Clinical characteristics.

Citrin deficiency can manifest in newborns or infants 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 citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods.

• NICCD. Children younger than age one year have a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia. NICCD is generally not severe and symptoms often resolve by age one year with appropriate treatment, although liver transplantation has been required in rare instances.
• FTTDCD. Beyond age one year, many children with citrin deficiency develop a protein-rich and/or lipid-rich food preference and aversion to carbohydrate-rich foods. Clinical abnormalities may include growth restriction, hypoglycemia, pancreatitis, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid (TCA) cycle metabolites. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2.
• CTLN2. Presentation is sudden and usually between ages 20 and 50 years. Manifestations are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery. Affected individuals may or may not have a prior history of NICCD or FTTDCD.

Diagnosis/testing.

The diagnosis of citrin deficiency is established in an individual with characteristic biochemical findings (in general, increased blood or plasma concentration of ammonia, plasma or serum concentration of citrulline and arginine, plasma or serum threonine-to-serine ratio, and serum concentration of pancreatic secretory trypsin inhibitor) and identification of biallelic pathogenic variants in SLC25A13.

Management.

Treatment of manifestations: NICCD: Supplement diet with fat-soluble vitamins and use of lactose-free and medium-chain triglyceride (MCT)-enriched formula. FTTDCD: In addition to dietary treatment, administration of sodium pyruvate may improve growth. CTLN2: Liver transplantation prevents hyperammonemic crises, corrects metabolic disturbances, and eliminates preferences for protein-rich foods; arginine administration decreases blood ammonia concentration and reduced calorie/carbohydrate intake; increased protein intake lessens hypertriglyceridemia. Use of arginine, sodium pyruvate, and MCT oil may delay the need for liver transplantation.

Prevention of primary manifestations: Lipid and protein-rich low-carbohydrate diet.

Surveillance: Periodic measurement of plasma concentration of ammonia and citrulline, and serum concentration of PSTI for all phenotypes associated with citrin deficiency. Follow up of children who have had NICCD for the laboratory and physical findings of FTTDCD.

Agents/circumstances to avoid: Low-protein high-carbohydrate diets; glycerol and fructose infusions for brain edema; alcohol; acetaminophen and rabeprozole.

Evaluation of relatives at risk: It is appropriate to identify affected sibs of a proband so that appropriate dietary management can be instituted before symptoms occur.

Genetic counseling.

Citrin deficiency is inherited in an autosomal recessive manner. When both parents are carriers of an SLC25A13 pathogenic variant, 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 SLC25A13 pathogenic variants, each sib of an affected individual has at conception a 50% chance of being affected and a 50% chance of being an asymptomatic carrier. Testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the SLC25A13 pathogenic variants in the family are known.

Suggestive Findings

Citrin deficiency should be suspected in individuals with the following findings (see Figure 2):

Figure 2.

Flow chart for diagnosis 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 restriction, hypoglycemia, pancreatitis, and (more...)

• Infants who have had a positive newborn screening test for:
  • Citrullinemia and/or prolonged jaundice; or
  • Galactosemia, hypermethionemia, tyrosinemia or hyperphenylalanemia, who on follow-up diagnostic testing were found not to have one of these disorders.
    Note: 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]. Although plasma tyrosine is elevated in some individuals, this is not a common feature. Instead, tyrosinemia is suspected because the 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate are increased on urinary GC-MS analysis.
• 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 a history of aversion to carbohydrate and fondness for protein- and lipid-rich foods
• Children and adults with unexplained recurrent pancreatitis, hyperlipidemia, fatty liver, or hepatoma

Establishing the Diagnosis

The diagnosis of citrin deficiency is established in a proband with biochemical testing results consistent with citrin deficiency and/or biallelic pathogenic variants in SLC25A13 identified on molecular genetic testing (see Table 3). Western blot analysis is available if the pathogenic variants cannot be identified.

Clinical Description

Citrin deficiency can manifest in newborns or infants 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 the individual's preference 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. For those with NICCD who have no special medical concerns other than dietary management, close medical observation is recommended since they still have biochemical alterations [Song et al 2011] even at the silent stage [Nagasaka et al 2009, Nagasaka et al 2017].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known for this disorder.

Penetrance

There appears to be a difference in penetrance of the CTLN2 phenotype related to the sex of the individual.

• The male-to-female ratio in NICCD is roughly equal (73:80) while 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, among individuals with biallelic SLC25A13 pathogenic variants, 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 biallelic SLC25A13 pathogenic variants.

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 argininosuccinate 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 pathogenic variants is calculated at 1:17,000 based on the carrier (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 individuals of Japanese heritage with biallelic SLC25A13 pathogenic variants 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 pathogenic variants have been identified in Israel, Pakistan, the United States, 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 a phenotype of citrin deficiency, the following are recommended:

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 sex-matched growth standards.
• Investigate feeding pattern.

CTLN2. Investigate carbohydrate, protein, and lipid composition of the diet.

All phenotypes. Consult with a clinical geneticist and/or genetic counselor.

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 and MCT-enriched therapeutic formulas [Ohura et al 2003, Song et al 2010, Hayasaka et al 2012, Zhang et al 2014a].

Two sibs 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, which could be the effect of reduction of breast milk and/or common formulas while simultaneously introducing solid supplements such as eggs and meat, which are rich in protein and lipid and therefore beneficial for citrin-deficient individuals [Song et al 2010].

The treatment with therapeutic formulas is not lifelong. Most infants with NICCD will recover clinically and biochemically by age one year, at which point protein- and lipid-enriched textured or solid supplements could be introduced. Whether continued treatment beyond a year can reduce the likelihood of the FTTDCD and CTLN2 phenotype is currently unknown.

Moreover, zinc deficiency is common in NICCD, and thus zinc supplementation should be encouraged when laboratory evidence indicates zinc deficiency, especially in individuals with marked failure to thrive.

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 third 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 restriction [Mutoh et al 2008, Saheki et al 2010]. Sodium pyruvate reduces the NADH/NAD⁺ ratio in the hepatocyte, a pivotal alteration for citrin deficiency development, and this could be associated with its ameliorating effect on growth restriction.

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 preference for protein-rich foods [Kobayashi & Saheki 2004]. Nearly all individuals with CTLN2 required liver transplantation in the past; however, the introduction of arginine and sodium pyruvate and medium chain triglyceride (MCT) oil administration has altered the situation. Other treatments include the following:

• Administration of arginine (5-10 g/day) 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 (4-9 g/day) was effective in decreasing frequency of hyperammonemic episodes and improving growth in several cases [Mutoh et al 2008; Saheki et al 2010; Yazaki et al 2010; Ohura et al, personal communication; Okano et al, personal communication].
• Administration of MCT oil (Mactone oil containing 85% MCT; 45 mL/day) was associated with complete recovery with all normal laboratory findings or improved with no hyperammonemic symptoms [Hayasaka et al 2014].

Prevention of Primary Manifestations

To prevent hyperammonemia and improve growth, 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].

High-carbohydrate meals and alcohol should be avoided.

Arginine administration may be effective in preventing hyperammonemic crises.

Prevention of Secondary Complications

Vitamin D deficiency and zinc deficiency are common complications in NICCD [Song et al, personal communication]. 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 persons with 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 (e.g., height, weight, and head circumference; serum lipid levels including triglycerides, total cholesterol, HDL-cholesterol, and LDL-cholesterol) is appropriate.

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 prompt 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 including 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 liver cytosol, which may disturb liver function [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 clarify the genetic status of 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.

Because asymptomatic or presymptomatic individuals with citrin deficiency do not always show biochemical abnormalities, definitive diagnosis of at-risk relatives (e.g., sibs) would depend heavily on SLC25A13 molecular genetic findings in the proband:

• If both SLC25A13 pathogenic variants in the index case have been identified, molecular genetic testing can be used reliably.
• If only one SLC25A13 pathogenic variant is ascertained in the index case, it may not be feasible to definitively exclude the diagnosis in at-risk relatives who have the one identified pathogenic variant. In such cases, serial clinical and biochemical assessment will be needed over time to confirm or rule out the diagnosis.
• If no SLC25A13 pathogenic variant is ascertained in the index case, molecular testing of at-risk individuals will not be helpful. In such cases, serial clinical and biochemical assessment will be needed over time to confirm or rule out the diagnosis

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

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 typically heterozygotes (i.e., carriers of one SLC25A13 pathogenic variant).
• Occasionally a parent may have two SLC25A13 pathogenic variants 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]. An asymptomatic father has been found to have the same SLC25A13 genotype as his son who had NICCD [Zeng et al 2014].
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• When both parents are carriers of an SLC25A13 pathogenic variant, each sib of an affected individual has, at conception, a 25% chance of inheriting two pathogenic variants, 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 SLC25A13 pathogenic variants, each sib of an affected individual has, at conception, a 50% chance of inheriting two SLC25A13 pathogenic variants and a 50% chance of inheriting one SLC25A13 pathogenic variant and being an asymptomatic carrier.
• In general, sibs who inherit biallelic SLC25A13 pathogenic variants will be affected and have clinical manifestations of citrin deficiency similar to those of the proband in the family; however, reduced penetrance and intrafamilial clinical variability have been observed [Kobayashi & Saheki 2004; Kobayashi et al 2006; Zeng et al 2014; Okano, personal communication].
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Unless an individual with citrin deficiency has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for an SLC25A13 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC25A13 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC25A13 pathogenic variants 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC25A13 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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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. As an investigator in the research group of Professor Takeyori Saheki (Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University, Japan), in 1999 she cloned the causative gene SLC25A13 and designated the term "citrin" for citrin deficiency. 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 more than 50 pathogenic variants in SLC25A13 and diagnosed more than 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 the Projects 81070279,81270957 and 81570793 supported by the National Natural Science Foundation (NSFC) of China.

Author History

Keiko Kobayashi, PhD; Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (2004-2010)
Takeyori Saheki, MD, PhD (2004-present)
Yuan-Zong Song, MD, PhD (2012-present)

Revision History

• 10 August 2017 (ha) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 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 live
• 5 November 2004 (kk) Original submission