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Citrin Deficiency

, PhD, , MD, PhD, and , MD, PhD.

Author Information
, PhD
Department of Molecular Metabolism and Biochemical Genetics
Kagoshima University Graduate School of Medical and Dental Sciences
Kagoshima, Japan
, MD, PhD
Institute of Resource Development and Analysis
Kumamoto University
Kumamoto, Japan
, MD, PhD
Department of Pediatrics
The First Affiliated Hospital
Jinan University
Guangzhou, China

Initial Posting: ; Last Update: July 31, 2014.

Summary

Disease characteristics. Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often citrin deficiency is characterized by fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods.

  • NICCD. Children younger than age one year have growth retardation with 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. Although NICCD is generally not severe and symptoms often resolve by age one year with appropriate treatment, some infants succumb to infection and liver cirrhosis and others require liver transplantation.
  • FTTDCD. Around age one to two years, many children with citrin deficiency develop the food preferences mentioned. Some have growth retardation, hypoglycemia, and fatigue as well as hyperlipidemia, pancreatitis, fatty liver, and hepatoma. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2.
  • CTLN2. Onset is sudden and usually between ages 11 and 79 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; death can result from brain edema. 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 suspected from clinical and 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 [PSTI]). Identification of biallelic pathogenic variants in SLC25A13 confirms the diagnosis.

Management. Treatment of manifestations: NICCD: Supplement diet with fat-soluble vitamins and use of lactose-free formula (in those with positive newborn screen for galactosemia) or formulas containing medium-chain triglycerides. 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 decreases blood ammonia concentration and lessens hypertriglyceridemia by a still unidentified mechanism. Arginine and sodium pyruvate may effectively treat hyperammonemia and fatty liver, thereby delaying 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the SLC25A13 pathogenic variants in the family are known.

GeneReview Scope

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

For synonyms and outdated names see Nomenclature.

Diagnosis

Citrin deficiency has two distinct well-recognized phenotypes – neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and citrullinemia type II (CTLN2) (see Figure 1) [Saheki & Kobayashi 2002, Yamaguchi et al 2002, Kobayashi & Saheki 2004, Saheki & Kobayashi 2005, Kobayashi et al 2006] –and a third intermediate phenotype, failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) [Song et al 2011, Song et al 2013].

Figure 1

Figure

Figure 1. Citrin deficiency

NICCD = neonatal intrahepatic cholestasis caused by citrin deficiency
CTLN2 = adult-onset type II citrullinemia
FTTDCD=failure to thrive and dyslipidemia caused by citrin deficiency
AFP= (more...)

  • Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is characterized by transient neonatal cholestasis and variable hepatic dysfunction. Some affected individuals have a poor prognosis due to liver cirrhosis.
  • Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) is characterized by post-NICCD growth retardation before CTLN2 onset and abnormalities of serum lipid concentrations, including triglycerides, total cholesterol, and HDL-cholesterol. Clinical diagnosis of citrin deficiency during this stage is difficult in the absence of a history of unique food preferences or without molecular testing.
  • Citrullinemia type II (CTLN2) is characterized by childhood- to adult-onset, recurring episodes of hyperammonemia and associated neuropsychiatric symptoms.

Suggestive Findings

Citrin deficiency is suspected in a proband with the following findings (see Figure 2 and Figure 3):

Figure 2

Figure

Figure 2. Diagnostic algorithm of citrin deficiency

Note that food preferences (e.g., aversion to sugars) are important in the diagnosis of citrin deficiency, not only in typical CTLN2 but also in cases of growth retardation, hypoglycemia, (more...)

Figure 3

Figure

Figure 3. Flow chart for diagnosis of citrin deficiency

TB = total bilirubin
DB = direct bilirubin
TBA = total bile acids
ALP = alkaline phosphatase
AFP = α-fetoprotein
PSTI = pancreatic (more...)

  • Infants who have had a positive newborn screening test for:
    • Citrullinemia and/or prolonged jaundice; or
    • Galactosemia, hypermethionemia or hyperphenylalanemia, who on follow-up diagnostic testing were found not to have one of these disorders.
      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].
  • Children beyond age one year who present with failure to thrive and dyslipidemia
  • Older children and adults with hepatic encephalopathy with hyperammonemia, especially those with aversion to carbohydrate and fondness for protein- and lipid-rich foods
  • Children and adults with unexplained recurrent pancreatitis, hyperlipidemia, fatty liver, or hepatoma

Preliminary Testing

The diagnosis of citrin deficiency is further supported by the following testing:

1.

Perform quantitative plasma amino acid analysis (children age 1-4 months) (see Table 1 and Table 2). Note that the amino acid changes in Table 1 and Table 2 are usually age dependent, and are not evident in some individuals with NICCD.

Table 1. Biochemical Findings in Citrin Deficiency by Phenotype

Phenotype (Age)Blood or Plasma Concentration of Ammonia
(µmol/L)
Plasma or Serum Concentration of Citrulline
(C) 1
Plasma or Serum Concentration of Arginine (A)
(µmol/L)
Plasma or Serum Threonine-to-Serine RatioSerum Concentration of Pancreatic Secretory Trypsin Inhibitor
(PSTI) 2(ng/mL)
Control18-47 317-43 354-130 31.10 4.6-20 3
NICCD
(0-6 months)
60 300 2052.29 30
FTTDCD
(>1 to 11 years)
Normal or slightly elevatedNormal or slightly elevatedUsually normalUnknownUnknown
CTLN2
(11-79 years)
152418 1982.32 71

Kobayashi et al [2006]

1. Citrullinemia, which can be detected on newborn screening, is the earliest identifiable biochemical abnormality of NICCD [Tamamori et al 2004].

2. Because the serum PSTI concentration is high in some individuals with NICCD [Tamamori et al 2002] and also in individuals before the onset of CTLN2 [Tsuboi et al 2001], the measurement of serum PSTI concentration may be useful in presymptomatic diagnosis of CTLN2.

3. Range

Table 2. Plasma Concentrations of Threonine, Methionine, and Tyrosine at Age 0-6 Months in NICCD

Amino AcidMedian
(25%-75% Range) (µmol/L)
Control Range
(µmol/L)
Threonine496 (291-741) 67-190
Methionine124 (53-337)19-40
Tyrosine178 (99-275)40-90
2.

Measure blood ammonia, plasma amino acids, PSTI, liver enzymes (when CTLN2 is suspected) (see Table 1).

3.

Perform dietary assessment, including food preferences (particularly important if FFTDCD or CTLN2 is suspected as individuals with those disorders have a fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods).

Confirming the Diagnosis

The diagnosis of citrin deficiency can be confirmed using molecular genetic testing (Table 3) or western blot analysis.

1.

Perform sequence analysis of SLC25A13, followed by deletion/duplication analysis if neither or only one pathogenic variant is identified. Identification of biallelic pathogenic variants inSLC25A13 confirms the diagnosis of citrin deficiency.

Table 3. Summary of Molecular Genetic Testing Used in Citrin Deficiency

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SLC25A13Sequence analysis 2>95% 3
Deletion/duplication analysis 4Unknown 5

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Kobayashi et al [1999], Yasuda et al [2000], Ben-Shalom et al [2002], Yamaguchi et al [2002], Saheki et al [2004], Lu et al [2005], Takaya et al [2005], Ko et al [2007a], Song et al [2008], Tabata et al [2008], Song et al [2009b], Xing et al [2010], Fu et al [2011], Song et al [2011], Wen et al [2011]

4. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Takaya et al [2005], Wong et al [2008]

2.

Consider western blot analysis for the protein citrin if neither or only one SLC25A13 pathogenic variant is identified by molecular genetic testing. Western blot analysis using anti-human citrin antibody specific for the amino-terminal half detects little or no cross-reactive immune material in liver, cultured fibroblasts, or lymphocytes from individuals with biallelic SLC25A13 pathogenic variants [Yasuda et al 2000, Takahashi et al 2006, Dimmock et al 2007, Tokuhara et al 2007, Fu et al 2011].

Clinical Description

Natural History

Citrin deficiency can manifest in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often FTTDCD and CTLN2 are characterized by fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Individuals with CTLN2 may or may not have a prior history of NICCD or FTTDCD. The proportion of persons with NICCD or FTTDCD that evolves into CTLN2 is unknown.

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)

Children under age one year with NICCD have transient intrahepatic cholestasis (see Table 4). Other findings include diffuse fatty liver with hepatomegaly and parenchymal cellular infiltration associated with hepatic fibrosis, low birth weight, growth retardation, hypoproteinemia, decreased coagulation factors, hemolytic anemia, variable (mainly mild) liver dysfunction, and/or hypoglycemia.

Table 4. Measurements of Hepatic Cell Function at Age 0-6 Months in NICCD

Assayed ItemMedian
(25%-75% range) (mg/dL)
Control Range
(mg/dL)
TB in NICCD4.9 (2.8-8.0)0.2-1.0
TB in CTLN20.8 (0.52-1.1)
DB in NICCD2.5 (1.5-3.7) 0-0.4
DB in CTLN20.3 (0.2-0.4)
TB/DB ratio in NICCD0.55 (0.41-0.66)
TBA239 (172-293)5-25
AFP91,900 (33,200-174,700)260-6,400 1, 2
2-55 2, 3

Kobayashi et al [2006]

TB= total bilirubin

DB= direct bilirubin

TBA= total bile acids

AFP= α-fetoprotein

1. 0-1 month

2. Tamamori et al [2002]

3. >1 month

NICCD is generally not severe, although liver transplantation has been required in rare instances [Tamamori et al 2002, Kobayashi et al 2006]. Symptoms typically resolve by age one year with treatment, including fat-soluble vitamin supplementation and use of lactose-free therapeutic formulas (for those with galactosemia) and/or medium-chain triglyceride (MCT)-enriched therapeutic formulas [Ohura et al 2003, Song et al 2010, Hayasaka et al 2012, Zhang et al 2014].

Starting around age one to two years, children show a strong preference for protein-rich and lipid-rich foods and an aversion to sugar-rich and carbohydrate-rich foods [Hachisu et al 2005, Saheki & Kobayashi 2005, Saheki et al 2008].

In the second or later decades, some individuals with citrin deficiency develop severe CTLN2 with neuropsychiatric symptoms [Saheki & Kobayashi 2002]. Typically the transition from the adaptation (and/or compensation) stage following NICCD to the onset of CTLN2 is gradual.

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

FTTDCD has recently been proposed as a novel post-NICCD phenotype before the onset of CTLN2 [Song et al 2011]. The clinical and laboratory features of FTTDCD are still being elucidated. During this period (traditionally assumed to be an “apparently healthy” stage before CTLN2 onset) some children were found to have laboratory and/or clinical abnormalities.

The laboratory abnormalities include dyslipidemia which manifests as abnormal levels of triglyceride and cholesterol (including total-, HDL- and LDL-cholesterol) [Song et al 2009a, Song et al 2011] and other findings such as increased lactate to pyruvate ratio, elevated cholesterol, and higher levels of urinary oxidative stress markers [Kobayashi & Saheki 2004, Saheki & Kobayashi 2005, Kobayashi et al 2006, Nagasaka et al 2009, Lee et al 2010].

The clinical abnormalities include growth retardation, hypoglycemia, and pancreatitis. Very recently, severe fatigue and impaired quality of life were identified in citrin-deficient children in the adaptation and compensation (traditionally assumed to be ‘silent’) stage [Okano et al 2013].

Citrullinemia Type II (CTLN2)

CTLN2 is characterized by recurring episodes of hyperammonemia and neurologic and psychotic symptoms that closely resemble those of hepatic encephalopathy or genetic urea cycle disorders, including nocturnal delirium, aberrant behaviors (aggression, irritability, and hyperactivity), delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Brain CT is normal, and EEG shows diffuse slow waves.

Onset is sudden and usually between ages 20 and 50 years (range: 11-79 years; mean age: 34.4 ±12.8 years; n=103) [Yasuda et al 2000].

Many individuals with CTLN2 have a strong preference for protein-rich and/or lipid-rich foods (e.g., beans, peanuts, eggs, milk, cheese, fish, and meat) and an aversion to carbohydrate-rich foods including rice, juice, and sweets. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery.

Most individuals are thin. More than 90% have a body mass index lower than 20 and approximately 40% have a body mass index lower than 17 (range: 15.6-19.1; n=110) [Kobayashi et al 2006] (range in healthy Japanese individuals: 20-24 in males; 19-23 in females).

The following complications occur in more than 10% of individuals with CTLN2 [Kobayashi et al 2000]. Studies regarding these complications are ongoing.

Intrahepatic cholestasis is rare; however, some individuals are noted in retrospect to have had signs of NICCD in early childhood [Kobayashi & Saheki 2004, Saheki & Kobayashi 2005]. For example, a 16-year-old with CTLN2 undergoing liver transplantation [Kasahara et al 2001] had had transient hypoproteinemia and jaundice in early infancy [Tomomasa et al 2001].

Abnormal laboratory findings

  • Pancreatic secretory trypsin inhibitor (PSTI) concentration is increased in the liver [Kobayashi et al 1997] (see Table 1). Note: PSTI mRNA is increased 30- to 140-fold in the liver of individuals with CTLN2
  • Fischer ratio (branched-chain amino acids [BCAAs] Val+Leu+Ile / aromatic amino acids [AAAs] Tyr+Phe) in the plasma or serum is decreased from ~3.4 to ~2 as a result of decreased BCAA.
  • Liver-specific argininosuccinate synthetase (ASS) enzyme activity is decreased to approximately 10% that of controls (secondary effect of mutation of SLC25A13) [Yasuda et al 2000].
  • Plasma α-fetoprotein concentration is normal in almost all individuals with CTLN2 [Kobayashi et al 1997], except some individuals with CTLN2 associated with hepatoma [Hagiwara et al 2003].

Pathologic findings include fatty infiltration and mild fibrosis of the liver despite little or no liver dysfunction.

Genotype-Phenotype Correlations

No significant correlation between SLC25A13 mutation types and decreased level of hepatic enzyme ASS activity/protein or age of onset in individuals with CTLN2 is observed [Yasuda et al 2000].

Penetrance

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

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

The unequal male-to-female ratio in CTLN2 suggests that for unknown reasons, among individuals with biallelic SLC25A13pathogenic 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 to be 1:17,000 based on the carrier or heterozygote rate of 1:65 [Saheki & Kobayashi 2002, Tabata et al 2008]. This is similar to the observed prevalence of NICCD [Shigematsu et al 2002], but different from the observed prevalence of CTLN2 (1:100,000-1:230,000) [Kobayashi et al 2006]. Based on their observations, the authors believe that most 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].

Differential Diagnosis

Plasma concentration of citrulline is increased in citrin deficiency as well as in the following disorders:

  • Citrullinemia type 1 (CTLN1; ASS deficiency). CTLN1 presents as a wide spectrum of overlapping phenotypes: an acute neonatal form (the "classic" form), a milder late-onset form, a form without symptoms and/or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum [Gao et al 2003]. Shortly after birth, infants with the acute neonatal form develop hyperammonemia and its complications, from which they die without prompt intervention. Those who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficit. In the late-onset form, the episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle.

    CTLN1 results from deficiency of the enzyme ASS, the third step in the urea cycle, in which citrulline is condensed with aspartate to form argininosuccinic acid. Untreated individuals with the severe form of CTLN1 have hyperammonemia, increased plasma concentration of citrulline, and decreased plasma concentration of arginine. Inheritance is autosomal recessive.

    In CTLN2, the liver-specific deficiency of the ASS protein is secondary by unknown mechanisms [Yasuda et al 2000] as no abnormalities are present in hepatic ASS mRNA or ASS1.
  • Argininosuccinic aciduria (argininosuccinate lyase [ASL] deficiency) (see Urea Cycle Disorders Overview)
  • Renal insufficiency
  • Classic galactosemia. In one neonate, classic galactosemia presented as citrin deficiency [Feillet et al 2008].

Hyperammonemia occurs in citrin deficiency as well as in the urea cycle disorders, which result from defects in the metabolism of the nitrogen produced by the breakdown of protein and other nitrogen-containing molecules (see Urea Cycle Disorders Overview). Severe deficiency or total absence of activity of any of the first four enzymes (CPSI, OTC, ASS, ASL) in the urea cycle, the ornithine transporter, or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life in most affected individuals.

Neonatal/infantile cholestasis occurs in citrin deficiency as well as the following disorders:

  • Idiopathic neonatal hepatitis (INH) and extrahepatic biliary atresia (EBA). In comparison with INH and EBA, NICCD is associated with lower levels of serum direct bilirubin or ALT and higher levels of serum total bile acids and alkaline phosphatase. NICCD also has higher levels of serum γ-GTP and lower levels of serum AST activity than are seen in INH [Tazawa et al 2005].
  • Progressive familial intrahepatic cholestasis (PFIC, Byler disease). The high-serum γ-GTP levels of NICCD may distinguish it from other intrahepatic cholestasis disorders with low-normal γ-GTP levels including PFIC and benign recurrent intrahepatic cholestasis (BRIC). PFIC is caused by biallelic pathogenic variants in ATP8B1 (FIC1) or ABCB11 (BSEP). Some cases of BRIC are caused by biallelic pathogenic variants in ATP8B1.

Hereditary jaundice and hyperbilirubinemia result from defects in the metabolism of bilirubin. These include disorders resulting in predominantly unconjugated (indirect) hyperbilirubinemia (UDP-glucuronosyltransferase 1-1deficiency) and those resulting in predominantly conjugated (direct) hyperbilirubinemia (deficiency in canalicular ATP-dependent transporters: ABCC2 [MRP2], ABCB11, or ATP8B1).

Other

  • Portal-systemic shunts can be excluded by angiography.
  • More than 30% of individuals with CTLN2 have been misdiagnosed initially as having epileptic seizures and/or a psychological disorder (e.g., depression, schizophrenia); others may be diagnosed as having diseases such as hepatoma, pancreatitis, and hyperlipidemia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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 gender-matched growth standards.
  • Investigate feeding pattern.

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

All phenotypes. Medical genetics consultation is indicated.

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 therapeutic formulas (in those with galactosemia) and/or medium-chain triglyceride (MCT)-enriched therapeutic formulas [Ohura et al 2003, Song et al 2010, Hayasaka et al 2012, Zhang et al 2014].

Two siblings improved after switching from breast milk to formula, which has higher proline content [Ben-Shalom et al 2002].

Some children with NICCD improve without treatment, 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 retardation [Mutoh et al 2008, Saheki et al 2010].

CTLN2. The most successful therapy to date has been liver transplantation [Ikeda et al 2001, Kasahara et al 2001, Yazaki et al 2004, Hirai et al 2008], which prevents episodic hyperammonemic crises, corrects the metabolic disturbances, and eliminates preferences for protein-rich foods [Kobayashi & Saheki 2004]. Nearly all individuals with CTLN2 required liver transplantation in the past; however, the introduction of arginine and sodium pyruvate has altered the situation:

  • Administration of arginine was reported to be effective in decreasing blood ammonia concentration. Reducing calorie/carbohydrate intake and increasing protein intake ameliorates hypertriglyceridemia [Imamura et al 2003].
  • Administration of sodium pyruvate was effective in several cases [Mutoh et al 2008; Saheki et al 2010; Yazaki et al 2010; Ohura et al, personal communication; Okano et al, personal communication].

Prevention of Primary Manifestations

To prevent hyperammonemia and resolve failure to thrive, a diet rich in protein and lipids and low in carbohydrates is recommended [Saheki & Kobayashi 2005, Saheki et al 2006, Dimmock et al 2007, Saheki et al 2008, Dimmock et al 2009].

Avoid high-carbohydrate meals and alcohol.

Arginine administration may be effective in preventing hyperammonemic crises.

Prevention of Secondary Complications

Vitamin D deficiency and zinc deficiency are common complications in NICCD [Song et al, in preparation]. Severe infection and liver cirrhosis have also been reported to be lethal complications in some individuals with NICCD. Therefore, vitamin D and zinc supplements and active infection control are recommended in NICCD.

Surveillance

To monitor for emergence of the FTTDCD phenotype in persons with citrin deficiency older than age one year: close surveillance of anthropometric indices (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, such as glycerol, fructose, and glucose. Severe brain edema treated with glycerol-containing osmotic agents has resulted in continued deterioration and is contraindicated in those with CTLN2 [Yazaki et al 2005]. Degradation of large amounts of glycerol and fructose generates NADH in the liver cytosol, which may disturb liver function and produce toxic substances [Saheki et al 2004, Yazaki et al 2005, Takahashi et al 2006].

Infusion of high-concentration glucose may also exacerbate hyperammonemia [Tamakawa et al 1994, Takahashi et al 2006].

Note: Mannitol infusion appears to be safer [Yazaki et al 2005].

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

Medications. Acetaminophen and rabeprozole may trigger CTLN2 [Shiohama et al 1993, Imamura et al 2003].

Evaluation of Relatives at Risk

It is appropriate to 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 such as sibs would depend heavily on the molecular genetic findings in SLC25A13 in the index case:

  • If both SLC25A13 pathogenic variants in the index case have been identified, molecular genetic testing can be used reliably.
  • If only oneSLC25A13 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 for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Glycerol or similar drugs containing glycerol and fructose for brain edema are not only ineffective but also dangerous for persons with citrin deficiency (see Agents/Circumstances to Avoid).

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Citrin deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (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].
  • 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 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 inheriting two SLC25A13 pathogenic variants and being affected and a 50% chance of inheriting one SLC25A13 pathogenic variant and being an asymptomatic carrier.
  • 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 of a proband. 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 family members is possible once the SLC25A13 pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

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

Family planning

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

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

Prenatal Testing

If the SLC25A13 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

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

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the SLC25A13 pathogenic variants have been identified.

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.

  • National Library of Medicine Genetics Home Reference
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Children's Liver Disease Foundation (CLDF)
    36 Great Charles Street
    Birmingham B3 3JY
    United Kingdom
    Phone: +44 (0) 121 212 3839
    Fax: +44 (0) 121 212 4300
    Email: info@childliverdisease.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

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Citrin Deficiency (View All in OMIM)

603471CITRULLINEMIA, TYPE II, ADULT-ONSET; CTLN2
603859SOLUTE CARRIER FAMILY 25 (CITRIN), MEMBER 13; SLC25A13
605814CITRULLINEMIA, TYPE II, NEONATAL-ONSET

Gene structure. SLC25A13 comprises 18 exons [Kobayashi et al 1999, Sinasac et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. To date, a total of 84 pathogenic allelic variants occurring in exons or introns resulting in missense mutations, predicted truncated forms of citrin, or abnormal mRNA splicing have been reported [Kobayashi et al 1999, Yasuda et al 2000, Ben-Shalom et al 2002, Yamaguchi et al 2002, Lu et al 2005, Takaya et al 2005, Hutchin et al 2006, Ko et al 2007a, Ko et al 2007b, Komatsu et al 2008, Song et al 2008, Tabata et al 2008, Wong et al 2008, Dimmock et al 2009, Hutchin et al 2009, Song et al 2009b, Xing et al 2010, Fu et al 2011, Lin et al 2011, Song et al 2011, Wen et al 2011, Lin et al 2012, Takahashi et al 2012, Chen et al 2013, Wen et al 2013, Song et al 2013, Tong et al 2013, Zhang et al 2014]. Among them, 61 variations were first reported by the present authors and their colleagues.

  • Two pathogenic variants (c.1177+1G>A and c.851-854del) account for the majority (~70%) of pathogenic alleles in Japanese persons with citrin deficiency.
  • In a cohort of 51 persons with citrin deficiency from 50 Chinese families, four pathogenic variants (c.851-854del, c.615+5G>A, c.1750+72_1751-4dup17insNM_138459.3:2667, and c.1638_1660dup23) accounted for 87% of the pathogenic alleles [Song et al 2011].
  • Only one pathogenic variant, p.Arg360Ter, has been found in both Japanese and northern European populations[Tabata et al 2008].

Some of the 20 pathogenic variants identified in Japanese individuals have been found in Chinese, Vietnamese, and Korean individuals with citrin deficiency (NICCD or CTLN2) [Lu et al 2005, Lee et al 2006, Song et al 2006, Tsai et al 2006, Yeh et al 2006, Ko et al 2007a, Ko et al 2007b, Song et al 2008, Tabata et al 2008].

Different pathogenic variants were found in Israel, the United States, the United Kingdom, and China [Ben-Shalom et al 2002, Hutchin et al 2006, Luder et al 2006, Dimmock et al 2007, Song et al 2008, Tabata et al 2008, Song et al 2009b, Xing et al 2010, Fu et al 2011, Song et al 2011].

Table 5. Selected SLC25A13 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference SequencesReference
c.15G>A
(Ex1-1G>A)
--NM_014251​.2
NP_055066​.1
Tabata et al [2008]
c.550C>Tp.Arg184TerSaheki et al [2004]
c.615+5G>A
(IVS6+5G>A)
--
c.615+1G>C
(IVS6+1G>C)
--Lu et al [2005]
c.674C>Ap.Ser225TerKobayashi et al [1999]
c.851_854del
(851del4)
p.Met285ProfsTer2
c.1078C>Tp.Arg360TerTabata et al [2008]
c.1177+1G>A
(IVS11+1G>A)
--Kobayashi et al [1999]
c.1311+1G>A
(IVS13+1G>A)
--
c.1592G>Ap.Gly531AspTabata et al [2008]
c.1638_1660dup23
(1638ins23)
p.Ala554GlyfsTer17Kobayashi et al [1999]
c.1799dupA
(1800_1801insA)
p.Tyr600TerYasuda et al [2000]
c.1801G>Tp.Glu601TerYamaguchi et al [2002]
c.1801G>Ap.Glu601Lys
c.1813C>Tp.Arg605TerYasuda et al [2000]
c.1750+72_1751-4dup17ins NM_138459.3:2667 2
(IVS16ins3kb)
--Tabata et al [2008]
g.20984997_20985512del516
(Ex16+74_IVS17-32del516)
--NT_007933​.14Takaya et al [2005]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. A complex allele with an insertion of 2667 nucleotides of processed cDNA in antisense orientation of NUS1 at 6q22.31 (reference sequence NM_138459​.3); this insertion is flanked by the 17 nucleotide duplication of intron 16 sequences (NM_014251​.2:c.1751-4_-22dup17) [Tabata et al 2008].

Normal gene product. Citrin and its homolog aralar [del Arco & Satrústegui 1998] are members of the SLC25 (solute carrier family 25) protein family. Both proteins are localized in the mitochondrial inner membrane and function as a Ca2+-binding/-stimulated aspartate-glutamate carrier (AGC), a component of the malate-aspartate NADH shuttle [Palmieri et al 2001, Kobayashi & Saheki 2003].

Citrin is expressed in the liver; aralar in the brain and skeletal muscle; both are expressed in the kidney and heart [Kobayashi et al 1999]. Citrin as a liver-type AGC plays arole in various metabolic pathways, including aerobic glycolysis, gluconeogenesis, the urea cycle, and protein and nucleotide syntheses [Saheki & Kobayashi 2002, Saheki et al 2004, Saheki & Kobayashi 2005, Saheki et al 2006].

Abnormal gene product. Most SLC25A13 pathogenic variants cause or predict truncation of the citrin protein or delete a loop between the mitochondrial transmembrane domains. The lack of significant citrin protein was confirmed by western blot analysis using antibody against the N-terminal half of the human citrin protein, which detected little or no cross-reactive immune material in liver, cultured fibroblasts, and lymphocytes from individuals with biallelic SLC25A13 pathogenic variants [Yasuda et al 2000, Takahashi et al 2006, Dimmock et al 2007, Tokuhara et al 2007, Fu et al 2011].

References

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Suggested Reading

  1. Chew HB, Ngu LH, Zabedah MY, Keng WT, Balasubramaniam S, Hanifah MJ, Kobayashi K. Neonatal intrahepatic cholestasis associated with citrin deficiency (NICCD): a case series of 11 Malaysian patients. J Inherit Metab Dis. 2010;33:S489–95. [PubMed: 21161389]
  2. Guo L, Li BX, Deng M, Wen F, Jiang JH, Tan YQ, Song YZ, Liu ZH, Zhang CH, Kobayashi K, Wang ZN (2011) Etiological analysis of neurodevelopmental disabilities: single-center eight-year clinical experience in south China. J Biomed Biotechnol 2011.pii: 318616. [PMC free article: PMC2948914] [PubMed: 20936111]
  3. Kobayashi K, Ushikai M, Song YZ, Gao HZ, Sheng JS, Tabata A, Okumura F, Ikeda S, Saheki T. Overview of citrin deficiency: SLC25A13 mutations and the frequency. J Appl Clin Pediatr. 2008;23:1553–7.
  4. Ngu HL, Zabedah MY, Kobayashi K. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) in three Malay children. Malays J Pathol. 2010;32:53–7. [PubMed: 20614727]
  5. Saheki T, Inoue K, Ono H, Tushima A, Katsura N, Yokogawa M, Yoshidumi Y, Kuhara T, Ohse M, Eto K, Kadowaki T, Sinasac DS, Kobayashi K. Metabolomic analysis reveals hepatic metabolite perturbations in citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mice, a model of human citrin deficiency. Mol Genet Metab. 2011;104:492–500. [PubMed: 21908222]
  6. Sawada S, Kinjo T, Makishi S, Tomita M, Arasaki A, Iseki K, Watanabe H, Kobayashi K, Sunakawa H, Iwamasa T, Mori N. Downregulation of citrin, a mitochondrial AGC, is associated with apoptosis of hepatocytes. Biochem Biophys Res Commun. 2007;364:937–44. [PubMed: 18273444]
  7. Shigeta T, Kasahara M, Kimura T, Fukuda A, Sasaki K, Arai K, Nakagawa A, Nakagawa S, Kobayashi K, Soneda S, Kitagawa H. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr Transplant. 2010;14:E86–8. [PubMed: 19413723]

Chapter Notes

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 geneSLC25A13 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 over 50 mutations in SLC25A13 and diagnosed over 500 citrin-deficient patients worldwide (Japan, Korea, China, Vietnam, Malaysia, Israel, Palestine, Australia, Czech, France, Britain, and the US). She also worked tirelessly to educate the medical community about citrin deficiency, thus improving the care and prognosis of affected patients worldwide. Less than a month before her death, Dr. Kobayashi delivered a lecture on citrin deficiency to the 9th Asia-Pacific Conference on Human Genetics.

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

Acknowledgments

This research was supported in part by Grants-in-Aid for Scientific Research (Nos. 16390100, 19390096 and 19591230) and for Asia-Africa Scientific Platform Program (AASPP) from the Japan Society for the Promotion of Science (JSPS), by a Grant for Child Health and Development (17-2) from the Ministry of Health, Labour and Welfare in Japan, by a Grant for Research for Promoting Technological Seeds from the Japan Science and Technology Agency and by the Projects 81070279 and 81270957 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 (2004-present)

Revision History

  • 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 to live Web site
  • 5 November 2004 (kk) Original submission.
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