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Citrullinemia Type I Genetic Testing
Short Description : Citrullinemia genetic testing

Test performed by: LabPLUS - Dept. Diagnostic Genetics - Molecular Genetics

Referral Requirements

Important Note:

All tests: Metabolic or Genetic Services only.


Genetic Health Service NZ can be contacted on 0800 476 123.

Specimen Collection
EDTA8 mL Adult EDTA Blood
EDTA4 mL Paediatric EDTA Blood


A minimum of 0.5ml can be processed. However, sufficient DNA for downstream testing cannot be guaranteed if less than 4.0ml blood is collected.

Transport all bloods at room temperature within 24-48 hours. If necessary specimens can be refrigerated overnight for transport at room temperature the following day.

For testing of other sample types please contact the laboratory prior to sending.

Turnaround Time: Within 13 weeks
Contact Information

Contact Molecular Genetics via:

Lablink                                                     ext 22000

Mark Greenslade (Technical Head)   ext 22010

Pippa Grainger (Section leader)              ext 22014

Email: DGen@adhb.govt.nz

Background Information

Citrullinemia type 1 is a rare urea-cycle disorder caused by a deficiency of argininosuccinate synthetase. This cytosolic enzyme catalyses the conversion of citrulline and aspartate to argininosuccinate, primarily in periportal hepatocytes, but also in other body tissues involved in the synthesis of arginine. The disorder is inherited in an autosomal recessive manner, and is due to a heterogeneous group of mutations in the ASS1 gene on chromosome 9.

In classical citrullinemia type 1, failure of the urea cycle leads to the accumulation of citrulline, glutamine and ammonia in the serum and increased excretion of orotic acid in the urine. Individuals with classical citrullinemia type 1 often present early in the neonatal period with metabolic coma due to hyperammonaemia, which if untreated proves fatal, but with treatment leads, instead, to developmental delay of varying degrees of severity. Late onset forms of citrullinemia can also occur, with metabolic decompensation triggered by increased catabolic stress, as in illness or the post-partum period.  Mild or asymptomatic forms of the disease, in which there is elevated serum citrulline, but no hyperammonaemia, have also been described. Treatment, when required, consists of dietary protein restriction, substitution of arginine and other essential amino acids, and the use of medication to allow the alternative detoxification of surplus nitrogen.

The clinical course and prognosis of citrullinemia are difficult to predict by biochemical means alone. The level of citrulline in the serum cannot be used to determine the severity of the disease, although a cut-off of 1000?mol/L has been proposed, as classical citrullinemia is almost always associated with levels higher than this. Since the discovery of the pivotal role of the ASS1 gene and the elucidation of its structure, it has been possible to perform molecular genetic analysis of affected individuals to determine the specific mutations underlying the disease. There are now a total of 87 mutations in the ASS1 gene that are known to cause type 1 citrullinemia, and this number continues to rise as sequence analysis is carried out on an increasing number of patients.  Mutations have been found in all exons, except exons 1 and 2, that encode the 5? untranslated region of the gene transcript, and exon 16. As yet there is no definite genotype-phenotype correlation, but increasing use of molecular analysis is leading to the establishment of firmer links between specific mutations and particular clinical courses ? e.g. mild or severe, requiring treatment or not requiring treatment.  This correlation is complicated, however, by compound heterozygosity. Of the twenty mutations detected in mild disease to date, only four have been seen in a homozygous state.

The c.787G>A (p.Val263Met) mutation in exon 12 of the ASS1 gene, which is associated with a mild or asymptomatic clinical course, appears to be common in people originating from the Pacific Islands and is therefore relatively prevalent in the Auckland population. Tetra-primer ARMS PCR may be effectively employed in order to screen for this mutation, using DNA extracted either from blood or directly from the newborn Guthrie card ? allowing for rapid confirmation of the benign mutation.

Molecular genetic testing of ASS1 is available.

For more information about the Molecular Genetics service:

Molecular Genetics information page

Last updated at 15:49:04 22/03/2021