Citrin Deficiency

Yuan-Zong Song; Kimihiko Oishi; Takeyori Saheki

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Citrin Deficiency

Yuan-Zong Song, MD, PhD, Kimihiko Oishi, MD, and Takeyori Saheki, MD, PhD.

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Initial Posting: September 16, 2005; Last Update: March 20, 2025.

Estimated reading time: 40 minutes

Summary

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, anemia, and/or hypoglycemia. NICCD is generally not severe, and clinical manifestations are often resolved by age one year with appropriate treatment, although liver failure may still occur; 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 poor weight gain, growth deficiency, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, recurrent hypoglycemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid cycle metabolites. One or more decades later, some adults with NICCD or FTTDCD may progress and develop features of CTLN2.

CTLN2: Presentation is sudden and usually between ages 20 and 50 years. Clinical manifestations include recurrent hyperammonemia with neuropsychiatric (aggression, irritability, restlessness, hyperactivity, delusions, nocturnal delirium) and neurologic manifestations (flapping tremors, memory loss, disorientation, drowsiness, convulsive seizures, coma). Clinical manifestations are often caused by alcohol and sugar intake, medication, and/or surgery. Complications include severe liver steatosis and pancreatitis. 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 analytes (increased blood or plasma concentration of ammonia, plasma or serum concentration of citrulline and arginine, plasma or serum threonine-to-serine ratio) and biallelic pathogenic variants in SLC25A13 identified by molecular genetic testing.

Management.

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

Surveillance: Periodic measurement of plasma concentration of ammonia and citrulline for all phenotypes associated with citrin deficiency. Assess growth and development throughout childhood; assessment of liver and pancreatic function as clinically indicated; neuropsychologic testing and quality of life assessment as clinically indicated; complete blood count and ferritin as clinically indicated.

Agents/circumstances to avoid: Low-protein and high-carbohydrate diets; glycerol, fructose, and glucose infusions due to risk of brain edema; alcohol.

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. If both parents are known to be heterozygous for an SLC25A13 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being a carrier, and a 25% chance of inheriting neither of the familial SLC25A13 pathogenic variants. If one parent is known to be heterozygous for an SLC25A13 pathogenic variant and the other parent is known to have biallelic SLC25A13 pathogenic variants, each sib of an affected individual has at conception a 50% chance of inheriting biallelic SLC25A13 pathogenic variants and a 50% chance of inheriting one SLC25A13 pathogenic variant. 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. Once the SLC25A13 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

GeneReview Scope

Citrin Deficiency: Included Phenotypes
Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) Citrullinemia type II (CTLN2)

Diagnosis

Citrin deficiency has three clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2) (see Figure 1). A symptomatic individual may have either untreated NICCD due to newborn screening (NBS) not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result, or manifestations associated with later-onset citrin deficiency (FTTDCD or CTLN2).

Figure 1.

Clinical and laboratory manifestations of citrin deficiency AA = amino acids; AFP = alpha-fetoprotein; Arg = arginine; Cit = citrulline; CTLN2 = type II citrullinemia; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; Met = methionine; (more...)

Suggestive Findings

Scenario 1: NICCD (includes abnormal NBS result and symptomatic newborn)

Abnormal NBS result. NBS for citrin deficiency is primarily based on quantification of the analyte citrulline on dried blood spots.

Note: Dried blood spots also show elevated galactose, methionine, and/or phenylalanine in 40% of children with NICCD [Ohura et al 2003, Ohura et al 2007]. Tyrosine may be elevated in some individuals. The ratio of citrulline to total amino acids is markedly elevated in individuals with NICCD. Simultaneously evaluating citrulline concentrations and ratios of citrulline to total amino acids can improve the diagnostic sensitivity of NBS [Shigetomi et al 2018]. A scoring system using threshold levels for arginine (≥9 μmol/L), citrulline (≥39 μmol/L), isoleucine and leucine (≥99 μmol/L), tyrosine (≥96 μmol/L), and C0:C5-DC ratio (≥327; ratio of free carnitine to gutarylcarnitine) was significantly effective in detecting newborns who later developed NICCD [Kido et al 2024a].

Citrulline values above the out-of-range cutoffs reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following:

Plasma amino acids show elevated threonine, methionine, and tyrosine.
Urinary organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.

Note: Normal citrulline values on NBS does not exclude the diagnosis of citrin deficiency.

If the follow-up biochemical testing supports the likelihood of citrin deficiency, additional testing is required to establish the diagnosis.

The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this is a true positive NBS result and to establish the diagnosis of citrin deficiency definitively:

Lactose-free and MCT-enriched formula
Fat-soluble vitamins (vitamins A, D, E, and K)

Clinical, laboratory, and histopathology features in a symptomatic infant

Variable liver disease (elevated liver transaminases, cholestasis with elevated conjugated bilirubin and subsequent jaundice, hyperlipidemia, hypoproteinemia, hyperammonemia, prolonged prothrombin time, markedly elevated serum alpha-fetoprotein) and hepatomegaly. Liver histopathology can show diffuse macrovesicular and microvesicular steatosis, parenchymal cellular infiltration, siderosis, and fibrosis.
Pre- and postnatal growth delays with full cheeks
Hypoglycemia
Anemia
Seizures
Plasma amino acids show elevated citrulline, threonine, arginine, methionine, and tyrosine concentrations; urine organic acids show normal 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate concentrations.
Positive reducing substances on urine testing

Scenario 2: FTTDCD and CTLN2 (symptomatic individual)

FTTDCD clinical and laboratory features

Poor weight gain and growth delays
Aversion to carbohydrates and fondness for protein- and lipid-rich foods
Abnormalities of serum lipid concentrations, including elevated triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL) can be elevated [Nagasaka et al 2017, Hirayama et al 2018].

CTLN2 clinical and laboratory features

Childhood- to adult-onset recurring episodes of hyperammonemia
Neuropsychiatric manifestations
Recurrent pancreatitis
Hyperlipidemia
Fatty liver or hepatoma
Elevated plasma citrulline, arginine, and threonine-to-serine ratio

Establishing the Diagnosis

The diagnosis of citrin deficiency is established in a proband with suggestive clinical findings and/or laboratory analytes consistent with citrin deficiency and biallelic pathogenic (or likely pathogenic) variants in SLC25A13 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic SLC25A13 variants of uncertain significance (or of one known SLC25A13 pathogenic variant and one SLC25A13 variant of uncertain significance) does not establish or rule out the diagnosis.

Scenario 1: Abnormal NBS Result for NICCD (includes symptomatic infant)

When NBS results and other laboratory analytes suggest the diagnosis of citrin deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of SLC25A13 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [Lu et al 2005, Tabata et al 2008, Song et al 2013, Lin et al 2016, Kido et al 2022] (see Table 8).
A multigene panel that includes SLC25A13 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Scenario 2: Symptomatic Individual

A symptomatic individual may have untreated NICCD (resulting from NBS not performed or false negative NBS result) or later-onset citrin deficiency not identified on NBS (FTTDCD or CTLN2).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not.

Single-gene testing. Sequence analysis of SLC25A13 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Japanese or Chinese ancestry [Lu et al 2005, Tabata et al 2008, Song et al 2013, Lin et al 2016, Kido et al 2022] (see Table 8).
A multigene panel that includes SLC25A13 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Exome or genome sequencing can be used and does not require the clinician to determine which gene is likely involved. Ordering a rapid turnaround time exome or genome sequencing is necessary when newborns or infants are critically ill. To date, most SLC25A13 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing [Lin et al 2016].
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Citrin Deficiency

Gene ¹	Method	Proportion of Pathogenic Variants ² Identified by Method
SLC25A13	Sequence analysis ³	85%-90% ⁴
SLC25A13	Gene-targeted deletion/duplication analysis ⁵	10%-15% ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Song et al [2013], Lin et al [2016], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
6.: Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

Clinical Characteristics

Clinical Description

Citrin deficiency has three age-dependent, variable clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2). Citrin deficiency can manifest in newborns or infants as NICCD characterized by a diverse set of metabolic abnormalities, including citrullinemia, galactosemia, hypoglycemia, and sometimes hyperammonemia that is likely secondary to liver dysfunction. In most individuals, the clinical manifestations of NICCD improve or resolve by age 12 months. However, some individuals remain symptomatic with progression to FTTDCD, which is characterized by poor weight gain, poor linear growth, dyslipidemia, recurrent hypoglycemia, and fatigue. These individuals may have a silent remission period until after adolescence; 10%-20% evolve into the very severe or even fatal metabolic condition CTLN2, characterized by hyperammonemia, severe liver steatosis, cognitive impairment with sudden episodes of unconsciousness due to brain edema, and pancreatitis. The proportion of people with NICCD that evolve into CTLN2 is unknown. 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.

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)

Table 2.

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency: Frequency of Select Features

Clinical Feature / Laboratory Analyte		Proportion of Persons w/Feature ¹	Comment
Liver disease	Cholestasis	79%	Present in early infancy
	↑ liver transaminases	71%
	Hypoproteinemia	39%
	Prolonged prothrombin time	34%
	Fatty liver	33%	Liver histology includes cholestasis, diffuse macrovesicular & microvesicular steatosis, inflammatory infiltration, & fibrosis
	Hyperlipidemia	24%
	Hepatomegaly	22%
	Hyperammonemia	11%	Ammonia >100 umol/L
Growth impairment (poor weight gain)		32%	Usually small for gestational age; growth failure until age 6-9 mos
Hypoglycemia		30%
Amino acid profile		↑ citrulline (~80%)	Also elevated threonine, methionine, arginine, tyrosine
Anemia		17%
Seizures		5%

1.: Tamamori et al [2004], Shigetomi et al [2018], Kido et al [2022]

Liver dysfunction. Children younger than age one year with NICCD have intrahepatic cholestasis. Other manifestations include diffuse fatty liver with hepatomegaly and inflammatory infiltration associated with hepatic fibrosis, hypoproteinemia, decreased coagulation factors, variable (mainly mild) liver dysfunction, and/or hypoglycemia. Varying degrees of spleen enlargement are observed in those with prolonged and profound cholestasis.

Growth deficiency / nutrition / diet preference. A history of low birth weight and growth restriction is not rare in infants with citrin deficiency. In one study, children who had NICCD showed statistically significant growth delays with low body weight until age six to nine months, reduced height for age until age 11 to 13 years, and low body weight in males age 7 to 12 years and females age 8 years [Numakura et al 2019].

Starting around age one to two years, children show a strong preference for protein- and lipid-rich foods and an aversion to sugar- and carbohydrate-rich foods. This might compensate for the metabolic derangement and result in improved growth [Hachisu et al 2005, Saheki & Kobayashi 2005, Saheki et al 2008, Inui et al 2024].

Forty-five percent of individuals experience hypoglycemic episodes, presenting with a loss of consciousness, convulsion, sweating, fatigue, or "not doing well" in a catabolic state. Some of these symptoms are repetitive or intractable. Milk or food intake can help to correct the hypoglycemia symptoms, and when necessary, intravenous glucose infusion to maintain normal blood glucose levels can be considered [Arai-Ichinoi et al 2021].

Anemia. Anemia (Hgb <10 g/dL) is observed in 17% of individuals with NICCD [Kido et al 2022]. Anemia is usually not severe and resolves as other clinical manifestations improve.

Seizures. Seizures occur in 5% of individuals with NICCD [Kido et al 2022]. Seizures are likely due to hypoglycemia [Okano et al 2019].

Zinc deficiency. Individuals with NICCD often experience zinc deficiency, and zinc supplementation should be provided when necessary [Y-Z Song, personal observation].

Prognosis. NICCD is generally not life-threatening, and clinical manifestations are often resolved in response to dietary therapy by age one year, sometimes without medical intervention. Liver transplantation has been required in rare instances [Tamamori et al 2002, Kobayashi et al 2006]. It is important to monitor for severe infection, cirrhosis, and liver failure to determine if transplant is necessary.

Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)

Growth deficiency / nutrition. Poor weight gain and growth deficiency are identified in 32%-45% of children with FTTDCD [Arai-Ichinoi et al 2021, Kido et al 2022]. 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. Growth gradually improves when individuals start following their preferred diet. Appetite loss and severe growth restriction can occur; a female age 12 years with citrin deficiency presenting with severe anorexia and weight loss mimicking the restricting type of anorexia nervosa has been reported [Takeuchi et al 2015]. Hypoglycemic episodes in early childhood (median: age 33.5 months) often appear after poor oral intake and/or during illness and catabolic states such as fever, vomiting, or enteritis [Arai-Ichinoi et al 2021].

Liver disease. Dyslipidemia can be observed in individuals with citrin deficiency. In such instances, elevated serum levels of triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol can be identified. Serum level of high-density lipoprotein (HDL) cholesterol can be elevated [Nagasaka et al 2009, Nagasaka et al 2017]. Some individuals simultaneously present with poor weight gain, growth deficiency, hepatomegaly, and fatty liver.

Zinc deficiency. Individuals with FTTDCD often experience zinc deficiency, and zinc supplementation should be provided when necessary. Poor appetite was previously assumed to be due to gastroenteropathy, but it is not known if reduced zinc intake or reduced absorption occurs. In individuals with citrin deficiency, assessment for zinc deficiency should be performed [Y-Z Song, personal observation].

Pancreatitis. Pancreatitis is not common in individuals with NICCD and FTTDCD, although juvenile-onset chronic pancreatitis in citrin deficiency has been described [Okano et al 2019, Kakiuchi et al 2020].

Prognosis. Severe fatigue and impaired quality of life were identified in citrin-deficient individuals (age range: 1-22 years)in the adaptation and compensation (traditionally assumed to be "silent") stage, the period of time between clinical manifestations of NICCD and CTLN2, during which affected individuals do not have clear symptoms except for a preference for protein- and lipid-rich foods [Okano et al 2013].

Citrullinemia Type II (CTLN2)

In the second or later decades, some individuals with citrin deficiency develop severe CTLN2 with neurobehavioral/psychiatric manifestations [Saheki & Kobayashi 2002]. Typically, the transition from the adaptation (and/or compensation) stage following NICCD and FTTDCD to the onset of CTLN2 is gradual, but the manifestations of CTLN2 usually occur suddenly.

Diet preferences / nutrition / weight. Many individuals with CTLN2 have a strong preference for protein-rich and/or lipid-rich foods (e.g., beans, peanuts, eggs, milk, cheese, fish, and meat) and an aversion to carbohydrate-rich foods including rice, juice, and sweets.

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).

Neurologic and neuropsychiatric/behavioral manifestations. CTLN2 is characterized by recurring episodes of hyperammonemia and neurologic and neuropsychiatric/behavioral manifestations. External factors, including alcohol consumption, excessive amounts of sugar intake, glycerol/fructose infusion, and surgical procedures may exacerbate neurologic and neuropsychiatric manifestations [Kido et al 2024b]. Although diet therapy, oral arginine, sodium pyruvate, and medium-chain triglyceride (MCT) oil reportedly help reduce these symptoms, liver transplantation remains an effective treatment.

Neurobehavioral/psychiatric manifestations include aggression, irritability, restlessness, hyperactivity, delusions, and nocturnal delirium that closely resemble those of hepatic encephalopathy or urea cycle disorders. Onset is typically sudden and usually between ages 20 and 50 years (range: 11-79 years; mean: 34.4±12.8 years; n=103) [Yasuda et al 2000].

Neurologic manifestations include flapping tremors, memory loss, disorientation, drowsiness, convulsive seizures, and coma. Brain imaging is normal, and EEG shows diffuse slow waves. Brain edema is observed in those with severe hyperammonemia.

Liver disease. Hypertriglyceridemia is frequently observed if high-carbohydrate meals are provided to individuals with citrin deficiency [Imamura et al 2003]. Most individuals with CTLN2 have fatty liver, which is histologically identical to nonalcoholic steatohepatitis [Takagi et al 2006, Fukumoto et al 2008, Komatsu et al 2008]. Mild fibrosis can also be seen despite little or no liver dysfunction [Kobayashi et al 2000]. Hepatoma may be present, even prior to identification of CTLN2 [Tanaka et al 2002, Hagiwara et al 2003, Tsai et al 2006, Soeda et al 2008]. Hepatocellular carcinoma without cirrhosis can precede the other manifestations of CTLN2 [Ikeda et al 2004].

Pancreatitis. Juvenile-onset chronic pancreatitis can precede the appearance of CTLN2 [Ikeda et al 2004]. Pancreatitis is observed in 24%-26% of individuals with CTLN2 [Komatsu et al 2008, Kido et al 2022]. In one individual with CTLN2 cause of death was reported to be pancreatitis [Kido et al 2022].

Prognosis. In general, the prognosis of individuals with citrin deficiency is favorable unless there is development of CTLN2. In a Japanese cohort of 222 individuals with citrin deficiency, three died, primarily due to unrelated causes, and one individual succumbed to pancreatitis. Most individuals with CTLN2 (11/17 individuals) were fully employed with no significant neurologic disability, registering at grades 0 or 1 on the Modified Rankin Scale. However, two individuals with CTLN2 developed severe disability (grade 5) [Kido et al 2024b].

Table 3.

Select Features of Citrin Deficiency (FTTDCD and CTLN2)

Clinical Feature / Laboratory Analyte		Presence of Feature by Phenotype
Clinical Feature / Laboratory Analyte		FTTDCD	CTLN2
Liver disease	Liver dysfunction	+
	Dyslipidemia	+	+
	Abdominal pain	+
	Pancreatitis	+	+
	Fatty liver		+
	Hyperlipidemia		+
	Hyperammonemia		+
	Hepatocellular carcinoma		+
	Cirrhosis, ascites		+
Neuropsychiatric manifestations	Aggression, irritability, restlessness, hyperactivity, delusions		+
Neurologic	Flapping tremor, memory loss, disorientation, drowsiness, seizures, coma		+
Growth impairment / nutrition	Failure to gain weight, low weight for height; loss of appetite	+	+
Gastroenteropathy		+
Zinc deficiency		+
Hypoglycemia		+
Citrullinemia		+	+
Brain edema			+

: Based on Okano et al [2019], Kido et al [2022]
: + = may be present

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations are known for this disorder.

Penetrance

Notably, the penetrance is not 100% for citrin deficiency as an autosomal recessive condition. In addition, there appears to be a difference in penetrance of the CTLN2 phenotype related to the sex of the individual.

Of 418 individuals with biallelic SLC25A13 pathogenic variants, seven individuals had no clinical manifestations, indicating a penetrance of 98.3% [Qiu 2019].
The male-to-female ratio in individuals with NICCD is roughly equal (73:80), while the male-to-female ratio in individuals with 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.

Prevalence

In Japan, the prevalence of CTLN2 is one in 100,000 and the prevalence of NICCD is one in 19,000. The carrier frequency of SLC25A13 pathogenic variants in Japan is 1/33 to 1/51 [Yamaguchi‐Kabata et al 2019]. In China, carrier frequencies in the Guangdong and Shaan Xi populations were calculated to be 1/51 and 1/95, and citrin deficiency morbidity rates were one in 10,053 and one in 35,865, respectively [Lin et al 2021]. Citrin deficiency has been observed in many world populations; however, it is most common in Asia.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in SLC25A13.

Differential Diagnosis

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)

Increased plasma concentration of citrulline is also present in citrullinemia type 1, argininosuccinate lyase deficiency, pyruvate carboxylase deficiency, and lysinuric protein intolerance (see Table 4).

Hyperammonemia also occurs in 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 in the pathway (CPSI, OTC, ASS1, ASL) 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.

Jaundice also occurs in pediatric genetic cholestatic liver disease (see Table 4) and in acquired conditions such as idiopathic neonatal hepatitis (INH), extrahepatic biliary atresia (EBA), and neonatal hemochromatosis [Okano et al 2019]. In comparison with INH and EBA, NICCD is associated with lower levels of serum direct bilirubin or alanine transaminase and higher levels of serum total bile acids and alkaline phosphatase.

Table 4.

Genetic Disorders of Interest in the Differential Diagnosis of Citrin Deficiency: NICCD

Key Feature	Gene	Disorder	MOI	Laboratory Analytes / Clinical Characteristics
Hypercitrullinemia ¹	ASS1	Citrullinemia type 1	AR	↑ citrulline (classic: >2,000 μmol/L, mild: up to 800 μmol/L) Shortly after birth, infants w/acute neonatal form develop hyperammonemia & its complications, from which they die w/o prompt intervention. Those who are treated promptly may survive for an indeterminate period of time, but usually w/significant neurologic deficit.
	ASL	Argininosuccinate lyase deficiency (ASL deficiency)	AR	↑ citrulline (up to 600 μmol/L) on NBS Severe neonatal-onset ASL deficiency is assoc w/hyperammonemia w/in 1st few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, & respiratory alkalosis.
	PC	Pyruvate carboxylase deficiency	AR	↑ citrulline (up to 200 μmol/L) on NBS Type A (infantile form): most affected children die in infancy or early childhood Type B (severe neonatal form): biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (incl high-amplitude tremor & dyskinesia), & abnormal ocular movements
	SLC7A7	Lysinuric protein intolerance	AR	Mildly ↑ plasma citrulline (up to 150 μmol/L) in NBS & later in life ↑ urinary excretion of cationic amino acids, esp lysine Recurrent vomiting, diarrhea, episodes of stupor, & coma after a protein-rich meal, poor feeding, aversion to protein-rich food, poor weight gain, hepatosplenomegaly, & muscular hypotonia
Hyperammonemia ¹	ASL	Argininosuccinate lyase deficiency	AR	Severe neonatal-onset form: hyperammonemia w/in 1st few days after birth Late-onset form: episodic hyperammonemia, cognitive impairment, behavioral abnormalities, learning disabilities
	CPS1	Carbamoylphosphate synthetase I (See Urea Cycle Disorders Overview.)	AR	Most severe cause of urea cycle disorders Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
	DLD	Dihydrolipoamide dehydrogenase deficiency (DLD deficiency)	AR	↑ citrulline on NBS ↑ ammonia & glutamine Early-onset DLD deficiency typically manifests in infancy as hypotonia w/lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation or die w/in 1st few years of life during a recurrent metabolic decompensation.
	NAGS	N-acetylglutamate synthase deficiency (See Urea Cycle Disorders Overview.)	AR	Symptoms mimic those of CPS1 deficiency.
	OTC	Ornithine transcarbamylase deficiency	XL	Males w/severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in 1st week of life, most often on day 2-, & are usually catastrophically ill when they come to medical attention.
Jaundice ¹	ABCB4 ABCB11 ATP8B1 KIF12 LSR MYO5B NR1H4 TJP2 USP53	Defects in transport of bile acids or phospholipids (progressive familial intrahepatic cholestasis [PFIC]) (See Pediatric Genetic Cholestatic Liver Disease Overview.)	AR (most common ²)	Primary cholestatic liver disease caused by defects that impair bile acid transport & result in progressive cholestasis The high-serum γ-GTP levels of NICCD may distinguish it from other intrahepatic cholestasis disorders w/low-normal γ-GTP levels, incl PFIC.
	AKR1D1 AMACR BAAT CYP7B1 CYP27A1 HSD3B7	Disorders of bile acid synthesis (See Pediatric Genetic Cholestatic Liver Disease Overview.)	AR (most common ²)	Primary cholestatic liver disease caused by disorders of bile acid synthesis
	JAG1 NOTCH2	Alagille syndrome	AD	Wide spectrum of clinical variability Major clinical manifestations are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects, butterfly vertebrae, ophthalmologic abnormalities, & characteristic facial features.
	NPC1 NPC2	Niemann-Pick type C	AR	Manifestations in perinatal period & infancy are predominantly visceral, w/hepatosplenomegaly, jaundice, & (in some instances) pulmonary infiltrates.
Hypergalactosemia ¹	GALT	Classic galactosemia	AR	Feeding problems, poor growth, hepatocellular damage, bleeding, & E coli sepsis in untreated infants In 1 neonate, classic galactosemia presented as citrin deficiency. ³

: AR = autosomal recessive; NBS = newborn screening; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency; MOI = mode of inheritance; XL = X-linked; γ-GTP = gamma-glutamyl transpeptidase
1.: Okano et al [2019], Häberle [2024]
2.: See Pediatric Genetic Cholestatic Liver Disease Overview, Genetic Counseling.
3.: Feillet et al [2008]

Other. Hypergalactosemia in a neonate may also be associated with portosystemic shunts [Okano et al 2019]. Portosystemic shunts can be excluded by angiography. These shunts refer to abnormal blood flow from the portal to the postcaval, hepatic, or splenic vein. Individuals with citrin deficiency have no such shunts on medical imaging tests (e.g., sonography, MRI).

Failure to Gain Weight and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)

Other etiologies to consider in children with poor weight gain and dyslipidemia include growth hormone deficiency, Turner syndrome, and familial hypercholesterolemia.

Citrullinemia Type II (CTLN2)

More than 30% of individuals with CTLN2 are misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia) [Y-Z Song, unpublished data]. Other diagnoses that can be considered in individuals with CTLN2 include hepatoma, pancreatitis, and hyperlipidemia.

Management

Although progress has been made [Saheki et al 2020, Hayasaka 2024, Inui et al 2024, Song et al 2024], no well-recognized clinical practice guidelines for citrin deficiency have been published. The following recommendations are based on the authors' personal experience managing large cohorts of individuals with this disorder over a long period of time.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with citrin deficiency, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Citrin Deficiency: Recommended Evaluations Following Initial Diagnosis by Phenotype

Evaluation	Phenotype
Evaluation	NICCD	FTTDCD	CTLN2
Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian ¹	Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended). Plasma amino acid analysis to measure citrulline & other amino acids Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).	Referral to specialist center w/experience in mgmt of inherited metabolic diseases; includes plasma amino acid analysis
Growth / Nutrition assessment	Perform detailed anthropometric exam & eval using age- & sex-matched growth standards.		Assess weight.
Growth / Nutrition assessment	Investigate feeding pattern.		Investigate carbohydrate, protein, & lipid composition of diet.
Assessment of liver function	Assess size & stiffness of liver & spleen; consider appropriate imaging studies (CT/MRI/US). Biochemical analytes (ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia) Coagulation Referral to GI as needed	Assess size & stiffness of liver; consider appropriate imaging studies (CT/MRI/US). Biochemical analytes(ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, & ammonia) Coagulation
Developmental assessment	Developmental assessment; consider referral to developmental pediatrician. ²		Cognitive assessment
Consultation w/neurologist	Assess for seizures, blood glucose as needed.	NA	Assess for neurologic manifestations (disorientation, drowsiness, memory loss, flapping tremor, & seizures).
Neuropsychiatric eval	NA	Assess for neuropsychiatric/behavioral manifestations: ADHD & IQ. ³	Assess for neuropsychiatric/behavioral manifestations.
Consultation w/psychologist &/or social worker	To ensure understanding of diagnosis & assess parental / affected person's coping skills & resources
Genetic counseling by genetics professionals ⁴	To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of citrin deficiency to facilitate medical & personal decision making	As needed (if not previously provided)

: ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; CTLN2 = citrullinemia type II; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; IQ = intelligence quotient; MOI = mode of inheritance; NA = not applicable; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency; US = ultrasound; γ-GTP = gamma-glutamyl transpeptidase
1.: After a new diagnosis of NICCD in a child, the closest hospital and local pediatrician should also be informed.
2.: Numakura et al [2019]
3.: Tsai et al [2025]
4.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

All individuals with citrin deficiency and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing diet in citrin deficiency. One of the most important components of management (as it relates to prevention of secondary complications) is the education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see Tables 5 and 6).

Treatment includes fat-soluble vitamin supplementation and use of lactose-free therapeutic formulas (for those with secondary galactosemia) and medium-chain triglyceride (MCT)-enriched therapeutic formulas [Ohura et al 2003, Song et al 2010, Hayasaka et al 2012, Zhang et al 2014, Saheki et al 2020, Hayasaka 2024, Inui et al 2024, Song et al 2024].

Table 6.

Citrin Deficiency: Treatment of Manifestations by Phenotype

Manifestation/Concern	Phenotype
Manifestation/Concern	NICCD	FTTDCD	CTNL2
Growth/Nutrition	Diet: lactose-free & MCT-enriched therapeutic formula ^1, 2 Fat-soluble vitamin supplementation Zinc supplementation as needed	Diet rich in protein & lipids & low in carbohydrates to prevent hyperammonemia & improve growth Sodium pyruvate, MCT oil may ↑ growth.	Diet: ↓ carbohydrate intake & ↑ protein/lipid intake to ameliorate hypertriglyceridemia Sodium pyruvate can ↑ weight.
Liver disease	NA		Sodium pyruvate (4-9 g/day) can ↓ frequency of hyperammonemia Arginine (5-10 g/day) to ↓ blood ammonia MCT oil (Macton oil containing 85% MCT) (45 mL/day) to help prevent hyperammonemia Use of sodium pyruvate, arginine, & MCT oil may delay need for liver transplantation.
Liver disease	NA		Liver transplant for severe liver failure, to prevent severe hyperammonemia-assoc encephalopathy, correct metabolic disturbances, & eliminate preference for protein-rich foods ⁴

: CTLN2 = citrullinemia type II; FTTDCD = failure to thrive and dyslipidemia caused by citrin deficiency; NA = not applicable; NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency
1.: 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 lipids and therefore beneficial for citrin-deficient individuals [Song et al 2010].
2.: The treatment with therapeutic formulas is not lifelong. Most infants with NICCD will recover clinically and biochemically by age one year, before which point protein- and lipid-enriched supplements could be introduced. Whether continued treatment beyond a year can reduce the likelihood of FTTDCD and CTLN2 is currently unknown.
4.: Introduction of arginine, sodium pyruvate, and MCT oil may help decrease the need for liver transplantation [Saheki et al 2020].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Citrin Deficiency: Recommended Surveillance

System/Concern	Evaluation	Frequency/Comment
Metabolic balance / Nutrition	Eval by an experienced metabolic physician & metabolic nutritionist; may include assessments of biochemical &/or metabolome analytes (incl plasma amino acids) w/adjustments in medication & dietary therapies based on age, weight, & diet	As recommended by metabolic center
Metabolic balance / Nutrition	Education of parents & caregivers such that diligent observation & mgmt can be administered expediently in setting of intercurrent illness or other catabolic stressors
Growth	Assess height, weight, & head circumference.	At each visit throughout childhood & adolescence; continue weight assessment at each visit throughout adulthood
Liver function	ALT, AST, albumin, γ-GTP, ALP, bilirubin, bile acids, cholesterol, triglyceride, AFP, coagulation, & ammonia to assess liver function	As clinically indicated
Pancreatic function	Serum amylase, lipase, & PSTI ¹ Imaging studies (CT/MRI/US)	As clinically indicated
Development/Behavior	Monitor developmental milestones.	At each visit & throughout childhood & adolescence
Development/Behavior	Neuropsychological testing using age-appropriate standardized assessment batteries Standardized quality-of-life assessment tools for affected persons & parents/caregivers	As clinically indicated
Anemia	Complete blood count, ferritin level	As clinically indicated

: AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; PSTI = pancreatic secretory trypsin inhibitor; US = ultrasound; γ-GTP = gamma-glutamyl transpeptidase
1.: Increases in plasma citrulline concentration and serum PSTI suggest onset of citrullinemia type II (CTLN2) [Tsuboi et al 2001, Mutoh et al 2008, Kido et al 2022] 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., neonatal intrahepatic cholestasis caused by citrin deficiency [NICCD)], failure to thrive and dyslipidemia caused by citrin deficiency [FTTDCD], or citrullinemia type II [CTLN2]) [Saheki et al 2020, Hayasaka 2024, Inui et al 2024, Song et al 2024]. A high-carbohydrate diet may increase nicotinamide adenine dinucleotide hydrogen (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]. Mannitol infusion appears to be safer [Yazaki et al 2005].

Alcohol. Drinking alcohol can trigger the onset of CTLN2 because alcohol dehydrogenase generates NADH in the cytosol of the liver.

Evaluation of Relatives at Risk

Prenatal testing of an at-risk fetus. Once the SLC25A13 pathogenic variants causing citrin deficiency in the family are known, molecular genetic prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling so that appropriate dietary management of infants and introduction of lactose-free and MCT-enriched formulas can be considered depending on the clinical context.

Newborn sib. If prenatal testing has not been performed, appropriate dietary management with MCT-containing formula should be considered at birth for newborns with an older sib with citrin deficiency pending results of SLC25A13 molecular genetic testing when citrin deficiency is clinically suspected.

Older sibs. The genetic status of older sibs (even if asymptomatic) of a child with citrin deficiency should be clarified so that appropriate dietary management can be instituted in a timely manner.

See Genetic Counseling for issues related to testing 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Citrin deficiency – encompassing neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2) – is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected child are presumed to be heterozygotes for an SLC25A13 pathogenic variant.
Occasionally a parent may have two SLC25A13 pathogenic variants without severe clinical manifestations of CTLN2, a finding reported in two of 48 fathers and one of 54 mothers tested in 163 Japanese families with NICCD [Kobayashi et al 2006]. An asymptomatic father had the same biallelic SLC25A13 pathogenic variants as his daughter, who had NICCD [Zeng et al 2014].
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC25A13 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
- A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity.
- Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

If both parents are known to be heterozygous for an SLC25A13 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant and being a carrier, and a 25% chance of inheriting neither of the familial SLC25A13 pathogenic variants.
If one parent is known to be heterozygous for an SLC25A13 pathogenic variant and the other parent is known to have biallelic SLC25A13 pathogenic variants, each sib of an affected individual has at conception a 50% chance of inheriting biallelic SLC25A13 pathogenic variants and a 50% chance of inheriting one SLC25A13 pathogenic variant.
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, intrafamilial clinical variability has been observed [Kobayashi & Saheki 2004; Kobayashi et al 2006; Zeng et al 2014; Y Okano, personal observation]. Moreover, a penetrance of 98.3% (411/418) has been described for citrin deficiency [Qiu 2019], and there appears to be a difference in penetrance of the CTLN2 phenotype related to the sex of the individual (see Penetrance).
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner is heterozygous for an SLC25A13 pathogenic variant (or has biallelic SLC25A13 pathogenic variants), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SLC25A13.

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 sibs for the purpose of early diagnosis and treatment.

Family planning

The optimal time for determination of genetic risk 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.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with citrin deficiency. Citrin deficiency has been observed in many world populations; however, it is most common in Asia, where the carrier frequency is one in 65 [Kido et al 2024b].

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). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC25A13 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Citrin Foundation
Singapore
citrinfoundation.org
MedlinePlus
Citrullinemia
Patient Association for Citrin Deficiency and Citrullinemia
Japan
citr-pfg.net
Liver UK
United Kingdom
Phone: 0800 652 7330
liveruk.org
Metabolic Support UK
United Kingdom
Phone: 0845 241 2173
metabolicsupportuk.org

Molecular Genetics

Information 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 Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
SLC25A13	7q21.3	Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial	SLC25A13 @ LOVD	SLC25A13	SLC25A13

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Citrin Deficiency (View All in OMIM)

603471	CITRIN DEFICIENCY, ADOLESCENT OR ADULT ONSET; CDAA
603859	SOLUTE CARRIER FAMILY 25 (CITRIN), MEMBER 13; SLC25A13
605814	CITRIN DEFICIENCY, NEONATAL OR INFANTILE ONSET; CDNI

Molecular Pathogenesis

Citrin (also called electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial), encoded by SLC25A13, is expressed mainly in the liver. This bipartite protein is located in the mitochondrial inner membrane, where it functions as a calcium‐binding aspartate-glutamate carrier, exporting aspartate from mitochondria to the cytosol and co-transporting glutamate with a proton into the mitochondrial matrix. Aspartate binds to citrulline in the cytosol to form argininosuccinate (catalyzed by argininosuccinate synthetase) and enters the urea cycle. Importantly, citrin is a member of the malate-aspartate (MAS) nicotinamide adenine dinucleotide hydrogen (NADH) shuttle, which functions to transport electrons from the cytosol into mitochondria. This crucial process supplies mitochondria with NADH for ATP production as well as providing NAD⁺ to the cytosol for the oxidation of nutrients in several metabolic pathways.

In citrin deficiency, NADH cannot be oxidized because the mitochondria cannot supply aspartate to the cytosol, and NADH produced in the cytoplasm is not taken up by the mitochondria, thereby increasing the cytoplasmic NADH:NAD ratio. SLC25A13 pathogenic variants result in a defective NADH shuttle, leading to disturbance of multiple metabolic pathways including the urea cycle, aerobic glycolysis, gluconeogenesis, galactose metabolism, and fatty acid synthesis. Thus, affected individuals may have diverse metabolic abnormalities, including hypoglycemia, hyperammonemia, citrullinemia, galactosemia, and abnormal acylcarnitine profiles.

Mechanism of disease causation. Loss of function

SLC25A13-specific laboratory technical considerations. Nearly 10% of individuals with citrin deficiency have only one SLC25A13 pathogenic variant identified [Kido et al 2022].

Table 8.

SLC25A13 Pathogenic Variants Referenced in This GeneReview

Reference Sequences	DNA Nucleotide Change (Alias ¹)	Predicted Protein Change	Comment [Reference]
NM_014251.3 NP_055066.1	c.615+5G>A (IVS6+5G>A)	p.Ala206ValfsTer7	7 variants that account for 85% of pathogenic variants in persons of Vietnamese, Chinese, Taiwanese, Korean, & Japanese ancestry [Kido et al 2024b] ²
	c.674C>A	p.Ser225Ter
	c.852_855delTATG	p.Met285ProfsTer2
	c.1177+1G>A (IVS11+1G>A)	p.Ala340_Arg392del
	c.1311+1G>A	p.Val411_Cys437del
	c.1638_1660dup23	p.Ala554GlyfsTer17
NG_012247.2	3-kb insertion in intron 16 (IVS16ins3kb)	p.Ala584ValfsTer2

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
1.: Variant designation that does not conform to current naming conventions
2.: The allele frequency varies between these populations [Kido et al 2024b].

Chapter Notes

Author Notes

Keiko Kobayashi, PhD, a great scientist, teacher, and friend in the field of citrin deficiency, died of colon cancer on December 21, 2010.

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." Dr 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 individuals worldwide (Japan, Korea, China, Vietnam, Malaysia, Israel, Palestine, Australia, Czech, France, Britain, and the United States). She also worked tirelessly to educate the medical community about citrin deficiency, thus improving the care and prognosis of affected individuals worldwide. The contribution of Dr Kobayashi is significant not only for the fundamental research but also for the molecular diagnosis and management of citrin deficiency.

Keiko Kobayashi, the "mother of citrin deficiency," will be remembered and sorely missed by her friends, students, colleagues, and the citrin-deficient individuals 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, 81570793, and 82400673 supported by the National Natural Science Foundation (NSFC) of China. The authors thank Dr Wei-Xia Lin for her technical assistance during the revision process of this review.

Author History

Kimihiko Oishi, MD (2025-present)
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

20 March 2025 (gf) Comprehensive update posted live
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
16 September 2005 (me) Review posted live
5 November 2004 (kk) Original submission

References

Literature Cited

Arai-Ichinoi N, Kikuchi A, Wada Y, Sakamoto O, Kure S. Hypoglycemic attacks and growth failure are the most common manifestations of citrin deficiency after 1 year of age. J Inherit Metab Dis. 2021;44:838-46. [PubMed: 33861477]
Feillet F, Merten M, Battaglia-Hsu SF, Rabier D, Kobayashi K, Straczek J, Brivet M, Favre E, Guéant JL. Evidence of cataplerosis in a patient with neonatal classical galactosemia presenting as citrin deficiency. J Hepatol. 2008;48:517–22. [PubMed: 18207281]
Fukumoto K, Sumida Y, Yoshida N, Sakai K, Kanemasa K, Itoh Y, Mitsufuji S, Kataoka K, Okanoue T. A case of adult-onset type II citrullinemia having a liver histology of nonalcoholic steatohepatitis (NASH). Nippon Shokakibyo Gakkai Zasshi. 2008;105:244–51. [PubMed: 18250596]
Häberle J. Citrin deficiency-the East-side story. J Inherit Metab Dis. 2024;47:1129-33. [PMC free article: PMC11586598] [PubMed: 38994653]
Hachisu M, Oda Y, Goto M, Kobayashi K, Saheki T, Ohura T, Noma S, Kitanaka S. Citrin deficiency presenting with ketotic hypoglycaemia and hepatomegaly in childhood. Eur J Pediatr. 2005;164:109–10. [PubMed: 15592876]
Hagiwara N, Sekijima Y, Takei Y, Ikeda S, Kawasaki S, Kobayashi K, Saheki T. Hepatocellular carcinoma in a case of adult-onset type II citrullinemia. Intern Med. 2003;42:978–82. [PubMed: 14606711]
Hayasaka K. Pathogenesis and management of citrin deficiency. Intern Med. 2024;63:1977-86. [PMC free article: PMC11309867] [PubMed: 37952953]
Hayasaka K, Numakura C, Toyota K, Kimura T. Treatment with lactose (galactose)-restricted and medium-chain triglyceride-supplemented formula for neonatal intrahepatic cholestasis caused by citrin deficiency. JIMD Rep. 2012;2:37–44. [PMC free article: PMC3509838] [PubMed: 23430852]
Hirayama S, Nagasaka H, Honda A, Komatsu H, Kodama T, Inui A, Morioka I, Kaji S, Ueno T, Ihara K, Yagi M, Kizaki Z, Bessho K, Kondou H, Yorifuji T, Tsukahara H, Iijima K, Miida T. Cholesterol metabolism is enhanced in the liver and brain of children with citrin deficiency. J Clin Endocrinol Metab. 2018;103:2488-97. [PubMed: 29659898]
Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
Ikeda S, Kawa S, Takei Y, Yamamoto K, Shimojo H, Tabata K, Kobayashi K, Saheki T. Chronic pancreatitis associated with adult-onset type II citrullinemia: clinical and pathologic findings. Ann Intern Med. 2004;141:W109-10. [PubMed: 15466765]
Imamura Y, Kobayashi K, Shibatou T, Aburada S, Tahara K, Kubozono O, Saheki T. Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease. Hepatol Res. 2003;26:68–72. [PubMed: 12787807]
Inui A, Ko JS, Chongsrisawat V, Sibal A, Hardikar W, Chang MH, Treepongkaruna S, Arai K, Kim KM, Chen HL. Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2024;78:178-87. [PubMed: 38374571]
Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
Kakiuchi T, Nakayama A, Akiyama T, Martsuo M. Chronic pancreatitis and pancreatic pseudocyst with adult-onset type II citrullinemia. Clin J Gastroenterol. 2020;13:97-101. [PubMed: 31256334]
Kido J, Häberle J, Sugawara K, Tanaka T, Nagao M, Sawada T, Wada Y, Numakura C, Murayama K, Watanabe Y, Kojima-Ishii K, Sasai H, Kosugiyama K, Nakamura K. Clinical manifestation and long-term outcome of citrin deficiency: report from a nationwide study in Japan. J Inherit Metab Dis. 2022;45:431-44. [PubMed: 35142380]
Kido J, Häberle J, Tanaka T, Nagao M, Wada Y, Numakura C, Bo R, Nyuzuki H, Dateki S, Maruyama S, Murayama K, Yoshida S, Nakamura K. Improved sensitivity and specificity for citrin deficiency using selected amino acids and acylcarnitines in the newborn screening. J Inherit Metab Dis. 2024a;47:1134-43. [PubMed: 37681292]
Kido J, Makris G, Santra S, Häberle J. Clinical landscape of citrin deficiency: a global perspective on a multifaceted condition. J Inherit Metab Dis. 2024b;47:1144-56. [PMC free article: PMC11586594] [PubMed: 38503330]
Kobayashi K, Iijima M, Ushikai M, Ikeda S, Saheki T. Citrin deficiency. J Jpn Pediatr Soc. 2006;110:1047–59.
Kobayashi K, Iijima M, Yasuda T, Sinasac DS, Yamaguchi N, Tsui L-C, Scherer SW, Saheki T. Type II citrullinemia (citrin deficiency): a mysterious disease caused by a defect of calcium-binding mitochondrial carrier protein. In: Pochet R, ed. Calcium: The Molecular Basis of Calcium Action in Biology and Medicine. Dordrecht, Netherlands: Kluwer; 2000:565-87.
Kobayashi K, Saheki T. Molecular basis of citrin deficiency. Seikagaku. 2004;76:1543–59. [PubMed: 15675368]
Komatsu M, Yazaki M, Tanaka N, Sano K, Hashimoto E, Takei Y, Song YZ, Tanaka E, Kiyosawa K, Saheki T, Aoyama T, Kobayashi K. Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J Hepatol. 2008;49:810–20. [PubMed: 18620775]
Lin WX, Yaqub MR, Zhang ZH, Mao M, Zeng HS, Chen FP, Li WM, Cai WZ, Li YQ, Tan ZY, Sheng W, Li ZM, Tao XL, Li YX, Zhang JP, Han YB, Li Y, Duan WQ, Ye BN, Li YR,Song YZ. Molecular epidemiologic study of citrin deficiency by screening for four reported pathogenic SLC25A13 variants in the Shaanxi and Guangdong provinces,China. Transl Pediatr, 2021;10:1658-67. [PMC free article: PMC8261583] [PubMed: 34295780]
Lin WX, Zeng HS, Zhang ZH, Mao M, Zheng QQ, Zhao ST, Cheng Y, Chen FP, Wen WR, Song YZ. Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution. Sci Rep. 2016;6:29732. [PMC free article: PMC4942605] [PubMed: 27405544]
Lu YB, Kobayashi K, Ushikai M, Tabata A, Iijima M, Li MX, Lei L, Kawabe K, Taura S, Yang Y, Liu TT, Chiang SH, Hsiao KJ, Lau YL, Tsui LC, Lee DH, Saheki T. Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency. J Hum Genet. 2005;50:338–46. [PubMed: 16059747]
Mutoh K, Kurokawa K, Kobayashi K, Saheki T. Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate. J Inherit Metab Dis. 2008;31 Suppl 2:S343–7. [PubMed: 18958581]
Nagasaka H, Komatsu H, Inui A, Nakacho M, Morioka I, Tsukahara H, Kaji S, Hirayama S, Miida T, Kondou H, Ihara K, Yagi M, Kizaki Z, Bessho K, Kodama T, Iijima K, Saheki T, Yorifuji T, Honda A. Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment. Mol Genet Metab. 2017;120:207–12. [PubMed: 28041819]
Nagasaka H, Okano Y, Tsukahara H, Shigematsu Y, Momoi T, Yorifuji J, Miida T, Ohura T, Kobayashi K, Saheki T, Hirano K, Takayanagi M, Yorifuji T. Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period. Mol Genet Metab. 2009;97:21–26. [PubMed: 19232506]
Numakura C, Tamiya G, Ueki M, Okada T, Maisawa SI, Kojima-Ishii K, Murakami J, Horikawa R, Tokuhara D, Ito K, Adachi M, Abiko T, Mitsui T, Hayasaka K. Growth impairment in individuals with citrin deficiency. J Inherit Metab Dis. 2019;42:501-8. [PubMed: 30715743]
Ohura T, Kobayashi K, Abukawa D, Tazawa Y, Aikawa J, Sakamoto O, Saheki T, Iinuma K. A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency. Eur J Pediatr. 2003;162:317–22. [PubMed: 12692712]
Ohura T, Kobayashi K, Tazawa Y, Abkawa D, Sakamoto O, Tsuchiya S, Saheki T. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency. J Inherit Metab Dis. 2007;30:139–44. [PubMed: 17323144]
Okano Y, Kobayashi K, Ihara K, Ito T, Yoshino M, Watanabe Y, Kaji S, Ohura T, Nagao M, Noguchi A, Mushiake S, Hohashi N, Hashimoto-Tamaoki T. Fatigue and quality of life in citrin deficiency during adaptation and compensation stage. Mol Genet Metab. 2013;109:9–13. [PubMed: 23453692]
Okano Y, Ohura T, Sakamoto O, Inui A. Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: strategy to prevent CTLN2. Mol Genet Metab. 2019;127:175-83. [PubMed: 31255436]
Qiu JW. Molecular diagnostic and clinical phenotypic analysis of citrin deficiency [Doctoral candidate thesis]. Jinan University. 2019
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
Saheki T, Iijima M, Li MX, Kobayashi K, Horiuchi M, Ushikai M, Okumura F, Meng XJ, Inoue I, Tajima A, Moriyama M, Eto K, Kadowaki T, Sinasac DS, Tsui L-C, Tsuji M, Okano A, Kobayashi T. Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mice recapitulate features of human citrin deficiency. J Biol Chem. 2007;282:25041–52. [PubMed: 17591776]
Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet. 2002;47:333–41. [PubMed: 12111366]
Saheki T, Kobayashi K. Physiological role of citrin, a liver-type mitochondrial aspartate-glutamate carrier, and pathophysiology of citrin deficiency. Recent Res Devel Life Sci. 2005;3:59–73.
Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, Li MX, Lu YB, Ushikai M, Tabata A, Moriyama M, Hsiao KJ, Yang Y. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab. 2004;81 Suppl 1:S20–6. [PubMed: 15050970]
Saheki T, Kobayashi K, Iijima M, Li MX, Horiuchi M, Tabata A, Lu YB, Ushikai M, Terashi M, Moriyama M. Pathophysiology of citrin deficiency. In: Haussinger D, Kircheis G, Schliess F, eds. Hepatic Encephalopathy and Nitrogen Metabolism. Dordrecht, Netherlands: Springer; 2006:320-8.
Saheki T, Kobayashi K, Terashi M, Ohura T, Yanagawa Y, Okano Y, Hattori T, Fujimoto H, Mutoh K, Kizaki Z, Inui A. Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis. 2008;31:386–94. [PubMed: 18415701]
Saheki T, Moriyama M, Funahashi A, Kuroda E. AGC2 (citrin) deficiency-from recognition of the disease till construction of therapeutic procedures. Biomolecules. 2020;10:1100. [PMC free article: PMC7465890] [PubMed: 32722104]
Shigetomi H, Tanaka T, Nagao M, Tsutsumi H. Early detection and diagnosis of neonatal intrahepatic cholestasis caused by citrin deficiency missed by newborn screening using tandem mass spectrometry. Int J Neonatal Screen. 2018;4:5. [PMC free article: PMC7548893] [PubMed: 33072931]
Soeda J, Yazaki M, Nakata T, Miwa S, Ikeda S, Hosoda W, Iijima M, Kobayashi K, Saheki T, Kojiro M, Miyagawa S. Primary liver carcinoma exhibiting dual hepatocellular-biliary epithelial differentiations associated with citrin deficiency: a case report. J Clin Gastroenterol. 2008;42:855–60. [PubMed: 18385606]
Song YZ, Deng M, Guo L, Lin WX. Full-cycle, multidisciplinary and systematic management of citrin deficiency]. Zhonghua Gan Zang Bing Za Zhi. 2024;32: 777-82. Chinese. [PMC free article: PMC12948681] [PubMed: 39375098]
Song YZ, Wen F, Chen FP, Kobayashi K, Saheki T. Neonatal intrahepatic cholestasis caused by citrin deficiency: efficacy of therapeutic formulas and update of clinical outcomes. Jpn J Inherit Metab Dis. 2010;26:57–69.
Song YZ, Zhang ZH, Lin WX, Zhao XJ, Deng M, Ma YL, Guo L, Chen FP, Long XL, He XL, Sunada Y, Soneda S, Nakatomi A, Dateki S, Ngu LH, Kobayashi K, Saheki T. SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in Asian patients, and the mutation distribution in a large pediatric cohort in China. PLoS One. 2013;8:e74544. [PMC free article: PMC3777997] [PubMed: 24069319]
Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
Tabata A, Sheng J-S, Ushikai M, Song Y-Z, Gao H-Z, Lu Y-B, Okumura F, Iijima M, Mutoh K, Kishida S, Saheki T, Kobayashi K. Identification of 13 novel mutations including a retrotransposal insertion in SLC25A13 gene and frequency of 30 mutations found in patients with citrin deficiency. J Hum Genet. 2008;53:534–45. [PubMed: 18392553]
Takagi H, Hagiwara S, Hashizume H, Kanda D, Sato K, Sohara N, Kakizaki S, Takahashi H, Mori M, Kaneko H, Ohwada S, Ushikai M, Kobayashi K, Saheki T. Adult onset type II citrullinemia as a cause of non-alcoholic steatohepatitis. J Hepatol. 2006;44:236–9. [PubMed: 16278034]
Takahashi H, Kagawa T, Kobayashi K, Hirabayashi H, Yui M, Begum L, Mine T, Takagi S, Saheki T, Shinohara Y. A case of adult-onset type II citrullinemia - deterioration of clinical course after infusion of hyperosmotic and high sugar solutions. Med Sci Monit. 2006;12:CS13–5. [PubMed: 16449956]
Takeuchi S, Yazaki M, Yamada S, Fukuyama T, Inui A, Iwasaki Y, Ikeda S. An adolescent case of citrin deficiency with severe anorexia mimicking anorexia nervosa. Pediatrics. 2015;136:e530-4. [PubMed: 26195537]
Tamakawa S, Nakamura H, Katano T, Yoshizawa M, Ohtake K, Kubota T. Hyperalimentation therapy produces a comatose state in a patient with citrullinemia. J Jpn Soc Intensive Care Med. 1994;1:37–41.
Tamamori A, Fujimoto A, Okano Y, Kobayashi K, Saheki T, Tagami Y, Takei H, Shigematsu Y, Hata I, Ozaki H, Tokuhara D, Nishimura Y, Yorifuji T, Igarashi N, Ohura T, Shimizu T, Inui K, Sakai N, Abukawa D, Miyakawa T, Matsumori M, Ban K, Kaneko H, Yamano T. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res. 2004;56:608–14. [PubMed: 15295082]
Tamamori A, Okano Y, Ozaki H, Fujimoto A, Kajiwara M, Fukuda K, Kobayashi K, Saheki T, Tagami Y, Yamano T. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr. 2002;161:609–13. [PubMed: 12424587]
Tanaka T, Nagao M, Tsutsumi H. Application of mutation analysis for the previously uncertain cases of adult-onset type II citrullinemia (CTLN2) and their clinical profiles. Tohoku J Exp Med. 2002;198:89–97. [PubMed: 12512993]
Tsai CW, Yang CC, Chen HL, Hwu WL, Wu MZ, Liu KL, Wu MS. Homozygous SLC25A13 mutation in a Taiwanese patient with adult-onset citrullinemia complicated with steatosis and hepatocellular carcinoma. J Formos Med Assoc. 2006;105:852–6. [PubMed: 17000460]
Tsai MM, Chang JC, Lu HY, Gau SS, Chien YH, Hwu WL, Ni YH, Chen HL, Lee NC. Long-term follow-up of neurocognitive function in patients with citrin deficiency and cholestasis. Clin Exp Pediatr. 2025;68:257-65. [PMC free article: PMC11884951] [PubMed: 39608367]
Tsuboi Y, Fujino Y, Kobayashi K, Saheki T, Yamada T. High serum pancreatic secretory trypsin inhibitor before onset of type II citrullinemia. Neurology. 2001;57:933. [PubMed: 11552040]
Yasuda T, Yamaguchi N, Kobayashi K, Nishi I, Horinouchi H, Jalil MA, Li MX, Ushikai M, Iijima M, Kondo I, Saheki T. Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Hum Genet. 2000;107:537–45. [PubMed: 11153906]
Yazaki M, Takei Y, Kobayashi K, Saheki T, Ikeda S. Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II citrullinemia (CTLN2). Intern Med. 2005;44:188–95. [PubMed: 15805705]
Zeng HS, Zhao ST, Deng M, Zhang ZH, Cai XR, Chen FP, Song YZ. Inspissated bile syndrome in an infant with citrin deficiency and congenital anomalies of the biliary tract and esophagus: Identification and pathogenicity analysis of a novel SLC25A13 mutation with incomplete penetrance. Int J Mol Med. 2014;34:1241–8. [PMC free article: PMC4199400] [PubMed: 25216257]
Zhang ZH, Lin WX, Deng M, Zhao ST, Zeng HS, Chen FP, Song YZ. Clinical, molecular and functional investigation on an infant with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). PLoS One. 2014;9:e89267. [PMC free article: PMC3931723] [PubMed: 24586645]

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Song YZ, Oishi K, Saheki T. Citrin Deficiency. 2005 Sep 16 [Updated 2025 Mar 20]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.
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GeneReviews® [Internet].

Citrin Deficiency

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

GeneReview Scope

Diagnosis

Figure 1.

Suggestive Findings

Scenario 1: NICCD (includes abnormal NBS result and symptomatic newborn)

Scenario 2: FTTDCD and CTLN2 (symptomatic individual)

Establishing the Diagnosis

Scenario 1: Abnormal NBS Result for NICCD (includes symptomatic infant)

Scenario 2: Symptomatic Individual

Table 1.

Clinical Characteristics

Clinical Description

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)

Table 2.

Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)

Citrullinemia Type II (CTLN2)

Table 3.

Genotype-Phenotype Correlations

Penetrance

Prevalence

Genetically Related (Allelic) Disorders

Differential Diagnosis

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)

Table 4.

Failure to Gain Weight and Dyslipidemia Caused by Citrin Deficiency (FTTDCD)

Citrullinemia Type II (CTLN2)

Management

Evaluations Following Initial Diagnosis

Table 5.

Treatment of Manifestations

Table 6.

Surveillance

Table 7.

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Carrier Detection

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

Table 8.

Chapter Notes

Author Notes

Acknowledgments

Author History

Revision History

References

Literature Cited

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