Degenerative Myelopathy (DM)
Gene: SOD1
Transmission: Autosomal, recessive (variable penetration)
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.
Mutations:
Exon 2 mutation: Substitution, SOD1 gene; c.118 G>A, p.(E40K), exon2
Exon 1 mutation (Bernese Mountain dog type): Substitution, SOD1 gene; c.52 A>T, p.(T18S), exon1
Medical systems: Neurologic, muscular
Breed: Airedale Terrier, Alaskan Malamute, American Bulldog, American Cocker Spaniel, American Eskimo Dog, American Foxhound, American Hairless Terrier, American Pit Bull Terrier, American Staffordshire Terrier/Amstaff, American Water Spaniel, Anatolian Shepherd Dog, Australian Cattle Dog, Australian Kelpie, Australian Shepherd, Australian Stumpy Tailed Cattle Dog, Australian Terrier, Beagle, Belgian Groenendael, Belgian Laekenois, Belgian Malinois, Belgian Tervueren, Berger Picard, Bernese Mountain Dog, Bichon Frise, Biewer Terrier, Bloodhound, Bluetick Coonhound, Border Collie, Border Terrier, Borzoi, Boston Terrier, Boxer, Boykin Spaniel, Bullmastiff, Canaan Dog, Cardigan Welsh Corgi, Carlin Pinscher, Catahoula Leopard Dog, Cavalier King Charles Spaniel, Chesapeake Bay Retriever, Chinese Crested, Chow Chow, Clumber Spaniel, Collie, Collie - Rough, Collie - Smooth, Coton de Tulear, Czechoslovakian Wolfdog, Dalmatian, Decker Terrier, Doberman Pinscher, Dogo Argentino, Dutch Shepherd, English Bulldog, English Cocker Spaniel, English Coonhound, English Shepherd, English Springer Spaniel, English Toy Spaniel, Eurasier, Finnish Lapphund, Finnish Spitz, Flat-Coated Retriever, Fox Terrier, Fox Terrier - Miniature, Fox Terrier - Smooth, Fox Terrier - Toy, Fox Terrier - Wire, French Bulldog, German Pinscher, German Shepherd, German Shorthaired Pointer, German Wirehaired Pointer, Golden Retriever, Goldendoodle, Gordon Setter, Great Pyrenees, Greyhound, Harrier, Hovawart, Irish Red and White Setter, Irish Setter, Irish Terrier, Irish Wolfhound, Jack Russell Terrier, Keeshond, Kerry Blue Terrier, King Shepherd, Komondor, Kooikerhondje, Koolie, Kuvasz, Labrador Retriever, Lacy Dog, Lancashire Heeler, Landseer, Lapponian Herder, Lucas Terrier, Maremmano Sheepdog, Mastiff (Old English), Miniature American Shepherd, Miniature Australian Shepherd, Mountain Cur, Newfoundland, Norfolk Terrier, Norwich Terrier, Nova Scotia Duck Tolling, Old English Sheepdog, Olde English Bulldogge, Parson Russell Terrier, Patterdale Terrier, Pembroke Welsh Corgi, Peruvian Hairless, Pharaoh Hound, Plott Hound, Pointer (English), Pomeranian, Poodle - Miniature (Dwarf), Poodle - Moyen, Poodle - Standard, Poodle - Toy, Portuguese Podengo, Presa Canario, Pug, Puli, Pumi, Rat Terrier, Rhodesian Ridgeback, Rottweiler, Russell Terrier, Saarloos Wolfhound, Saint-Bernard, Saluki, Samoyed, Scandinavian Hound, Schnauzer - Giant, Schnauzer - Miniature, Schnauzer - Standard, Sealyham Terrier, Shetland Sheepdog, Shih Tzu, Shiloh Shepherd, Siberian Husky, Siberian Laika, Silken Windhound, Silky Terrier, Soft-coated Wheaten Terrier, Stabyhoun, Staffordshire Bull Terrier, Swedish Lapphund, Tamaskan, Teddy Roosevelt Terrier, Tenterfield Terrier, Tibetan Spaniel, Tibetan Terrier, Toy Australian Shepherd, Treeing Walker Coonhound, Wachtelhund / German Spaniel, Welsh Terrier, Whippet, White Swiss Shepherd, Wirehaired Pointing Griffon, Yorkshire Terrier
Age of onset of symptoms: 9 years of age on average.
Degenerative Myelopathy (DM) is a neuro-muscular degenerative disease caused by a gene mutation that has been identified in many dog breeds. Environmental factors as well as other genetic factors may contribute to the time of onset and progression of the disease. Degenerative Myelopathy is a disease that affects the white matter of the spinal cord and is equivalent to Amyotrophic Lateral Sclerosis (ALS) also known as Lou Gehrig’s disease in humans. Affected dogs usually start showing symptoms of progressive muscular atrophy with initial loss of coordination of the hind limbs, and can lose mobility six months to two years after the onset of clinical signs. Pain is not associated with the progression of symptoms. There is no treatment for the disease which can progress to the point that the animal is incontinent and eventually paraplegic. Often the affected animal is euthanized for humanitarian reasons before these final stages.
DM is an autosomal recessive disease that displays variable penetration. The major genetic risk factor for dogs is a mutation within exon2 of the SOD1 gene (c.118, G>A). In the Bernese Mountain Dog, an additional mutation, in exon1 of the SOD1 gene, is reported, albeit at a lower frequency than the exon2 mutation. Bernese Mountain Dogs that are showing neurological signs consistent with degenerative myelopathy should be tested first for the exon2 mutation. If they are clear or carrier for the exon2 mutation, they should then be tested for the exon1 mutation. It is possible that a Bernese Mountain Dog can be a double carrier (double heterozygote, one copy of the exon2 mutation and one copy of the exon1 mutation) and at risk of developing DM.
References:
OMIA link: [0263-9615]
Bouché TV, Coates JR, Moore SA, et al. (2023) Diagnosis and management of dogs with degenerative myelopathy: A survey of neurologists and rehabilitation professionals. J Vet Intern Med. [pubmed/37606360]
Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs. PLoS Genet. 19(2):e1010651. [pubmed/36848397]
Draper ACE, Wilson Z, Maile C, et al. (2020) Species-specific Consequences of an E40K Missense Mutation in Superoxide Dismutase 1 (SOD1). FASEB J. 34(1):458-473. [pubmed/31914665]
Turba ME, Loechel R, Rombola E, et al. (2017) Evidence of a genomic insertion in intron 2 of SOD1 causing allelic drop-out during routine diagnostic testing for canine degenerative myelopathy. Animal Genetics 48(3):365-368. [pubmed/27917507]
Holder AL, Price JA, Adams JP, Volk HA, Catchpole B. (2014) A retrospective study of the prevalence of the canine degenerative myelopathy associated superoxide dismutase 1 mutation (SOD1:c.118G > A) in a referral population of German Shepherd dogs from the UK. Canine Genet Epidemiol. 1:10. [pubmed/26401327]
Zeng R, Coates JR, Johnson GC, et al. (2014) Breed distribution of SOD1 alleles previously associated with canine degenerative myelopathy. J Vet Intern Med 28(2):515-521. [pubmed/24524809]
Crisp MJ, Beckett J, Coates JR, Miller TM. (2013) Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model. Exp Neurol. 248:1-9. [pubmed/23707216]
Wininger FA, Zeng R, Johnson GS, et al. (2011) Degenerative myelopathy in a Bernese Mountain Dog with a novel SOD1 missense mutation. J Vet Intern Med 25:1166-1170. [pubmed/21848967]
Coates JR, Wininger FA. (2010) Canine degenerative myelopathy. Vet Clin North Am Small Anim Pract. 40(5):929-50. [pubmed/20732599]
Awano T, Johnson GS, Wade CM, Katz ML, et al. (2009) Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. PNAS 106(8), 2794-2799. [pubmed/19188595]