Citrullinemia

 

Gene: ASS1

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, ASS1 gene; c.256C>T, exon 5, p.Arg 86 STOP, bovine chromosome 11.

Medical system: Urinary, metabolic, neurologic

Breed: Holstein Friesian

Age of onset of symptoms: symptoms can become evident soon after birth.

Citrullinemia is a genetic disease seen in Holstein Friesian calves involving ammonia intoxication.  This is due to an enzyme defect in the urea cycle that normally converts ammonia to urea. Specifically, a mutation in the ASS1 gene causes a defect in the enzyme argininosuccinate synthetase (ASS) resulting in an accumulation of citrulline and consequently ammonia in the blood.

Ammonia levels are elevated from birth but increase considerably during the first days of the calf’s life, causing severe neurological dysfunction. Symptoms observed in affected calves include depression, tongue protrusion, foaming of the muzzle and neurological signs such as wall pushing or unsteady gait and loss of vision.  Death usually occurs within 3 to 5 days. Since homozygous animals do not survive to breeding age, transmission of the mutation is exclusively through heterozygous carrier cattle that have no clinical signs.

Citrullinemia was one of the first genetic diseases in cows to be characterized at the DNA level.  It was first described in Australia and originated from the export of the son of a Canadian bull identified as the original carrier of the mutation. Citrullinemia is a genetic disease in Holstein cows of historical interest that now has very low prevalence due to DNA testing for the mutation and careful selection of animals for breeding.

 

References:

OMIA link: [0194-9913]

Caivio-Nasner S, López-Herrera A, González-Herrera LG, Rincón JC. (2021) Frequency of genotypic markers for genetic disorders, colour, polledness, and major genes in Blanco Orejinegro cattle. Trop Anim Health Prod 53:546. [pubmed/34779908]

Meydan H, Yildiz MA, Agerholm JS. (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. [pubmed/20929557]

Robinson JL, Burns JL, Magura CE, Shanks RD. (1993) Low incidence of citrullinemia carriers among dairy cattle of the United States. J Dairy Sci. 76(3):853-8. [pubmed/8463494]

Healy PJ, Dennis JA, Camilleri LM, et al. (1991) Bovine Citrullinaemia Traced to the Sire of Linmack Kriss King Australian Veterinary Journal 68:155. [pubmed/2069549]

Healy PJ, Harper PAW, Dennis JA . (1990) Bovine Citrullinaemia – A Clinical, Pathological, Biochemical and Genetic Study Australian Veterinary Journal 67:255-258. [pubmed/2393373]

Dennis JA, Healy PJ, Beaudet AL, Obrien WE. (1989) Molecular Definition of Bovine Argininosuccinate Synthetase Deficiency.  PNAS USA 86:7947-7951 [pubmed/2813370]

Harper PAW, Healy PJ, Dennis JA, et al. (1986) Citrullinaemia as a cause of neurological disease in neonatal Friesian calves Australian Veterinary Journal 63:373-379. [pubmed/3827779]
Contributed by : Dr. Anaïs Fournier-Leclaire, Class of 2023, Faculté de médecine vétérinaire, Université de Montréal.   (Translation DWS).