Serum Amino Acid Pattern of Type II Citrullinemic Patients and Effect of Oral Administration of Citrulline

Saheki, Takeyori; Kobayashi, Keiko; Miura, Tsutomu; Hashimoto, Shuji; Ueno, Yoshio; Yamasaki, Toshihiro; Araki, H; Nara, Hidehasu; Shiozaki, Yasuko; Sameshima, Yoshiko; Suzuki, Masayoshi; Yamauchi, Y.; Sakazume, Yoshiki; Akiyama, Kenji; Yamamura, Yoshinori

doi:10.3164/jcbn.1.129

Cited by 38 publications

(18 citation statements)

References 14 publications

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“…Blood citrulline concentrations failed to rise to more than ϩ2 SD in only one of the 20 individuals with SLC25A13 mutations. A previous study reported high threonine/serine ratio and low branched chain amino acid levels in CTLN2 (2). Also in this study, serine and leucine plus isoleucine in patients with SLC25A13 were similar or slightly decreased to those in controls, as shown in Figure 1.…”

supporting

confidence: 60%

“…Abbreviations CTLN2, adult-onset type II citrullinemia NICCD, neonatal intrahepatic cholestasis caused by citrin deficiency NMS, newborn mass screening CTLN2 (OMIM #603471) is characterized by late onset (age, 11-79 y), frequent attacks of hyperammonemia, mental derangement, sudden attacks of unconsciousness, and ultimately death within a few years of onset (1,2). CTLN2 is caused by mutations of the SLC25A13 gene (3)(4)(5), which is localized on chromosome 7q21.3 and encodes a calcium-ratio in the cytosol and failure of aspartate supply from the mitochondria to the cytoplasm for synthesis of argininosuccinate, resulting in high blood levels of citrulline and ammonia.…”

Section: (Pediatr Res 56: 608-614 2004)mentioning

confidence: 99%

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Effects of Citrin Deficiency in the Perinatal Period: Feasibility of Newborn Mass Screening for Citrin Deficiency

Tamamori

Fujimoto²,

Okano

et al. 2004

Pediatr Res

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Deficiency of citrin due to mutations of the SLC25A13 gene causes adult-onset type II citrullinemia (CTLN2) and one type of neonatal intrahepatic cholestasis (NICCD). About half of the NICCD patients are detected based on high galactose, phenylalanine, and/or methionine concentrations on newborn mass screening (NMS). To clarify the perinatal and neonatal effects and the inconsistent results on NMS, we examined aminograms, the levels of bile acids and galactose in dried blood spots for NMS from 20 patients with NICCD. Birth weight was low for gestational age (Ϫ1.4 Ϯ 0.7 SD). Affected fetuses may have suffered intrauterine citrin deficiency. The first abnormality detected after birth was citrullinemia, and 19 of 20 patients had citrulline levels higher than ϩ2 SD of controls. Tyrosine, phenylalanine, methionine, galactose, and bile acids were less affected than citrulline on d 5 after birth. Galactose and bile acids levels were increased at 1 mo in comparison with d 5 after birth due to impairment of the cytosolic NADH reducingequivalent supply into mitochondria of hepatocytes. Patients with negative findings on NMS had low levels of total 20 amino acids. Citrulline/serine, citrulline /leucine plus isoleucine, and citrulline/ total amino acids ratios, controlled for the confounding effect of low amount of total amino acids, were higher in all patients than ϩ2 SD, ϩ2 SD, and ϩ3 SD of controls, respectively. NMS for citrin deficiency (frequency of homozygote with SLC25A13 mutation: 1/10,000 -1/38,000 in East Asia) will be useful for clarification of the clinical course, treatment, and prevention of this disease. ABSTRACT608

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confidence: 60%

Section: (Pediatr Res 56: 608-614 2004)mentioning

confidence: 99%

Effects of Citrin Deficiency in the Perinatal Period: Feasibility of Newborn Mass Screening for Citrin Deficiency

Tamamori

Fujimoto²,

Okano

et al. 2004

Pediatr Res

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“…9,11,12 In patients with CTLN2, serum arginine concentrations are increased as well as citrulline concentrations. 21 Furthermore, argininosuccinic acid is excreted in the urine. 22 Establishment of the DNA diagnosis for citrin de¢ciency in CTLN2 revealed that SLC25A13 mutations are also the molecular cause of a particular type of neonatal hepatitis: neonatal intrahepatic cholestasis caused by citrin de¢ciency: NICCD, OMIM #605814.…”

Section: ^20mentioning

confidence: 99%

Moderate citrullinaemia without hyperammonaemia in a child with mutated and deficient argininosuccinate synthetase

Ruitenbeek¹,

Kobayashi

Iijima

et al. 2003

Ann Clin Biochem

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In a patient with microcephaly, feeding problems and restlessness, moderately increased serum and urine citrulline concentrations were observed. Protein and allopurinol loading did not result in additional indications for a urea cycle defect. The diagnosis of citrullinaemia was made at both the enzyme and DNA level, resulting from a novel mutation in the argininosuccinate synthetase gene. The fact that the patient has not suffered from severe deterioration, and that there were only minor abnormalities in metabolite concentrations, suggests that the argininosuccinate synthetase capacity was less affected in vivo than in vitro. In vitro nuclear magnetic resonance investigation suggested an active acetylation mechanism for citrulline. This case illustrates the importance of performing extensive biochemical and molecular investigations in order to reach a de nitive diagnosis, particularly in instances of moderate citrullinaemia.

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“…The liver-specific ASS deficiency in CTLN2 patients leads to a lesser increase in plasma Cit levels than that in CTLN1 patients, proportionally elevated levels of plasma arginine (Arg), and an increase in urine argininosuccinate (36)(37)(38). Furthermore, CTLN2 patients exhibit an increase in their plasma threonine-to-serine (Thr/Ser) ratio (13,37) as well as elevated levels of pancreatic secretory trypsin inhibitor (PSTI) in serum, the latter resulting from its up-regulated transcriptional expression in the liver (13,16).…”

mentioning

confidence: 99%

Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia

Sinasac

Moriyama

Jalil

et al. 2004

Molecular and Cellular Biology

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Adult-onset type II citrullinemia (CTLN2) is an autosomal recessive disease caused by mutations in SLC25A13, the gene encoding the mitochondrial aspartate/glutamate carrier citrin. The absence of citrin leads to a liver-specific, quantitative decrease of argininosuccinate synthetase (ASS), causing hyperammonemia and citrullinemia. To investigate the physiological role of citrin and the development of CTLN2, an Slc25a13-knockout (also known as Ctrn-deficient) mouse model was created. The resulting Ctrn ؊/؊ mice were devoid of Slc25a13 mRNA and citrin protein. Liver mitochondrial assays revealed markedly decreased activities in aspartate transport and the malate-aspartate shuttle. Liver perfusion also demonstrated deficits in ureogenesis from ammonia, gluconeogenesis from lactate, and an increase in the lactate-to-pyruvate ratio within hepatocytes. Surprisingly, Ctrn ؊/؊ mice up to 1 year of age failed to show CTLN2-like symptoms due to normal hepatic ASS activity. Serological measures of glucose, amino acid, and ammonia metabolism also showed no significant alterations. Nitrogen-loading treatments produced only minor changes in the hepatic ammonia and amino acid levels. These results suggest that citrin deficiency alone may not be sufficient to produce a CTLN2-like phenotype in mice. These observations are compatible, however, with the variable age of onset, incomplete penetrance, and strong ethnic bias seen in CTLN2 where additional environmental and/or genetic triggers are now suspected.

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Serum Amino Acid Pattern of Type II Citrullinemic Patients and Effect of Oral Administration of Citrulline

Cited by 38 publications

References 14 publications

Effects of Citrin Deficiency in the Perinatal Period: Feasibility of Newborn Mass Screening for Citrin Deficiency

Effects of Citrin Deficiency in the Perinatal Period: Feasibility of Newborn Mass Screening for Citrin Deficiency

Moderate citrullinaemia without hyperammonaemia in a child with mutated and deficient argininosuccinate synthetase

Slc25a13-Knockout Mice Harbor Metabolic Deficits but Fail To Display Hallmarks of Adult-Onset Type II Citrullinemia

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