Citrullinemia Type II & Citrin Deficiency

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), also known as neonatal onset type II citrullinemia
Citrullinemia type II (CTLN2), also known as adult-onset type II citrullinemia
Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD)
This condition is not to be confused with Citrullinemia Type 1 (primary defect of arginosuccinate synthetase, not citrin deficiency).

ICD-10 Coding

E72.23, Citrullinemia

Disorder Category

Amino acidemia

Screening

Abnormal Finding

Elevated citrulline

Tested By

Tandem mass spectrometry (MS/MS)

Description

Citrin deficiency arises from a deficiency of citrin protein, whose role in mitochondrial transport is critical to the citric acid/Krebs and urea cycles. This condition is not to be confused with Citrullinemia Type 1 (primary defect of arginosuccinate synthetase).
There are 3 subtypes of citrin deficiency largely defined by the timing of their symptom onset:
  1. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), also known as neonatal-onset type II citrullinemia, typically presenting before 1 year of age
  2. Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) with symptom onset from 1 year of age to adolescence
  3. Citrullinemia type II (CTLN2), also known as adult-onset type II citrullinemia, presenting in adulthood
In all 3 subtypes, patients will have a naturally developed preference for protein and lipid-rich foods and relative avoidance of carbohydrates, regardless of treatment. Clinical manifestations are highly variable and range from neonatal cholestasis and liver dysfunction in NICCD to failure to thrive and dyslipidemia in FTTDCD, and hyperammonemia with neuropsychiatric symptoms in CTLN2. It is unclear why some patients develop a more severe form of the condition.
The therapeutic approaches vary based on the form of citrin deficiency but typically consist of some nutritional guidance with a diet high in protein and lipids and low in carbohydrates. Supplementation with various vitamins and minerals may be necessary, and in some cases of CTLN2, liver transplantation may be indicated.

Clinical Characteristics

With treatment, NICCD intrahepatic cholestasis usually resolves by 1 year of age, but symptoms can be minimized with:
  • Fat-soluble vitamin supplementation (ADEK)
  • Medium-chain triglyceride enriched formulas
If galactosemia is also present, zinc and Vitamin D supplementation and lactose-free formulas are often necessary to improve growth parameters. [Song: 2010]
Even with these interventions, patients with NICCD are still at risk for developing FTTDCD and CTLN2, although the exact risk and whether treatment helps prevent them is unclear.
For patients with FTTDCD and CTLN2, sodium pyruvate has been linked to accelerated growth, and arginine effectively decreased the recurrence of hyperammonemia. [Saheki: 2010]
Though liver transplantation historically was necessary for many patients with CTLN2, metabolic stability can be achieved with a combined therapeutic approach, including arginine supplementation, sodium pyruvate, MCT oil, and reduced carbohydrate intake. [Hayasaka: 2014] In severe cases of all subtypes, though, liver transplantation has been shown to be the most effective treatment option.
Without treatment, NICCD can cause intrahepatic cholestasis, hemolytic anemia, liver dysfunction (decreased coagulation factors, increased total and direct bilirubin), hepatomegaly, hepatic fibrosis, hypoglycemia, a carbohydrate aversion, and growth restriction/failure to thrive in the neonatal period. This usually resolves by 1 year of age regardless of treatment. [Saheki: 2010] However, in some cases, it gradually may evolve into the FTTDCD and CTLN2 form with age.
FTTDCD classically presents between 1 year of age and adolescence with failure to thrive, dyslipidemia, recurrent pancreatitis, and avoidance of carbohydrate-rich foods. [Nagasaka: 2017]
The adult form, citrullinemia II (CTLN2), most commonly has an onset between ages 20-50 years with a thin body habitus and potentially life-threatening recurrent hyperammonemia resembling hepatic encephalopathy. [Yasuda: 2000] Triggers of hyperammonemia include high carbohydrate intake, alcohol use, acetaminophen, and surgery.

Incidence

It is most commonly seen in Asian populations, particularly Japan, with a prevalence of 1:17,000, although it is now recognized as pan-ethnic. The penetrance of the CTLN2 form is uniquely greater in males compared to females.

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see RI providers [2]).
  • Biochemical testing following an abnormal newborn screen may include plasma ammonia, plasma amino acids, lactate, and liver function tests. Additional testing and potentially hospitalization may be necessary for symptomatic patients in consultation with a metabolic geneticist.
  • Confirmation can be made with genetic testing for variants in the SLC25A13 gene.
  • In addition to genetic testing, findings suggestive of citrin deficiency may include hyperammonemia, citrullinemia, increased plasma tyrosine, argininemia, galactosemia, increased plasma threonine-to-serine ratio, and increased pancreatic secretory trypsin inhibitor (PSTI) levels.

If the Diagnosis is Confirmed

Resources

Information & Support

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Citrin Deficiency (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis.

Disease InfoSearch for Citrullinemia Type II (Genetic Alliance)
Compilation of information, articles, research, case studies, and genetics links.

Communicating Newborn Screening Results to Families (ACHDNC) (PDF Document 289 KB)
One-page guide to help clinicians effectively communicate positive newborn screening results to parents; Advisory Committee on Heritable Disorders in Newborns and Children.

For Parents and Patients

Citrullinemia (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Tools

RI ACT Sheet for Elevated Citrulline (ACMG) (PDF Document 108 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Confirmatory Algorithm for Elevated Citrulline (ACMG) (PDF Document 175 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Services for Patients & Families in Rhode Island (RI)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: April 2022
Current Authors and Reviewers:
Author: Michael Angerbauer
Senior Author: Brian J. Shayota, MD, MPH
Reviewer: Nancy C. Rose, MD

Page Bibliography

Hayasaka K, Numakura C, Toyota K, Kakizaki S, Watanabe H, Haga H, Takahashi H, Takahashi Y, Kaneko M, Yamakawa M, Nunoi H, Kato T, Ueno Y, Mori M.
Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia.
Mol Genet Metab Rep. 2014;1:42-50. PubMed abstract / Full Text

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(3):207-212. PubMed abstract

Saheki T, Inoue K, Tushima A, Mutoh K, Kobayashi K.
Citrin deficiency and current treatment concepts.
Mol Genet Metab. 2010;100 Suppl 1:S59-64. PubMed abstract
The historical aspects of citrin and citrin deficiency and current treatment concepts for citrin deficiency are described. Developing novel therapeutics based on the pathophysiology, such as sodium pyruvate, are discussed.

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.

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(6):537-45. PubMed abstract