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

BACKGROUND: The 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 E...

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Autores principales: Treepongkaruna, Suporn, Jitraruch, Suttiruk, Kodcharin, Porawee, Charoenpipop, Dussadee, Suwannarat, Pim, Pienvichit, Paneeya, Kobayashi, Keiko, Wattanasirichaigoon, Duangrurdee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483206/
https://www.ncbi.nlm.nih.gov/pubmed/23067347
http://dx.doi.org/10.1186/1471-230X-12-141
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author Treepongkaruna, Suporn
Jitraruch, Suttiruk
Kodcharin, Porawee
Charoenpipop, Dussadee
Suwannarat, Pim
Pienvichit, Paneeya
Kobayashi, Keiko
Wattanasirichaigoon, Duangrurdee
author_facet Treepongkaruna, Suporn
Jitraruch, Suttiruk
Kodcharin, Porawee
Charoenpipop, Dussadee
Suwannarat, Pim
Pienvichit, Paneeya
Kobayashi, Keiko
Wattanasirichaigoon, Duangrurdee
author_sort Treepongkaruna, Suporn
collection PubMed
description BACKGROUND: The 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. RESULTS: Five 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. CONCLUSION: NICCD 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.
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spelling pubmed-34832062012-10-30 Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants Treepongkaruna, Suporn Jitraruch, Suttiruk Kodcharin, Porawee Charoenpipop, Dussadee Suwannarat, Pim Pienvichit, Paneeya Kobayashi, Keiko Wattanasirichaigoon, Duangrurdee BMC Gastroenterol Research Article BACKGROUND: The 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. RESULTS: Five 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. CONCLUSION: NICCD 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. BioMed Central 2012-10-15 /pmc/articles/PMC3483206/ /pubmed/23067347 http://dx.doi.org/10.1186/1471-230X-12-141 Text en Copyright ©2012 Treepongkaruna et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Treepongkaruna, Suporn
Jitraruch, Suttiruk
Kodcharin, Porawee
Charoenpipop, Dussadee
Suwannarat, Pim
Pienvichit, Paneeya
Kobayashi, Keiko
Wattanasirichaigoon, Duangrurdee
Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants
title Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants
title_full Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants
title_fullStr Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants
title_full_unstemmed Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants
title_short Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants
title_sort neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and slc25a13 mutations among thai infants
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483206/
https://www.ncbi.nlm.nih.gov/pubmed/23067347
http://dx.doi.org/10.1186/1471-230X-12-141
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