Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients

Tazawa, Yusaku; Kobayashi, Keiko; Abukawa, Daiki; Nagata, Ikuo; Maisawa, Shunichi; Sumazaki, Ryo; Iizuka, Toshiyuki; Hosoda, Yuzuru; Okamoto, Manabu; Murakami, Jun; Kaji, Shuichiro; Tabata, Ayako; Lu, Yebo; Sakamoto, Osamu; Matsui, Akira; Kanzaki, Sho; Takada, Goro; Saheki, Takeyori; Iinuma, Kazuie; Ohura, Toshihiro

doi:10.1016/j.ymgme.2004.06.018

Cited by 58 publications

(51 citation statements)

References 21 publications

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“…The PCR-RFLP method to detect two mutations established was used for DNA diagnosis of the patients and/or the parents and for population analysis in control individuals. DNA diagnosis of the parents revealed that the NICCD patient (Tazawa et al 2004 (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Other features shown in NICCD patients are hypoproteinemia, hypoglycemia, hemolytic anemia, a-fetoproteinemia, fatty liver, and/or mild liver dysfunction. The clinical data from CTLN2 or NICCD patients have been described Yazaki et al 2004Yazaki et al , 2005Tazawa et al 2004;Hachisu et al 2005) and will be reported elsewhere. In addition to DNA samples from 1,372 Japanese, 1,008 Chinese, 1,314 Taiwanese, and 201 Korean controls Saheki et al 2004), the dried spot blood specimens collected at newborn screening centers (54 in Liaoning, 302 in Shandong, 175 in Henan, 200 in Hubei, 638 in Guangdong, and 2,254 in Korea) were anonymized and used as controls without selection.…”

Section: Patients and Control Individualsmentioning

confidence: 99%

“…For CTLN2 patients with poor prognosis and high mortality, there is no effective treatment at the present except liver transplantation (Ikeda et al 2001;Kasahara et al 2001;Yazaki et al 2004). On the other hand, NICCD shows multiple metabolic abnormalities, including an aminoacidemia (involving citrulline, threonine, methionine, tyrosine, and arginine), galactosemia, hypoproteinemia, hypoglycemia, cholestasis, and fatty liver Ohura et al 2003;Tazawa et al 2004;Hachisu et al 2005). The NICCD is usually not severe and can be managed using nutritional manipulation; symptoms usually disappear within a year.…”

Section: Introductionmentioning

confidence: 99%

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Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency

et al. 2005

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Deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier (AGC), encoded by the SLC25A13 gene on chromosome 7q21.3, causes autosomal recessive disorders: adult-onset type II citrullinemia (CTLN2) and neonatal hepatitis associated with intrahepatic cholestasis (NICCD). So far, we have described 12 SLC25A13 mutations: 11 were from Japan and one from Israel. Three mutations found in Chinese and Vietnamese patients were the same as those in Japanese patients. In the present study, we identified a novel mutation IVS6+1G>C in a Japanese CTLN2 patient and widely screened 12 SLC25A13 mutations found in Japanese patients in control individuals from East Asia to confirm our preliminary results that the carrier frequency was high in Asian populations. Mutations 851-854del and 1638-1660dup were found in all Asian countries tested, and 851-854del associated with 290-haplotype in microsatellite marker D7S1812 was especially frequent. Other mutations frequently detected were IVS11+1G>A in Japanese and Korean, S225X in Japanese, and IVS6+5G>A in Chinese populations. We found a remarkable difference in carrier rates in China (including Taiwan) between north (1/ 940) and south (1/48) of the Yangtze River. We detected many carriers in Chinese (64/4169 = 1/65), Japanese (20/1372 = 1/69) and Korean (22/2455 = 1/112) populations, suggesting that over 80,000 East Asians are homozygotes with two mutated SLC25A13 alleles.

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Section: Resultsmentioning

confidence: 99%

Section: Patients and Control Individualsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency

et al. 2005

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“…Detailed methods for identification and diagnosis of a novel mutation, [XIX]:IVS16ins3kb, will be described elsewhere (Tabata et al unpublished data). Clinical and biochemical data have been reported previously in Japanese (8) and Korean (9) NICCD patients with the [XIX] mutation.…”

Section: Mutation Analysis and Dna Diagnosis Of The Slc25a13 Genementioning

confidence: 69%

“…Biochemical findings of NICCD include significantly high levels of galactose, bile acids, γ-glutamyl transferase and alkaline phosphatase. Hypoproteinemia and mildly elevated aminotransferase levels have also been detected (8). The symptoms of NICCD are resolved by 12 months of age without special treatment.…”

Section: Discussionmentioning

confidence: 98%

Six cases of citrin deficiency in Korea

Kim

et al. 2007

Int J Mol Med

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Abstract. Citrin deficiency resulting from mutations of the SLC25A13 gene is associated with two major clinical phenotypes; neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type 2 citrullinemia (CTLN2). In Korea, 6 cases of citrin deficiency were diagnosed based on biochemical and molecular findings. Four NICCD patients (2 boys and 2 girls) presented high citrulline levels on a newborn screening test or neonatal cholestasis. They were associated with conjugated hyperbilirubinemia, elevated liver enzymes, hypoalbuminemia, mild hyperammonemia, elevated citrulline, methionine and threonine. All of the hepatic manifestations were resolved spontaneously at the age of 5-9 months. Mutation analysis identified them as compound heterozygotes carrying each of the c.851del4, IVS11+1G>A, IVS13+1G>A, G393S, and IVS16ins3kb mutant alleles. Two adult male CTLN2 patients were identified. They were aged 24 and 37 years, and presented sudden loss of consciousness, hyperammonemia and citrullinemia. They were compound heterozygotes with IVS13+1G>A and IVS16ins3kb, and with c.851del4 and IVS11+1G>A mutant alleles. This report describes the clinical characteristics, biochemical findings and molecular analysis of the SLC25A13 gene of patients with citrin deficiency in Korea.

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Hypermethioninemias of genetic and non‐genetic origin: A review

Mudd

2011

American J of Med Genetics Pt C

166

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This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia. The genetic conditions are: (1) Homocystinuria due to cystathionine β-synthase (CBS) deficiency. At least 150 different mutations in the CBS gene have been identified since this deficiency was established in 1964. Hypermethioninemia is due chiefly to remethylation of the accumulated homocysteine. (2) Deficient activity of methionine adenosyltransferases I and III (MAT I/III), the isoenzymes the catalytic subunit of which are encoded by MAT1A. Methionine accumulates because its conversion to S-adenosylmethionine (AdoMet) is impaired. (3) Glycine N-methyltrasferase (GNMT) deficiency. Disruption of a quantitatively major pathway for AdoMet disposal leads to AdoMet accumulation with secondary down-regulation of methionine flux into AdoMet. (4) S-adenosylhomocysteine (AdoHcy) hydrolase (AHCY) deficiency. Not being catabolized normally, AdoHcy accumulates and inhibits many AdoMet-dependent methyltransferases, producing accumulation of AdoMet and, thereby, hypermethioninemia. (5) Citrin deficiency, found chiefly in Asian countries. Lack of this mitochondrial aspartate-glutamate transporter may produce (usually transient) hypermethioninemia, the immediate cause of which remains uncertain. (6) Fumarylacetoacetate hydrolase (FAH) deficiency (tyrosinemia type I) may lead to hypermethioninemia secondary either to liver damage and/or to accumulation of fumarylacetoacetate, an inhibitor of the high K(m) MAT. Additional possible genetic causes of hypermethioninemia accompanied by elevations of plasma AdoMet include mitochondrial disorders (the specificity and frequency of which remain to be elucidated). Non-genetic conditions include: (a) Liver disease, which may cause hypermethioninemia, mild, or severe. (b) Low-birth-weight and/or prematurity which may cause transient hypermethioninemia. (c) Ingestion of relatively large amounts of methionine which, even in full-term, normal-birth-weight babies may cause hypermethioninemia.

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Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients

Cited by 58 publications

References 21 publications

Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency

Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency

Six cases of citrin deficiency in Korea

Hypermethioninemias of genetic and non‐genetic origin: A review

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