01213-A: Determination of Outcome Measures for Clinical Progression and Morphometric Studies of Spinal Cord Disease in Degenerative Myelopathy Dogs
Grant Status: Closed
Project SummaryDegenerative myelopathy (DM) is a disease of the spinal cord causing progressive weakness in the hind limbs in adult dogs. Though most commonly reported in German Shepherds, high disease prevalence also exists in other dog breeds, such as Cardigan and Pembroke Welsh Corgis (PWC), Rhodesian Ridgebacks, and Boxer dogs. Genome-wide association mapping and a candidate gene approach identified a mutation in the canine SOD1 gene. Homozygosity for the mutant allele was associated with DM in five dog breeds which segregate for DM (Boxers, Pembroke Welsh Corgis, Rhodesian Ridgebacks, Chesapeake Bay Retrievers and German Shepherd dogs). Canine DM caused by SOD1 mutations resembles some forms of human ALS - Lou Gehrig's disease. Better characterization of outcome assessment measures and understanding of the spinal cord pathology will assist in establishing collaborations with ALS researchers and in development of therapeutic drug trials similar to those of human ALS. The researchers hypothesize for this proposal that the spinal cord dysfunction and nerve root deterioration of canine DM will compare to that of human ALS. They are testing their hypothesis by performing clinical studies of gait and studies of spinal cord and nerve root tissues in DM affected dogs. The investigators were successful in obtaining matching funding from the ALS Association for completion of the proposed work. For the gait studies, they have digitized previously recorded gaits from DM affected dogs that have been serially evaluated over time. They continue to follow 2 DM-affected dogs and thus, will need to rely on archived cases recorded from 31 DM-affected dogs. The PI has one of her residents assigned to the project who will organize the blinded gait scoring using a validated gait scale. Thus far in total, they have 152 spinal cords submitted to the University of Missouri Veterinary Medical Diagnostic Laboratory specifically with a presumptive diagnosis of DM of which 109 have been DM confirmed (26 Boxer DM confirmed) and homozygous for the SOD1:c.118A allele; one dog (Chesapeake Bay Retriever) has been confirmed for DM and was A/G heterozygous. They have 44 spinal cords from various breeds (6 Boxers) submitted as control samples. They have decided to focus on three breeds to include the Pembroke Welsh Corgi, Bernese Mountain dog and Boxer because these are the breeds from which they have received the greatest number of samples. However, they continue to collect and preserve specimens from all breeds. It has been opted to focus on the lower thoracic spinal cord for counting of neurons, neurons and evaluation of the aggregates. The investigators have established measurement techniques to quantitate SOD-1 aggregates which accumulate in the neuron, the cell body of the neuron and nerve roots. They have refined the techniques using an image analysis software program to evaluate the nerve roots and motor neurons and are analyzing these samples. Final results from this study will provide them with a much better understanding of the pathology that underlies DM and will provide quantitative markers to measure the efficacy of therapeutic studies.
Publication(s)Coates JR, Johnson GS, Katz ML, Kanazono S, Johnson GC. Phenotypic characterization of degenerative myelopathy in breeds of dogs. Journal of Veterinary Internal Medicine (in preparation) Shelton GD, GC Johnson, GS Johnson, DP O'Brien, ML Katz, JR Coates. Neuromuscular pathology in canine degenerative myelopathy with mutation in superoxide dismutase 1 Gene. Acta Neuropathologica (in preparation) Vasquez L, Kanazono S, O'Brien DP, Dhand S, Coates JR. Development of a motor unit number estimate technique as an outcome measure for assessment of therapeutic strategies in degenerative myelopathy dogs: a spontaneous animal model of amyotrophic lateral sclerosis. Journal of Veterinary Internal Medicine (in preparation) Platt SR, TBD, Kanazono S, Coates JR. Evaluation of potential biomarkers in cerebrospinal fluid of degenerative myelopathy affected dogs. (in preparation) Zeng R, Coates JR, Johnson GC, Katz ML, Taylor JF, Awano T, Khan S, Villamil A, Hahn AW, Lindblad-Toh K, Johnson GS. The degenerative myelopathy-associated A allele at SOD1:c.188 occurs in many dog breeds. Journal of the American Veterinary Medical Association. Submitted July 2010 [prospective / retrospective study] Coates JR, Wininger FA. Canine degenerative myelopathy. Veterinary Clinics of North America: Small Animal Practice, Elsevier St. Louis, MO, 2010;40(5):929-950. Awano T, Johnson GS, Wade C, Katz ML, Johnson GC, Taylor JF, Perloski M, Long S, March PA, Olby NJ, Khan S, O'Brien DP, Lindblad-Toh K, Coates JR. Genome-wide association analysis reveals a SOD1 missense mutation canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2009;106 (8):2794-2799. March PA, Coates JR, Abyad R, Williams DA, O'Brien DP, Olby NJ, Keating JH, Oglesbee M. Degenerative myelopathy in 18 Pembroke Welsh Corgi dogs. Veterinary Pathology, 2009;46:241-250. Coates JR, March PA, Ogelsbee M, Ruaux CG, Olby NL, Berghaus R, O'Brien DP, Johnson GS, Williams DA. Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. Journal of Veterinary Internal Medicine, 2007;21:1323-1331.
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