperbilirubinemia. We would like to determine whether the variation of UGT1A1 gene, SLCO1B1 gene and GST gene may play a significant role in neonatal hyperbilirubinemia in Thai infants.

Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants

BackgroundThe most common causes of cholestatic jaundice are biliary atresia and idiopathic neonatal hepatitis (INH). Specific disorders underlying INH, such as various infectious and metabolic causes, including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) especially, in East Asian populations are increasingly being identified. Since most NICCD infants recovered from liver disease by 1 year of age, they often are misdiagnosed with INH, leading to difficulty in determining the true prevalence of NICCD. Mutation(s) of human SLC25A13 gene encoding a mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), can lead to AGC2 deficiency, resulting in NICCD and an adult-onset fatal disease namely citrullinemia type II (CTLN2). To study the prevalence of NICCD and SLC25A13 mutations in Thai infants, and to compare manifestations of NICCD and non-NICCD, infants with idiopathic cholestatic jaundice or INH were enrolled. Clinical and biochemical data were reviewed. Urine organic acid and plasma amino acids profiles were analyzed. PCR-sequencing of all 18 exons of SLC25A13 and gap PCR for the mutations IVS16ins3kb and Ex16+74_IVS17-32del516 were performed. mRNA were analyzed in selected cases with possible splicing error.ResultsFive out of 39 (12.8%) unrelated infants enrolled in the study were found to have NICCD, of which three had homozygous 851del4 (GTATdel) and two compound heterozygous 851del4/IVS16ins3kb and 851del4/1638ins23, respectively. Two missense mutations (p.M1? and p.R605Q) of unknown functional significance were identified. At the initial presentation, NICCD patients had higher levels of alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) and lower level of alanine aminotransferase (ALT) than those in non-NICCD patients (p< 0.05). NICCD patients showed higher citrulline level and threonine/serine ratio than non-NICCD infants (p< 0.05). Fatty liver was found in 2 NICCD patients. Jaundice resolved in all NICCD and in 87.5% of non-NICCD infants at the median age of 9.5 and 4.0 months, respectively.ConclusionNICCD should be considered in infants with idiopathic cholestasis. The preliminary estimated prevalence of NICCD was calculated to be 1/48,228 with carrier rate of 1/110 among Thai infants. However, this number may be underestimated and required further analysis with mutation screening in larger control population to establish the true prevalence of NICCD and AGC2 deficiency.

Mutations of ATP7B gene in two Thai siblings with Wilson disease.

Background: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in ATP7B gene. Objective: Report the clinical data and mutation analysis of two Thai siblings suspected of WD. Subject and methods: A 13-year-old boy who presented with cirrhosis, arthralgia, hypoalbuminemia, and coagulopathy, and his 11-year-old sister who was asymptomatic but had hepatomegaly with elevation of transaminases, were studied. Mutation analysis of ATP7B gene and mRNA analysis was performed in both patients and their parents. Results: Investigations were consistent with WD, and their liver diseases improved after standard treatment for WD. DNA analyses in these two patients revealed two novel mutations, which were a deletion of the first 2bp of exon 6 (c.1870_1871delGA), and a single base substitution from A to G at nucleotide 4075 (c.4075A>G) in the exon 20 (p.M1359V). PCR-restriction digestion with NcoI restriction enzyme was employed as the second method for confirmation of the c.4075A>G mutation and for rapid screening in 100 chromosomes from unrelated healthy controls, and this variant was not present in the controls. The c.1870_1871delGA deletion caused a frameshift effect, which results in a premature stop codon (p.E624fsX753), and the p.M1359V mutation is a substitution of methionine with valine, which may have effects upon its orientation and interaction with other adjacent amino acids. Conclusion: Two novel mutations of ATP7B gene were identified in two Thai siblings with WD.