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Phenotype: Affected dogs display signs of neurotoxicity following administration of certain drugs, such as ivermectin, acepromazine, loperamide, digoxin, and others. Signs may include tremors, impaired coordination (i.e., ataxia), excess salivation, seizures, slow hear rate (i.e., bradycardia), dilated pupils and respiratory arrest.
Mode of Inheritance: Autosomal recessive
Breeds appropriate for testing: Mixed breed dogs and purebred dogs, particularly of the following breeds: Australian Shepherd, Border Collie, Collie, English Shepherd, German Shepherd, Longhaired Whippet, McNab Shepherd, Miniature Australian Shepherd, Old English Sheepdog, Rough Collie, Shetland Sheepdog, Silken Windhound, Smooth Collie, Wäller, and White Swiss Shepherd.
Explanation of results:
- Dogs with N/N genotype are expected to not have multidrug sensitivity. They cannot transmit this MDR1 variant to any of their offspring.
- Dogs with N/MDR1 genotype will transmit this MDR1 variant to 50% of their offspring. Matings between two carriers of MDR1 may, on average, produce 25% of puppies with multidrug sensitivity.
- Dogs with MDR1/MDR1 genotypes are homozygous for this MDR1 variant and will exhibit multidrug sensitivity even at low doses.
Multidrug Sensitivity is a heritable condition that affects several purebred and mixed breed dogs. Affected dogs are highly susceptible to neurotoxicity following the administration of certain commonly used drugs, such as ivermectin, moxidectin, selamectin, erythromycin, ketoconazole, levofloxacin, acepromazine, morphine, loperamide, digoxin, cortisol, cimetidine, and others. Administration of these drugs to dogs with two copies of the MDR1 multidrug sensitivity variant should be avoided as they may be potentially lethal even when used at very low doses.
The ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene, also known as the multidrug resistance (MDR1) gene, encodes for a drug transporter protein called P-glycoprotein (P-gp). This protein plays an important role in the blood-brain barrier, acting as a drug-transport pump that prevents certain drugs from accumulating in the brain. A 4-base pair deletion in the ABCB1 gene results in a defective P-gp transporter protein that is no longer able to remove these drugs from the central nervous system, resulting in abnormally high levels of the substances in the brain. Dogs affected by multidrug sensitivity are, therefore, highly sensitive to certain drugs making them susceptible to neurotoxicity even when the drugs are administered at very low doses. Signs of neurotoxicity may include tremors, impaired coordination (i.e., ataxia), excess salivation, seizures, slow hear rate (i.e., bradycardia), dilated pupils and respiratory arrest.
The MDR1 variant was originally identified in association with ivermectin sensitivity in Collies but has since been identified in several other breeds as well as mixed breed dogs. Dogs that have two copies of the MDR1 variant (i.e., homozygous for the MDR1 variant) are affected and will exhibit multidrug sensitivity.
Testing recommendations: The MDR1 variant has been identified in several breeds and mixed breed dogs. Genetic testing for MDR1 is recommended to identify dogs at risk for multidrug sensitivity. Affected dogs will only exhibit signs of neurotoxicity if exposed to certain drugs. Test results should be shared with the dog’s veterinarian prior to pharmacological treatments. Administration of certain drugs to dogs with this MDR1 variant should be avoided since they may be potentially lethal even when administered at very low doses. Breeding of two MDR1 carriers may result in 25% MDR1-affected puppies.
Species
Breed
Type of Test
|
Test Result |
Multidrug Sensitivity |
|
N/N |
Normal. Dog does not have this variant associated with multidrug sensitivity. |
|
N/MDR1 |
Carrier. Dog has one copy of this variant associated with multidrug sensitivity. |
|
MDR1/MDR1 |
Affected. Dog has two copies of this variant associated with multidrug sensitivity. Dog will likely display multidrug sensitivity. |
Mealey, K. L., Bentjen, S. A., Gay, J. M., & Cantor, G. H. (2001). Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics, 11(8), 727–733. https://doi.org/10.1097/00008571-200111000-00012
Barbet, J.L., Snook, T., Gay, J.M. and Mealey, K.L. (2009), ABCB1-1Δ (MDR1-1Δ) genotype is associated with adverse reactions in dogs treated with milbemycin oxime for generalized demodicosis. Veterinary Dermatology, 20: 111-114. https://doi.org/10.1111/j.1365-3164.2008.00725.x
Gramer, I., Leidolf, R., Döring, B., Klintzsch, S., Krämer, E. M., Yalcin, E., Petzinger, E., & Geyer, J. (2011). Breed distribution of the nt230(del4) MDR1 mutation in dogs. Veterinary journal, 189(1), 67–71. https://doi.org/10.1016/j.tvjl.2010.06.012
Geyer, J., & Janko, C. (2012). Treatment of MDR1 mutant dogs with macrocyclic lactones. Current pharmaceutical biotechnology, 13(6), 969–986. https://doi.org/10.2174/138920112800399301
Mackin, A. J., Riggs, C., Beatty, T., Mealey, K., Boothe, D., & Archer, T. (2020). Excessive Cyclosporine-Associated Immunosuppression in a Dog Heterozygous for the MDR1 (ABCB1-1Δ) Mutation. Journal of the American Animal Hospital Association, 56(3), 190. https://doi.org/10.5326/JAAHA-MS-7004
