Get Help in Rhode IslandCitrullinemia Type 2 & Citrin Deficiency
Guidance for primary care clinicians receiving a positive newborn screen result
Other Names
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:
- Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), also known as neonatal-onset type II citrullinemia, typically presenting before 1 year of age
- Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) with symptom onset from 1 year of age to adolescence
- 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
- Fat-soluble vitamin supplementation (ADEK)
- Medium-chain triglyceride enriched formulas
Primary Care Management
Next Steps After a Positive Screen
- Contact the family and evaluate the infant for poor feeding, vomiting, jaundice, lethargy, and tachypnea.
- Consult a metabolic geneticist in Medical Genetics (see RI providers [4]) to provide emergency treatment/referral for symptoms of vomiting, hypotonia, tachypnea, seizures, or signs of liver disease. See the ACT Sheet for Elevated Citrulline (ACMG) for additional information.
- Contact Newborn Screening Services (see RI providers [2]) to determine what testing is required.
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
- For evaluation and ongoing collaborative management, consult Medical Genetics (see RI providers [4]).
- Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill. See Citrullinemia - Information for Parents (STAR-G).
- Assist in the maintenance of a high-protein and lipid diet and supplementation of necessary vitamins and minerals.
- Regular monitoring of growth parameters. For those identified after irreversible consequences, assist in management, particularly with developmental and educational resources. See Early Intervention for Children with Disabilities/Delays (see RI providers [13]).
- A dietician may work with the family to devise an optimal approach to dietary management. See Dieticians and Nutritionists (see RI providers [3]).
- Genetic Testing and Counseling (see RI providers [8]) to assist the family in understanding the diagnosis and risks for future pregnancies and relatives.
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)
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) (
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)
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)
| Service Categories | # of providers* in: | RI | NW | Other states (3) (show) | | NM | NV | UT |
|---|---|---|---|---|---|---|---|---|
| Dieticians and Nutritionists | 3 | 1 | 1 | 4 | 6 | |||
| Early Intervention for Children with Disabilities/Delays | 13 | 3 | 34 | 30 | 51 | |||
| Genetic Testing and Counseling | 8 | 6 | 6 | 12 | 11 | |||
| Medical Genetics | 4 | 1 | 2 | 5 | 7 | |||
| Newborn Screening Services | 2 | 1 | 3 | 2 | 3 | |||
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.
Page Bibliography
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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