From Cow
The efficiency of adenoviral transduction in a citrullinemic Holstein calf treated with hepatocyte gene therapy. Staining for β-galactosidase expression in the liver

Bovine citrullinemia is a rare Holstein and Holstein-Friesian-specific metabolic genetic disorder of cattle worldwide[1].

Similar to leukocyte adhesion deficiency and uridine monophosphate synthase deficiency, this genetic disease is autosomal recessive and breed specific[2].

The genetic disorder results in a deficiency in argininosuccinate synthetase, leading to enzymatic disruption of the urea cycle. The mutation involves a single-base substitution (C-T) in exon 5 of argininosuccinate synthetase (ASS), which converts the CGA codon that codes for arginine-86 to TGA, a translational termination codon. This results in a truncated peptide product (85 amino acids instead of 412) deprived of functional activity.

Clinically, citrullinemia causes ammonemia (increased circulatory ammonia) and associated neurological signs. Affected calves present with ataxia, aimless wandering, blindness, head pressing, convulsions and death[3].

Diagnosis is based on PCR analysis (polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)) of suspect cases and for screening of potential sires[4].

A differential diagnosis would include other causes of neurological signs such as listeriosis, epizootic encephalomyelitis, sporadic bovine encephalomyelitis, Aino virus, rabies and toxoplasmosis.

Treatment is usually unsuccessful and most affected animals are euthanized. Recent gene therapy, using viral vectors to express human argininosuccinate synthetase resulted in calves showing clinical improvement and normalization of plasma glutamine levels after treatment[5].

As artificial insemination is widely used in dairy cattle breeding, carriers of citrullinemia are likely present within the population of breeding sires. It is recommended to screen breeding sires for these defective genes in order to avoid an unwanted spread within the population[6].


  1. Windsor P & Agerholm J (2009) Inherited diseases of Australian Holstein-Friesian cattle. Aust Vet J 87(5):193-199
  2. Sun DX et al (2011) Short communication: Distribution of recessive genetic defect carriers in Chinese Holstein. J Dairy Sci 94(11):5695-5698
  3. Dennis, JA et al (1989) Molecular definition of bovine argininosuccinate synthetase deficiency. Proceedings of the National Academy of Sciences. 86:7947-7951
  4. Patel RK et al (2006) Lack of carriers of citrullinaemia and DUMPS in Indian Holstein cattle. J Appl Genet 47(3):239-242
  5. Lee B et al (1999) Hepatocyte gene therapy in a large animal: a neonatal bovine model of citrullinemia. Proc Natl Acad Sci U S A 96(7):3981-3986
  6. Meydan H et al (2010) Screening for bovine leukocyte adhesion deficiency, deficiency of uridine monophosphate synthase, complex vertebral malformation, bovine citrullinaemia, and factor XI deficiency in Holstein cows reared in Turkey. Acta Vet Scand 52:56