Hypersensitivity to Medications (MDR1)

 

Gene: ABCB1 (MDR1)

Transmission: Autosomal dominant, with variable penetration.

Mutation: Deletion, ABCB1 gene; c.1930_1931, del.TC, exon 15, cat chromosome A2.

Medical systems: neurological, pharmacological

Breed: Balinese, Domestic Cat, Maine Coon, Ragdoll, Russian Blue, Siamese, Turkish Angora

Age of onset of symptoms: induced by exposure to pharmacological agents.

Sensitivity to medication, also called MDR1 toxicity, is an inherited condition wherein medications at doses that would normally be well tolerated to an animal become toxic and potentially fatal.  The condition, seen in both cats and dogs, is caused by mutations within the ABCB1 gene, which codes for a cell membrane protein (P-glycoprotein) involved in transport of biomolecules out of cells.  Although P-glycoprotein is widely expressed in the body, it has a particularly important role to play within the cells contributing the blood-brain-barrier, whereby the brain is protected from potentially neurotoxic metabolites being transported in the blood.  Mutations within the ABCB1 gene results in a failure of this protective function and a susceptibility of the brain to neurotoxicity, particularly when the animal is exposed to pharmacological products including (but not limited to) macrocyclic lactones such as ivermectin, a antiparasitic drug commonly used in veterinary medicine.  Neurotoxic effects seen in susceptible animals include vision loss, vomiting, behavioral changes, trembling, drowsiness, difficulty breathing (dyspnea), convulsions and even death.  Note that signs of toxicity are much more severe for the animal that is double mutant but have been recorded (in the dog) for animals that carry a single mutation.  For this reason, the heredity of hypersensitivity to medications is classified as dominant with variable penetration, and although the double mutant animal is most at risk, care should still be taken when giving medication to carrier animals.  A potentially susceptible animal, in the absence of drug exposure, will have no symptoms and will enjoy a normal life with a normal lifespan.   A DNA test for the mutation is available.

 

References:

List of problematic drugs: [https://vcpl.vetmed.wsu.edu/problem-drugs]

OMIA link: [1402-9685]

Mealey KL, Burke NS, Villarino NF, Court MH, Heusser JP. (2024) Application of eprinomectin-containing parasiticides at label doses causes neurological toxicosis in cats homozygous for ABCB11930_1931del TC. J Vet Pharmacol Ther.  [pm/38366723]

Mealey KL, Owens JG, Freeman E. (2023) Canine and feline P-glycoprotein deficiency: What we know and where we need to go. J Vet Pharmacol Ther 46:1-16. [pubmed/36326478]

Anderson H, Davison S, Lytle KM, et al. (2022) Genetic epidemiology of blood type, disease and trait variants, and genome-wide genetic diversity in over 11,000 domestic cats.  PLoS Genet. 16;18(6):e1009804.  [pubmed/35709088]

Mealey KL, Burke NS, Connors RL. (2021) Role of an ABCB11930_1931del TC gene mutation in a temporal cluster of macrocyclic lactone-induced neurologic toxicosis in cats associated with products labeled for companion animal use. JAVMA 259(1), 72-76. [pubmed/34125616]

Mealey KL, Burke NS. (2015) Identification of a nonsense mutation in feline ABCB1. Journal of Veterinary Pharmacology and Therapeutics, 38(5), 429-433. [pubmed/25660379]

 

Contributed by: Kim Gagnon-Clusiault et Jennifer Lebel, class of 2027, Faculté de médecine vétérinaire, Université de Montréal.