Clinical Diagnosis

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].

Figure

Figure 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 dysfunction
• Failure 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 symptoms

Testing

In addition to the findings in Table 1, the following are observed in citrin deficiency:

NICCD

• Plasma 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).

• Plasma concentration of bilirubin, bile acids, and alpha-fetoprotein are elevated (see Table 3).

FTTDCD

• Dyslipidemia 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].

Testing Strategy

Confirming/establishing the diagnosis of citrin deficiency in a proband (see Figure 2 and Figure 3)

Figure

Fig. 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...)

Figure

Figure 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; or
  • Galactosemia, 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 testing

• Perform 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) Disorders

CTLN2, NICCD, and FTTDCD are the only phenotypes currently known to be associated with mutations in SLC25A13.

Natural History

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.

Genotype-Phenotype Correlations

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].

Penetrance

The male-to-female ratio in NICCD is roughly equal (73:80) [Kobayashi & Saheki 2004].

The male-to-female ratio in CTLN2 is 2.4 to 1 (120:50) [Kobayashi & Saheki 2004].

The unequal male-to-female ratio in CTLN2 suggests that for unknown reasons, homozygous females are more resistant to the CTLN2 phenotype than males.

Nomenclature

NICCD. NICCD was known as "idiopathic neonatal hepatitis with fatty liver of unknown origin" [Ohura et al 1997] before molecular genetic testing confirmed the presence of SLC25A13 mutations.

CTLN2. Miyakoshi et al [1968] reported that blood citrulline concentrations were increased in individuals with hyperammonemia and a unique chronic recurrent hepatocerebral degeneration. This hepatocerebral degeneration came to be known as "pseudo-ulegyric hepatocerebral disease" on the basis of pathologic brain changes, and "nutritional hepatocerebral disease" on the basis of metabolic disturbance resulting from a highly unbalanced diet or developmental disturbance caused by endocrine abnormalities.

Saheki et al [1981] reported this hepatocerebral disease as a type of citrullinemia with a qualitative and liver-specific decrease of the arginosuccinate synthetase activity/protein, and later Saheki et al [1985] named it "adult-onset type II citrullinemia."

Prevalence

In Japan, the frequency of homozygotes or compound heterozygotes for SLC25A13 mutations is calculated to be 1:17,000 based on the carrier or heterozygote rate of 1:65 [Saheki & Kobayashi 2002, Tabata et al 2008]. This is similar to the observed prevalence of NICCD [Shigematsu et al 2002], but different from the observed prevalence of CTLN2 (1:100,000-1:230,000) [Kobayashi et al 2006]. Based on their observations, the authors believe that most homozygotes of Japanese heritage have NICCD.

Until recently, citrin deficiency was thought to be restricted to Japan; citrin deficiency is now recognized to be pan ethnic [Dimmock et al 2009]. Individuals with novel SLC25A13 mutations have been identified in Israel, Pakistan, the US, the United Kingdom, China, and the Czech Republic [Ben-Shalom et al 2002, Hutchin et al 2006, Luder et al 2006, Dimmock et al 2007, Fiermonte et al 2008, Song et al 2008, Tabata et al 2008, Song et al 2009b, Song et al 2011].

The carrier frequency is also high in China (1/65), especially southern China including Taiwan (1/48), and in Korea (1/112) [Lu et al 2005, Lee et al 2011].

Evaluations 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 Manifestations

NICCD. 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 Manifestations

To 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 Complications

Vitamin 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.

Surveillance

To 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 concentration
• Serum PSTI concentration

Increases 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 Avoid

Low-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 Risk

It 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 Investigation

Search 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.

Other

Glycerol 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).

Mode of Inheritance

Citrin deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
• Occasionally a parent may have two mutated SLC25A13 alleles without severe symptoms of CTLN2, a finding in two of 48 fathers and one of 54 mothers tested in 163 Japanese families with NICCD [Kobayashi et al 2006].
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• When both parents are carriers, each sib of an affected individual has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• When one parent is a carrier and the other parent has two mutated SLC25A13 alleles, each sib of an affected individual has, at conception, a 50% chance of inheriting two mutated SLC25A13 alleles and being affected and a 50% chance of inheriting one mutated SLC25A13 allele and being an asymptomatic carrier.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with citrin deficiency are obligate heterozygotes (carriers) for a disease-causing mutation in SLC25A13.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis [Zhao et al 2011] usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like citrin deficiency) have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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Suggested Reading

1. Chew HB, Ngu LH, Zabedah MY, Keng WT, Balasubramaniam S, Hanifah MJ, Kobayashi K. Neonatal intrahepatic cholestasis associated with citrin deficiency (NICCD): a case series of 11 Malaysian patients. J Inherit Metab Dis. 2010 [PubMed: 21161389]
2. Guo L, Li BX, Deng M, Wen F, Jiang JH, Tan YQ, Song YZ, Liu ZH, Zhang CH, Kobayashi K, Wang ZN (2011) Etiological analysis of neurodevelopmental disabilities: single-center eight-year clinical experience in south China. J Biomed Biotechnol 2011.pii: 318616. [PMC free article: PMC2948914] [PubMed: 20936111]
3. Kobayashi K, Ushikai M, Song YZ, Gao HZ, Sheng JS, Tabata A, Okumura F, Ikeda S, Saheki T. Overview of citrin deficiency: SLC25A13 mutations and the frequency. J Appl Clin Pediatr. 2008;23:1553–7.
4. Ngu HL, Zabedah MY, Kobayashi K. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in three Malay children. Malays J Pathol. 2010;32:53–7. [PubMed: 20614727]
5. Saheki T, Inoue K, Ono H, Tushima A, Katsura N, Yokogawa M, Yoshidumi Y, Kuhara T, Ohse M, Eto K, Kadowaki T, Sinasac DS, Kobayashi K. Metabolomic analysis reveals hepatic metabolite perturbations in citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mice, a model of human citrin deficiency. Mol Genet Metab. 2011;104:492–500. [PubMed: 21908222]
6. Sawada S, Kinjo T, Makishi S, Tomita M, Arasaki A, Iseki K, Watanabe H, Kobayashi K, Sunakawa H, Iwamasa T, Mori N. Downregulation of citrin, a mitochondrial AGC, is associated with apoptosis of hepatocytes. Biochem Biophys Res Commun. 2007;364:937–44. [PubMed: 18273444]
7. Shigeta T, Kasahara M, Kimura T, Fukuda A, Sasaki K, Arai K, Nakagawa A, Nakagawa S, Kobayashi K, Soneda S, Kitagawa H. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr Transplant. 2010;14:E86–8. [PubMed: 19413723]

Author Notes

The first author of this review, Keiko Kobayashi, PhD, died of colon cancer on December 21, 2010. The scientific community has lost a great scientist, teacher, and friend.

Keiko Kobayashi is recognized internationally as a pioneer in citrin deficiency research. An investigator with the research group of Professor Takeyori Saheki (Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University, Japan), in 1999 she cloned the gene in which mutation is causative (SLC25A13) and designated the term citrin. Kobayashi also played essential roles in the discovery and designation of NICCD and FTTDCD, two early onset forms of citrin deficiency. As an outstanding molecular geneticist, she identified over 50 mutations in SLC25A13 and diagnosed over 500 citrin-deficient patients worldwide (Japan, Korea, China, Vietnam, Malaysia, Israel, Palestine, Australia, Czech, France, Britain, and the US). She also worked tirelessly to educate the medical community about citrin deficiency, thus improving the care and prognosis of affected patients worldwide. Less than a month before her death, Dr. Kobayashi delivered a lecture on citrin deficiency to the 9th Asia-Pacific Conference on Human Genetics.

Keiko Kobayashi, the “mother of citrin deficiency,” will be remembered and sorely missed by her friends, students, colleagues, and the citrin-deficient patients whom she diagnosed.

Acknowledgments

This research was supported in part by Grants-in-Aid for Scientific Research (Nos. 16390100, 19390096 and 19591230) and for Asia-Africa Scientific Platform Program (AASPP) from the Japan Society for the Promotion of Science (JSPS), by a Grant for Child Health and Development (17-2) from the Ministry of Health, Labour and Welfare in Japan, by a Grant for Research for Promoting Technological Seeds from the Japan Science and Technology Agency and by Project 81070279 supported by the National Natural Science Foundation (NSFC) of China.

Revision History

• 5 January 2012 (me) Comprehensive update posted live
• 1 July 2008 (me) Comprehensive update posted live
• 28 December 2006 (kk) Revision: sequence analysis for SLC25A13 clinically available
• 16 September 2005 (me) Review posted to live Web site
• 5 November 2004 (kk) Original submission