Citrullinemia type II belongs to the class of urea cycle disorders and is caused by mutations in the gene SLC25A13 (CTLN2, citrin) encoding the liver-type aspartate-glutamate carrier located in the mitochondrial membrane.
Most cases are reported in Japan (PMID:24508627).
Citrullinemia type II is characterized by increased serum citrulline and ammonia levels, but patients also display various neuropsychiatric symptoms.
Citrullinemia type II can be confirmed by a decrease in CTLN2 activity with normal kinetic properties in liver, but normal ASS1 activity in other tissues (PMID:24508627).
Adult-onset type II citrullinemia is an autosomal recessive metabolic disorder characterized clinically by the sudden onset of various neuropsychologic symptoms such as disorientation, abnormal behavior, convulsions, and coma due to hyperammonemia. In some cases, rapid progression can lead ... Adult-onset type II citrullinemia is an autosomal recessive metabolic disorder characterized clinically by the sudden onset of various neuropsychologic symptoms such as disorientation, abnormal behavior, convulsions, and coma due to hyperammonemia. In some cases, rapid progression can lead to brain edema and death if liver transplantation is not possible. Some patients may present with nonalcoholic hepatic steatosis or may develop hepatic fibrosis or hepatocellular carcinoma. Patients with this disorder have a natural aversion to carbohydrates and favor protein, which is in contrast to protein aversion usually observed in patients with urea cycle defects (summary by Komatsu et al., 2008).
In Japan a distinct late-onset form of citrullinemia was reported; see review by Walser (1983). Significant clinical abnormality had onset in childhood or not until adulthood, age 48 years in 1 case. Symptoms included enuresis, delayed menarche, insomnia, ... In Japan a distinct late-onset form of citrullinemia was reported; see review by Walser (1983). Significant clinical abnormality had onset in childhood or not until adulthood, age 48 years in 1 case. Symptoms included enuresis, delayed menarche, insomnia, sleep reversal, nocturnal sweats and terrors, recurrent vomiting (especially at night), diarrhea, tremors, episodes of confusion after meals, lethargy, convulsions, delusions, hallucinations, and brief episodes of coma. Delayed mental and physical development was shown by some patients. Most had a peculiar fondness for beans, peas, and peanuts from early childhood and a dislike for rice, other vegetables, and sweets. Since the preferred foods are high in arginine, the dietary predilection of these patients may reflect an arginine deficiency. As the patients get older, episodic disturbances become more frequent, and bizarre behavior, including manic episodes, echolalia, and frank psychosis, appears. Citrulline concentrations in the plasma were increased. The late-onset form is apparently autosomal recessive because sibs have been affected and some of the parents have been consanguineous. Most of the reports of the late-onset form appeared in Japanese journals; see Walser (1983) for references. An exception was the report by Matsuda et al. (1976). Also see Scott-Emuakpor et al. (1972) for a similar case reported from the United States. In the study of adult-onset type II citrullinemia in Japanese, Yasuda et al. (2000) found that the onset of serious and recurring symptoms in CTLN2 varied from age 11 to age 79, with a mean of 34.4 years. Almost all patients suffered from a sudden disturbance of consciousness associated with disorientation, restlessness, drowsiness, and coma, and most died mainly of cerebral edema within a few years of onset. Komatsu et al. (2008) found that 17 (89%) of 19 patients with genetically confirmed CTLN2 had hepatic steatosis. Four (21%) had been diagnosed with nonalcoholic fatty liver disease before the appearance of neuropsychologic symptoms that are usually characteristic of CTLN2. Hepatic steatosis occurred in the absence of obesity or features of the metabolic syndrome; all patients were lean. Some patients showed hepatic fibrosis, suggesting progression of liver damage. Laboratory abnormalities in CTLN2 patients included citrullinemia, abnormal liver enzymes, low albumin, increased serum triglycerides, and decreased activity of argininosuccinate synthetase. CTLN2 patients had a higher frequency of pancreatitis compared to those without mutations. Increased levels of pancreatic secretory protease inhibitor (PSTI, SPINK1; 167790) were associated with citrin deficiency, which could be a useful method of distinguishing CTLN2 patients from those with nonalcoholic fatty liver disease.
Kobayashi et al. (1993) found on sequence analysis no mutation in the ASS1 mRNA from 2 patients with adult-onset type II citrullinemia. They also reported RFLP analysis of ... - Exclusion of Mutations in the ASS1 Gene Kobayashi et al. (1993) found on sequence analysis no mutation in the ASS1 mRNA from 2 patients with adult-onset type II citrullinemia. They also reported RFLP analysis of a consanguineous family with type II citrullinemia in which 3 polymorphisms located within the ASS1 gene locus were examined. In spite of having consanguineous parents, the patient was not homozygous for the ASS1 gene haplotype. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 had the heterozygous pattern for 1 of the 3 DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggested that the primary defect of type II citrullinemia was not within the ASS1 gene locus. - Pathogenic Mutations in the SLC25A13 Gene In 18 adult patients with CTLN2 from consanguineous parents, Kobayashi et al. (1999) identified 5 distinct mutations (603859.0001-603859.0005) in the SLC25A13 gene, encoding citrin, and confirmed their causative role in the disease. The studies of adult-onset type II citrullinemia in Japanese were extended by Yasuda et al. (2000), who identified 2 novel mutations in the SLC25A13 gene (603859). Diagnostic analysis for the 7 known mutations in 103 CTLN2 patients diagnosed by biochemical and enzymatic studies revealed that 102 patients had 1 or 2 of the 7 mutations and 93 patients were homozygotes or compound heterozygotes. Five of 22 patients from consanguineous unions were compound heterozygotes, suggesting a high frequency of the mutated genes. The frequency of homozygotes was calculated to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. By Western blot analysis with antihuman citrin antibody, the authors detected no cross-reactive immune materials in the liver of CTLN2 patients with any of the 7 mutations. From these findings, Yasuda et al. (2000) hypothesized that CTLN2 is caused by a complete deletion of citrin, although this did not explain the mechanism of argininosuccinate synthetase deficiency. In a 38-year-old Pakistani man living in Europe who had episodic confusion, elevated plasma ammonia and arginine levels, citrullinemia, normal glutamine, low serine levels, and fatal hyperammonemic encephalopathy, Fiermonte et al. (2008) identified homozygosity for a mutation at a highly conserved residue in the SLC25A13 gene (R588Q; 603859.0007). The authors noted that type II citrullinemia has rarely been reported outside of East Asia but must be considered in adults presenting with hyperammonemic encephalopathy, since the management is different from the management of classic urea-cycle defects (see 311250).
Kobayashi et al. (1999) stated that the frequency of CTLN2 in Japan is approximately 1 in 100,000.
Yasuda et al. (2000) calculated the frequency of homozygotes of SLC25A13 mutations to be more than 1 in 20,000 ... Kobayashi et al. (1999) stated that the frequency of CTLN2 in Japan is approximately 1 in 100,000. Yasuda et al. (2000) calculated the frequency of homozygotes of SLC25A13 mutations to be more than 1 in 20,000 from carrier detection (6 in 400 individuals tested) in the Japanese population. Among 1,315 Japanese individuals tested, Yamaguchi et al. (2002) found that 18 were carriers of an SLC25A13 mutation; this provided an estimate of minimally 1 in 21,000 for homozygotes. They referred to 2 Chinese CTLN2 patients in Taiwan and a Vietnamese neonatal-onset type II citrullinemia (NICCD) patient in Australia who had the same SLC25A13 mutations as those identified in Japanese patients. Lu et al. (2005) estimated the frequencies of SLC25A13 homozygotes to be 1 in 19,000 in Japan, 1 in 50,000 in Korea, and 1 in 17,000 in China. Specific mutations were identified in all Asian countries tested, with the most common mutations being a 4-bp deletion (603859.0001) and a splice site mutation (603859.0002). The frequencies of SLC25A13 homozygotes in China were calculated to be 1 in 9,200 to the south of the Yangtze River and 1 in 3,500,000 to the north of the Yangtze River. The findings were consistent with the historical boundary of the Yangtze River; modern Chinese are thought to derive from 2 distinct populations, 1 originating in the Yellow River valley and the other in the Yangtze River valley, during early Neolithic times (3,000 to 7,000 years ago).
Citrin deficiency has two distinct well-recognized phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and citrullinemia type II (CTLN2) (see Figure 1) [Saheki & Kobayashi 2002, Yamaguchi et al 2002, Kobayashi & Saheki 2004, Saheki & Kobayashi 2005, Kobayashi et al 2006]. Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD was recently proposed as a novel intermediate phenotype [Song et al 2011]....
DiagnosisClinical DiagnosisCitrin deficiency has two distinct well-recognized phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and citrullinemia type II (CTLN2) (see Figure 1) [Saheki & Kobayashi 2002, Yamaguchi et al 2002, Kobayashi & Saheki 2004, Saheki & Kobayashi 2005, Kobayashi et al 2006]. Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD was recently proposed as a novel intermediate phenotype [Song et al 2011].FigureFigure 1. Citrin deficiency NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency CTLN2 = adult-onset type II citrullinemia Cit = citrulline Thr = threonine Met = methionine Arg = arginine Tyr (more...)Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) characterized by transient neonatal cholestasis and variable hepatic dysfunctionFailure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) characterized by post-NICCD growth retardation before CTLN2 onset and abnormalities of serum lipid concentrations, including triglycerides, total cholesterol, and HDL-cholesterol. Clinical diagnosis of citrin deficiency during this stage is difficult in the absence of a history of unique food preferences or without molecular testing.Citrullinemia type II (CTLN2) characterized by childhood- to adult-onset, recurring episodes of hyperammonemia and associated neuropsychiatric symptomsTestingTable 1. Biochemical Findings in Citrin Deficiency by Phenotype View in own windowPhenotype (Age)Blood or Plasma Concentration of Ammonia (µmol/L)Plasma or Serum Concentration of Citrulline (C) 1Plasma or Serum Concentration of Arginine (A) (µmol/L)Plasma or Serum Threonine-to-Serine RatioSerum Concentration of Pancreatic Secretory Trypsin Inhibitor (PSTI) 2 (ng/mL)Control18-47 3 17-43 354-130 31.10 4.6-20 3 NICCD (0-6 months)60 300 2052.29 30 FTTDCD (>1 to 11 years)Normal, or slightly elevatedNormal, or slightly elevatedUsually normalUnknownUnknownCTLN2 (11-79 years)152418 1982.32 71 Kobayashi et al [2006]1. Citrullinemia, which can be detected on newborn screening, is the earliest identifiable biochemical abnormality of NICCD [Tamamori et al 2004].2. Because the serum PSTI concentration is high in some individuals with NICCD [Tamamori et al 2002] and also in individuals before the onset of CTLN2 [Tsuboi et al 2001], the measurement of serum PSTI concentration may be useful in presymptomatic diagnosis of CTLN2.3. RangeIn addition to the findings in Table 1, the following are observed in citrin deficiency: NICCDPlasma concentration of galactose, methionine, and/or phenylalanine is elevated in newborn screening blood spots in approximately 40% of children with NICCD [Ohura et al 2003, Ohura et al 2007].Plasma concentrations of threonine, methionine, and tyrosine are elevated (see Table 2).Table 2. Plasma Concentrations of Threonine, Methionine, and Tyrosine at Age 0-6 Months in NICCD View in own windowAmino AcidMedian (25%-75% Range) (µmol/L)Control Range (µmol/L)Threonine496 (291-741) 67-190Methionine124 (53-337)19-40Tyrosine178 (99-275)40-90Kobayashi et al [2006]Plasma concentration of bilirubin, bile acids, and alpha-fetoprotein are elevated (see Table 3). Table 3. Measurements of Hepatic Cell Function at Age 0-6 Months in NICCD View in own windowAssayed ItemMedian (25%-75% range) (mg/dL)Control Range (mg/dL)TB in NICCD4.9 (2.8-8.0)0.2-1.0TB in CTLN20.8 (0.52-1.1)DB in NICCD2.5 (1.5-3.7) 0-0.4DB in CTLN20.3 (0.2-0.4) TB/DB ratio in NICCD0.55 (0.41-0.66)—TBA239 (172-293)5-25AFP91,900 (33,200-174,700)260-6,400 1, 22-55 2, 3Kobayashi et al [2006]TB= total bilirubinDB= direct bilirubinTBA= total bile acidsAFP= α-fetoprotein1. 0-1 month2. Tamamori et al [2002]3. >1 monthFTTDCDDyslipidemia manifests as abnormal levels of triglyceride and cholesterol (including total-, HDL- and LDL-cholesterol) [Song et al 2009a, Song et al 2011]. Other abnormal laboratory findings include increased lactate to pyruvate ratio, elevated cholesterol, and higher levels of urinary oxidative stress markers [Kobayashi & Saheki 2004, Saheki & Kobayashi 2005, Kobayashi et al 2006, Nagasaka et al 2009, Lee et al 2010]. CTLN2 Pancreatic secretory trypsin inhibitor (PSTI) concentration is increased in the liver [Kobayashi et al 1997] (see Table 1). Note: PSTI mRNA is increased 30-140 fold in the liver of individuals with CTLN2 Fischer ratio (branched-chain amino acids [BCAAs] Val+Leu+Ile / aromatic amino acids [AAAs] Tyr+Phe) in the plasma or serum is decreased from ~3.4 to ~2 as a result of decreased BCAA. Liver-specific argininosuccinate synthetase (ASS) enzyme activity is decreased to approximately 10% that of controls (secondary effect of mutations) [Yasuda et al 2000]. Plasma α-fetoprotein concentration is normal in almost all individuals with CTLN2 [Kobayashi et al 1997], except some individuals with CTLN2 associated with hepatoma [Hagiwara et al 2003].Both NICCD and CTLN2 Western blot analysis using anti-human citrin antibody specific for the amino-terminal half detects little or no cross-reactive immune material in liver, cultured fibroblasts, or lymphocytes from individuals with SLC25A13 mutations [Yasuda et al 2000, Takahashi et al 2006, Dimmock et al 2007, Tokuhara et al 2007, Fu et al 2011].Molecular Genetic TestingGene. SLC25A13 is the only gene in which mutations are known to cause citrin deficiency.Table 4. Summary of Molecular Genetic Testing Used in Citrin DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySLC25A13Sequence analysis Sequence variants 2>95% 3Clinical Deletion / duplication analysis 4Exonic and whole-gene deletionsUnknown 51. Because the criteria for clinical and biochemical diagnosis of citrin deficiency other than CTLN2 are not yet established, it is difficult to calculate the mutation detection frequency.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Kobayashi et al [1999], Yasuda et al [2000], Ben-Shalom et al [2002], Yamaguchi et al [2002], Saheki et al [2004], Lu et al [2005], Takaya et al [2005], Ko et al [2007a], Song et al [2008], Tabata et al [2008], Song et al [2009b], Xing et al [2010], Fu et al [2011], Song et al [2011], Wen et al [2011]4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. 5. Takaya et al [2005], Wong et al [2008] Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming/establishing the diagnosis of citrin deficiency in a proband (see Figure 2 and Figure 3) FigureFig. 2. Diagnostic algorithm of citrin deficiency. Note that food preferences (e.g., aversion to sugars) are important in the diagnosis of citrin deficiency, not only in typical CTLN2 but also in cases of growth retardation, hypoglycemia, pancreatitis, (more...)FigureFigure 3. \Flow chart for diagnosis of citrin deficiency The following testing strategy (see Order of testing) should be considered for: Infants who have had a positive newborn screening test for:Citrullinemia and/or prolonged jaundice; orGalactosemia, hypermethionemia or hyperphenylalanemia, who on follow-up diagnostic testing were found not to have one of these disorders.Children beyond age one year who present with failure to thrive and dyslipidemia;Older children and adults with hepatic encephalopathy with hyperammonemia, especially those with aversion to carbohydrate and fondness for protein- and lipid-rich foods;Children and adults with unexplained recurrent pancreatitis, hyperlipidemia, fatty liver or hepatoma.Order of testingPerform quantitative plasma amino acid analysis (children age 1-4 months).Measure blood ammonia, plasma amino acids, PSTI, liver enzymes (when CTLN2 is suspected).Perform dietary assessment, including food preferences (particularly important if FFTDCD or CTLN2 is suspected).Perform molecular genetic testing: Sequence analysis of SLC25A13, followed by deletion/duplication analysis if neither or only one disease-causing mutation is identified. Note: Western blotting for citrin protein is considered if no or only one disease-causing mutation is identified by molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersCTLN2, NICCD, and FTTDCD are the only phenotypes currently known to be associated with mutations in SLC25A13.
Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often FTTDCD and CTLN2 are characterized by fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Individuals with CTLN2 may or may not have a prior history of NICCD or FTTDCD. The proportion of persons with NICCD or FTTDCD that evolves into CTLN2 is unknown....
Natural HistoryCitrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often FTTDCD and CTLN2 are characterized by fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Individuals with CTLN2 may or may not have a prior history of NICCD or FTTDCD. The proportion of persons with NICCD or FTTDCD that evolves into CTLN2 is unknown.Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)Children under age one year with NICCD have transient intrahepatic cholestasis. Other findings include diffuse fatty liver with hepatomegaly and parenchymal cellular infiltration associated with hepatic fibrosis, low birth weight, growth retardation, hypoproteinemia, decreased coagulation factors, hemolytic anemia, variable (mainly mild) liver dysfunction, and/or hypoglycemia.NICCD is generally not severe, although liver transplantation has been required in rare cases [Tamamori et al 2002, Kobayashi et al 2006]. Symptoms typically resolve by age one year with treatment, including fat-soluble vitamin supplementation and use of lactose-free formulas (for those with galactosemia) or formulas containing medium-chain triglycerides [Ohura et al 2003, Song et al 2010].Starting around age one to two years, children show a strong preference for protein-rich and lipid-rich foods and an aversion to sugar-rich and carbohydrate-rich foods [Hachisu et al 2005, Saheki & Kobayashi 2005, Saheki et al 2008].In the second or later decades, some individuals with citrin deficiency develop severe CTLN2 with neuropsychiatric symptoms [Saheki & Kobayashi 2002]. Typically the transition from the adaptation (and/or compensation) stage following NICCD to the onset of CTLN2 is gradual.Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)FTTDCD has recently been proposed as a novel post-NICCD phenotype before the onset of CTLN2 [Song et al 2011]. The clinical and laboratory features of FTTDCD are still being elucidated. During this period (traditionally assumed to be an “apparently healthy” stage before CTLN2 onset) some children were found to have laboratory abnormalities (see Diagnosis) and/or clinical abnormalities including fatigue, growth retardation, hypoglycemia, and pancreatitis.Citrullinemia Type II (CTLN2)CTLN2 is characterized by recurring episodes of hyperammonemia and neurologic and psychotic symptoms that closely resemble those of hepatic encephalopathy or genetic urea cycle disorders, including nocturnal delirium, aberrant behaviors (aggression, irritability, and hyperactivity), delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Brain CT is normal, and EEG shows diffuse slow waves.Onset is sudden and usually between ages 20 and 50 years (range: 11-79 years; mean age: 34.4 ±12.8 years; n=103) [Yasuda et al 2000]. Many individuals with CTLN2 have a strong preference for protein-rich and/or lipid-rich foods (e.g., beans, peanuts, eggs, milk, cheese, fish, meat) and an aversion to carbohydrate-rich foods including rice, juice, and sweets. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery. Most individuals are thin. More than 90% have a body mass index lower than 20 and approximately 40% have a body mass index lower than 17 (range: 15.6-19.1; n=110) [Kobayashi et al 2006] (range in healthy Japanese individuals: 20-24 in males; 19-23 in females).The following complications occur in more than 10% of individuals with CTLN2 [Kobayashi et al 2000]. Studies regarding these complications are ongoing. Pancreatitis. Juvenile-onset chronic pancreatitis and hepatocellular carcinoma without cirrhosis can precede the appearance of CTLN2 [Ikeda et al 2004]. Hyperlipidemia. Hypertrigyceridemia is frequently observed if high carbohydrate meals are provided to individuals with citrin deficiency [Imamura et al 2003].Fatty liver. Most individuals with NICCD and CTLN2 have fatty liver, which is histologically identical to NASH (non-alcoholic steatohepatitis) [Takagi et al 2006, Fukumoto et al 2008, Komatsu et al 2008]. Mild fibrosis can also be seen [Kobayashi et al 2000].Hepatoma may be present, even before the diagnosis of CTLN2 is made [Tanaka et al 2002, Hagiwara et al 2003, Tsai et al 2006, Soeda et al 2008]Intrahepatic cholestasis is rare; however, some individuals are noted in retrospect to have had signs of NICCD in early childhood [Kobayashi & Saheki 2004, Saheki & Kobayashi 2005]. For example, a 16-year-old with CTLN2 undergoing liver transplantation [Kasahara et al 2001] had had transient hypoproteinemia and jaundice in early infancy [Tomomasa et al 2001].Pathologic findings include fatty infiltration and mild fibrosis of the liver despite little or no liver dysfunction.
No significant correlation between SLC25A13 mutation types and decreased level of hepatic enzyme ASS activity/protein or age of onset in individuals with CTLN2 is observed [Yasuda et al 2000]. ...
Genotype-Phenotype CorrelationsNo significant correlation between SLC25A13 mutation types and decreased level of hepatic enzyme ASS activity/protein or age of onset in individuals with CTLN2 is observed [Yasuda et al 2000].
Plasma concentration of citrulline is increased in citrin deficiency as well as in the following disorders:...
Differential DiagnosisPlasma concentration of citrulline is increased in citrin deficiency as well as in the following disorders:Citrullinemia type 1 (CTLN1; ASS deficiency). CTLN1 presents as a wide spectrum of overlapping phenotypes: an acute neonatal form (the "classic" form), a milder late-onset form, a form without symptoms and/or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum [Gao et al 2003]. Shortly after birth, infants with the acute neonatal form develop hyperammonemia and its complications, from which they die without prompt intervention. Those who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficit. In the late-onset form, the episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle. CTLN1 results from deficiency of the enzyme ASS, the third step in the urea cycle, in which citrulline is condensed with aspartate to form argininosuccinic acid. Untreated individuals with the severe form of CTLN1 have hyperammonemia, increased plasma concentration of citrulline, and decreased plasma concentration of arginine. Inheritance is autosomal recessive. In CTLN2, the liver-specific deficiency of the ASS protein is secondary by unknown mechanisms [Yasuda et al 2000] as no abnormalities are present in hepatic ASS mRNA or ASS1.Argininosuccinic aciduria (argininosuccinate lyase [ASL] deficiency) (see Urea Cycle Disorders Overview)Lysinuric protein intolerance (LPI)Pyruvate carboxylase (PC) deficiencyRenal insufficiencyGalactosemia. In one neonate, classic galactosemia presented as citrin deficiency [Feillet et al 2008].Hyperammonemia occurs in citrin deficiency as well as in the urea cycle disorders, which result from defects in the metabolism of the nitrogen produced by the breakdown of protein and other nitrogen-containing molecules (see Urea Cycle Disorders Overview). Severe deficiency or total absence of activity of any of the first four enzymes (CPSI, OTC, ASS, ASL) in the urea cycle, the ornithine transporter, or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life in most affected individuals.Neonatal/infantile cholestasis occurs in citrin deficiency as well as the following disorders: Idiopathic neonatal hepatitis (INH) and extrahepatic biliary atresia (EBA). In comparison with INH and EBA, NICCD is associated with lower levels of serum direct bilirubin or ALT and higher levels of serum total bile acids and alkaline phosphatase. NICCD also has higher levels of serum γ-GTP and lower levels of serum AST activity than are seen in INH [Tazawa et al 2005].Progressive familial intrahepatic cholestasis (PFIC, Byler disease). The high-serum γ-GTP levels of NICCD may distinguish it from other intrahepatic cholestasis disorders with low-normal γ-GTP levels including PFIC and benign recurrent intrahepatic cholestasis (BRIC). PFIC is caused by mutations in ATP8B1 (FIC1) or ABCB11 (BSEP). Some cases of BRIC are caused by mutations in ATP8B1.Hereditary jaundice and hyperbilirubinemia result from defects in the metabolism of bilirubin. These include disorders resulting in predominantly unconjugated (indirect) hyperbilirubinemia (UDP-glucuronosyltransferase 1-1 deficiency) and those resulting in predominantly conjugated (direct) hyperbilirubinemia (deficiency in canalicular ATP-dependent transporters: ABCC2 [MRP2], ABCB11, or ATP8B1).OtherPortal-systemic shunts can be excluded by angiography.More than 30% of individuals with CTLN2 have been misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia); others may be diagnosed as having diseases such as hepatoma, pancreatitis, and hyperlipidemia.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).CTLN2NICCD
To establish the extent of disease and needs of an individual diagnosed with citrin deficiency the following are recommended by phenotype:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with citrin deficiency the following are recommended by phenotype:NICCD Assess the size of the liver and spleen. Seek evidence of fatty liver by abdominal US, CT, or MRI. Investigate feeding pattern. FTTDCD Perform detailed anthropometric examination and evaluation using age- and gender-matched growth standards.Investigate feeding pattern. CTLN2 Investigate carbohydrate, protein, and lipid composition of the diet. Treatment of ManifestationsNICCD. The symptoms in most children with NICCD resolve by age 12 months following supplementation with fat-soluble vitamins and use of lactose-free formula (in those with galactosemia) or formulas containing medium-chain triglycerides (MCT) [Ohura et al 2003]. Moreover, the efficacy of lactose-free and/or MCT-enriched therapeutic formulas has also been demonstrated in a Chinese NICCD cohort [Song et al 2010]. Two siblings improved after switching from breast milk to formula, which has higher proline content [Ben-Shalom et al 2002]. Some children with NICCD improve without treatment.Four infants with NICCD and severe liver dysfunction were diagnosed as having tyrosinemia of unknown cause and underwent liver transplantation at age ten to 12 months [Tamamori et al 2002, Kobayashi et al 2006].FTTDCD. Few treatment measures have been described for this novel citrin-deficient phenotype. A toddler with FTTDCD was fed in accordance with his own food preferences (including aversion to rice and fondness for fish); FTT improved gradually, with weight-for-age recovering beyond the thirrd percentile at age three years. The dyslipidemia also improved gradually [Song et al 2009a]. In addition to dietary treatment, administration of sodium pyruvate may be effective in correcting growth retardation [Mutoh et al 2008, Saheki et al 2010].CTLN2. The most successful therapy to date has been liver transplantation [Ikeda et al 2001, Kasahara et al 2001, Yazaki et al 2004, Hirai et al 2008], which prevents episodic hyperammonemic crises, corrects the metabolic disturbances, and eliminates preferences for protein-rich foods [Kobayashi & Saheki 2004]. Nearly all cases of CTLN2 need liver transplantation in the past, but this situation starts to change since introduction of arginine and sodium pyruvate.Administration of arginine was reported to be effective in decreasing blood ammonia concentration. Reducing calorie/carbohydrate intake and increasing protein intake ameliorates hypertriglyceridemia [Imamura et al 2003].Administration of sodium pyruvate was effective in several cases [Yazaki et al 2005; Mutoh et al 2008; Saheki et al 2010; Yazaki et al 2010; Ohura et al, personal communication; Okano et al, personal communication]. Prevention of Primary ManifestationsTo prevent hyperammonemia and resolve failure to thrive, a diet rich in protein and lipids and low in carbohydrates is recommended [Saheki & Kobayashi 2005, Saheki et al 2006, Dimmock et al 2007, Saheki et al 2008, Dimmock et al 2009].Avoid high-carbohydrate meals and alcohol.Arginine administration may be effective in preventing hyperammonemic crisis.Prevention of Secondary ComplicationsVitamin D deficiency and zinc deficiency are common complications in NICCD [Song et al, in preparation]. Severe infection and liver cirrhosis have also been reported to be lethal complications in some individuals with NICCD. Therefore, vitamin D and zinc supplements and active infection control are recommended in NICCD. SurveillanceTo monitor for emergence of the FTTDCD phenotype in persons with citrin deficiency older than age one year: close surveillance of anthropometric indices, such as height, weight, and head circumference; serum lipid levels, including triglycerides, total cholesterol, HDL-cholesterol, and LDL-cholesterol.It is recommended that the following be measured every several months:Plasma ammonia concentration (especially in the evening or 2 hours after feeding)Plasma citrulline concentrationSerum PSTI concentrationIncreases in plasma citrulline concentration and serum PSTI suggest onset of CTLN2 [Tsuboi et al 2001, Mutoh et al 2008] and should trigger initiation of treatment.Agents/Circumstances to AvoidLow-protein/high-caloric (high-carbohydrate) diet. Although a low-protein/high-caloric diet helps prevent hyperammonemia in urea cycle enzyme deficiencies, it is harmful for individuals with all forms of citrin deficiency (i.e., NICCD, FTTDCD, or CTLN2) [Saheki et al 2004, Saheki & Kobayashi 2005, Saheki et al 2006]. A high-carbohydrate diet may increase NADH production, disturb urea synthesis, and stimulate the citrate-malate shuttle, resulting in hyperammonemia, fatty liver, and hypertriglyceridemia [Saheki & Kobayashi 2002, Imamura et al 2003, Saheki et al 2006, Saheki et al 2007].Infusion of sugars, such as glycerol, fructose, and glucose. Severe brain edema treated with glycerol-containing osmotic agents has resulted in continued deterioration and is contraindicated in those with CTLN2 [Yazaki et al 2005]. Degradation of large amounts of glycerol and fructose generates NADH in the liver, which may disturb liver function and produce toxic substances [Saheki et al 2004, Yazaki et al 2005, Takahashi et al 2006]. Infusion of high-concentration glucose may also exacerbate hyperammonemia [Tamakawa et al 1994, Takahashi et al 2006].Note: Mannitol infusion appears to be safer [Yazaki et al 2005].Alcohol. Drinking alcohol can trigger the onset of CTLN2 because alcohol dehydrogenase (ADH) generates NADH in the cytosol of the liver.Medications. Acetaminophen and rabeprozole may trigger CTLN2 [Shiohama et al 1993, Imamura et al 2003]. Evaluation of Relatives at RiskIt is appropriate to test at-risk asymptomatic sibs of a proband for citrin deficiency so that appropriate dietary management of infants (discontinuation of breast feeding and introduction of lactose-free and/or MCT-enriched formulas) can be instituted before symptoms occur. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherGlycerol or similar drugs containing glycerol and fructose for brain edema are not only ineffective but also dangerous for persons with citrin deficiency (see Agents/Circumstances to Avoid).
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Citrin Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC25A137q21.3Calcium-binding mitochondrial carrier protein Aralar2SLC25A13 @ LOVDSLC25A13Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Citrin Deficiency (View All in OMIM) View in own window 603471CITRULLINEMIA, TYPE II, ADULT-ONSET; CTLN2 603859SOLUTE CARRIER FAMILY 25 (CITRIN), MEMBER 13; SLC25A13 605814CITRULLINEMIA, TYPE II, NEONATAL-ONSETNormal allelic variants. The normal SLC25A13 gene comprises 18 exons [Kobayashi et al 1999, Sinasac et al 1999].Pathologic allelic variants. To date, 59 pathologic allelic variants occurring in exons or introns resulting in missense mutations, predicted truncated forms of citrin, or abnormal mRNA splicing have been reported [Kobayashi et al 1999, Yasuda et al 2000, Ben-Shalom et al 2002, Yamaguchi et al 2002, Lu et al 2005, Takaya et al 2005, Hutchin et al 2006, Ko et al 2007a, Ko et al 2007b, Komatsu et al 2008, Song et al 2008, Tabata et al 2008, Wong et al 2008, Dimmock et al 2009, Hutchin et al 2009, Song et al 2009b, Xing et al 2010, Fu et al 2011, Lin et al 2011, Song et al 2011, Wen et al 2011]. Thirteen novel pathologic variations have been identified by the authors [Song et al, unpublished data]. Two mutations (c.1177+1G>A and c.851-854del) account for the majority (~70%) of pathologic alleles in Japanese persons with citrin deficiency. In a cohort of 51 persons with citrin deficiency from 50 Chinese families, four mutations (c.851-854del, c.615+5G>A, c.1750+72_1751-4dup17insNM_138459.3: 2667, and c.1638_1660dup23) accounted for 87% of the mutated alleles [Song et al 2011]. Only one mutation, p.Arg360*, has been found in both Japanese and Northern European populations [Tabata et al 2008]. Some of the 20 mutations identified in Japanese individuals have been found in Chinese, Vietnamese, and Korean individuals with citrin deficiency (NICCD or CTLN2) [Lu et al 2005, Lee et al 2006, Song et al 2006, Tsai et al 2006, Yeh et al 2006, Ko et al 2007a, Ko et al 2007b, Song et al 2008, Tabata et al 2008]. Different mutations were found in Israel, the United States, the United Kingdom, and China [Ben-Shalom et al 2002, Hutchin et al 2006, Luder et al 2006, Dimmock et al 2007, Song et al 2008, Tabata et al 2008, Song et al 2009b, Xing et al 2010, Fu et al 2011, Song et al 2011].Table 10. Selected SLC25A13 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1) Protein Amino Acid ChangeReference SequencesReferencec.15G>A (Ex1-1G>A)--NM_014251.2 NP_055066.1Tabata et al [2008]c.550C>Tp.Arg184*Saheki et al [2004]c.615+5G>A (IVS6+5G>A)--c.615+1G>C (IVS6+1G>C)--Lu et al [2005]c.674C>Ap.Ser225*Kobayashi et al [1999]c.851_854del (851del4)p.Met285Profs*2c.1078C>Tp. Arg360*Tabata et al [2008]c.1177+1G>A (IVS11+1G>A)--Kobayashi et al [1999]c.1311+1G>A (IVS13+1G>A)--c.1592G>Ap.Gly531AspTabata et al [2008]c.1638_1660dup23 (1638ins23)p.Ala554Glyfs*17Kobayashi et al [1999]c.1799dupA (1800_1801insA)p.Tyr600*Yasuda et al [2000]c.1801G>Tp.Glu601*Yamaguchi et al [2002]c.1801G>Ap.Glu601Lysc.1813C>Tp.Arg605*Yasuda et al [2000]c.1750+72_1751-4dup17ins NM_138459.3: 2667 2(IVS16ins3kb)--Tabata et al [2008]g.20984997_20985512del516 (Ex16+74_IVS17-32del516)--NT_007933.14Takaya et al [2005]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. A complex allele with an insertion of 2667 nucleotides of processed cDNA in antisense orientation of NUS1 at 6q22.31 (reference sequence NM_138459.3); this insertion is flanked by the 17 nucleotide duplication of intron 16 sequences (NM_014251.2:c.1751-4_-22dup17) [Tabata et al 2008].Normal gene product. Citrin and its homolog aralar [del Arco & Satrústegui 1998] are members of the SLC25 (solute carrier family 25) protein family. Both proteins are localized in the mitochondrial inner membrane and function as a Ca2+-binding/-stimulated aspartate-glutamate carrier (AGC), a component of the malate-aspartate NADH shuttle [Palmieri et al 2001, Kobayashi & Saheki 2003]. Citrin is expressed in the liver; aralar in the brain and skeletal muscle; both are expressed in the kidney and heart [Kobayashi et al 1999]. Citrin as a liver-type AGC plays a role in various metabolic pathways, including aerobic glycolysis, gluconeogenesis, the urea cycle, and protein and nucleotide syntheses [Saheki & Kobayashi 2002, Saheki et al 2004, Saheki & Kobayashi 2005, Saheki et al 2006].Abnormal gene product. Most SLC25A13 mutations cause or predict truncation of the citrin protein or delete a loop between the mitochondrial transmembrane domains. The lack of significant citrin protein was confirmed by Western blot analysis using antibody against the N-terminal half of the human citrin protein, which detected little or no cross-reactive immune material in liver, cultured fibroblasts, and lymphocytes from individuals with SLC25A13 mutations [Yasuda et al 2000, Takahashi et al 2006, Dimmock et al 2007, Tokuhara et al 2007, Fu et al 2011].