Citrullinemia

Other Names

Citrullinemia I or type 1 (classic form)

Citrullinemia type II

Citrin deficiency

Citrullinuria

Argininosuccinate synthetase deficiency (AS or ASS)

Argininosuccinic acid synthetase deficiency (ASAS)

Diagnosis Coding

Disorder Category

An amino acidemia

Screening

Overview

Citrullinemia results from deficiency of argininosuccinate synthase (ASS), disrupting the 3rd step of the urea cycle. Mutations in the ASS1 gene provide instructions to make ASS which is needed for the third step in the urea cycle. Timing of clinical manifestations ranges from acute, early onset to asymptomatic to onset during pregnancy, depending on the residual enzyme activity left by the specific mutations. Milder forms of the disease are triggered by catabolic state or excess dietary proteins and can present with acute hyperammonemia, psychotic changes or acute liver failure . There is a second form of citrullinemia, called Type 2 or Citrin deficiency. Type 2 ,is caused by a mutation in SLC25A13 and is more common in people of Japanese descent. This is caused by a defect in a mitochondrial transporter unrelated to ASS and can result in nenonatal cholestasis or in adult-onset disease. It is extremely important to distinguish the two forms since treatment is completely different. [Salek: 2010]

Incidence

Approximately 1 in 250,000 live births [Schulze: 2003]

Inheritance

Autosomal recessive

Prenatal Testing

For both types of citrullinemia, DNA testing is possible by amniocentesis if both disease causing mutations of an affected family member have been identified.

Other Testing

For both types of citrullinemia, genetic testing is possible for at-risk family members if both disease causing mutations of an affected family member have been identified.

Clinical Characteristics

With treatment preventing serious hyperammonemic episodes, normal IQ and development are possible. Without treatment, classical citrullinemia type I generally presents in the first week of life. Less acute forms may present later in life (childhood, pregnancy) with severe symptoms during prolonged fasting, periods of increased energy demands (fever, stress, lack of sleep), and after meals high in protein. There are even milder forms with only mildly increased citrulline that might remain asymptomatic for life (periodic monitoring without therapy is recommended in these forms). Citrullinemia type 2 (citrin deficiency) can cause intrahepatic cholestasis in the neonatal period that usually improves over time [Saheki: 2010]. Adults with this condition can have acute liver failure and hyperammonemia.

Initial symptoms may include:

• poor appetite
• vomiting
• lethargy
• increased intracranial pressure
• apnea
• seizures
• coma, possibly leading to death and
• lab findings:
  • hyperammonemia
  • elevated citrulline and glutamine
  • absent argininosuccinic acid

Symptoms of the milder form in children may include:

• poor growth
• poor appetite
• vomiting
• headaches
• learning disabilities
• behavior problems
• hyperactivity
• balance and coordination problems, and
• spasticity

Symptoms of citrullinemia in aduts may include:

• Psychotic changes
• Acute liver failure

Therapy consists in protein restriction, the administration of arginine supplements and nitrogen scavengers (phenylbutyrate, phenylacetate, benzoate) in citrullinemia type 1. By contrast, a diet low in carbohydrates is indicated in citrullinemia type 2.

Follow-up Testing after Positive Screen

Quantitative plasma ammonia and amino acid analysis, urine for orotic acid, genetic testing for the ASS (ASS1) or citrin (SLC25A13) gene as indicated.

Primary Care Management

Specialty Care Collaboration

Initial consultation with the following service(s): Pediatric Genetics (see UT providers [7]); and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.

Resources

Page Bibliography

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.

Salek J, Byrne J, Box T, Longo N, Sussman N.
Recurrent liver failure in a 25-year-old female.
Liver Transpl. 2010;16(9):1049-53. PubMed abstract
Urea cycle defects such as Citrullinemia type I are not generally considered causes of ALF in adults and are described rarely in children beyond the neonatal period. Prompt diagnosis and treatment can enable the patient to recover fully.

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract