Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 105400 (trait) , 147450 (gene) , 618598 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2009

Species-specific name: Canine degenerative myelopathy, hereditary canine spinal muscular atrophy

Species-specific symbol: DM

Species-specific description: This is an adult onset degeneration of the spinal cord that progresses to paraplegia and tetraparesis. There is no successful treatment. A genetic test is available. A different mutation in the SOD1 gene causes an early onset disease: OMIA:002322-9615 : Dyskinesia, paroxysmal, SOD1-related in Canis lupus familiaris.

Mapping: By conducting a GWAS on 38 affected and 17 control Pembroke Welsh corgis, each genotyped with the Affymetrix Canine Genome 2.0 Array (yielding 49,663 SNPs for analysis), Awano et al. (2009) highlighted a region of chromosome CFA31 that contains the comparative candidate gene, SOD1. By conducting a GWAS on 15 affected and 69 control German Shepherd dogs, each genotyped with the Affymetrix v2 canine SNP chip (Yielding 48,415 SNPs for the analysis), Tsai et al. (2012) highlighted a 1.615Mb region on chromosome CFA31 (the same as that highlighted by Awano et al., 2009), which contains the SOD1 gene, mutations in which had already been shown to be causal (see Molecular basis section).

Molecular basis: The first likely causative variant described is a G to A transition (c.118G>A; p.E40K) in exon 2 of SOD1. All affected dogs tested were homozygous mutant. However, some homozygous mutant dogs had no signs of degenerative myelopathy, which suggests incomplete penetrance or other causative loci (Awano et al., 2009). The mutation is hypothesized to lead to SOD1 aggregation, as cytoplasmic inclusions in affected dogs stain with anti-SOD1 antibodies (Awano et al., 2009). A second causal mutation (c.52A>T; p.Thr18Ser) in the same gene, in a Bernese Mountain Dog, was reported by Wininger et al. (2011). Having genotyped 408 Bernese Mountains dogs for both the above mutations, Pfahler et al. (2014) reported that "The c.118G>A mutation was heterozygous in 188 (46.1%) and homozygous in 27 (6.6%) BMD (Table S2). The c.52A>T mutation was heterozygous in 65 (15.9%) and homozygous in two (0.5%) dogs. Twenty-two of the animals had both SOD1 mutations heterozygous (5.4%). The haplotype analysis for all BMD revealed no haplotype with both mutated alleles on a single chromosome (Figs S1 and S2). Therefore, these 22 dogs are likely to be compound heterozygous for the SOD1 haplotypes AA and TG." One of the 22 compound heterozygotes showed clinical signs of degenerative myelopathy. Summarising all available evidence, Pfahler et al. (2014) concluded that "compound heterozygosity [for the two mutations] may confer a similar risk to DM like the c.118G>A homozygous mutation". Ivansson et al. (2016) reported "that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation" Mandrioli et al. (2021) reported that "three [affected Hovawart] dogs were homozygous for the c.118A allele, but none had the SP110 'risk' haplotype, suggesting a weak association of SP110 with the onset of DM in this breed. Our data suggest that the Hovawart breed is predisposed to the SOD1:c.118G>A mutation, which is associated with the development of DM."

Clinical features: Most dogs are at least 8 years of age at the onset of clinical signs, which include hyporeflexia, upper motor neuron proprioceptive spasticity and ataxia in the pelvic limbs. Widespread limb muscle atrophy can be observed and the disease progresses to paraplegia and eventually flaccid tetraparesis (Awano et al., 2009). Hyperesthesia, cranial nerve signs (e.g. difficulty in swallowing and barking), urinary and fecal incontinence (Coates et al., 2010) can be observed and in final stages of the disease respiratory muscles fail (Nardone et al., 2016). There is no effective treatment. [IT thanks DVM student Jane Lai for contributions to this entry in April 2022].

Pathology: Histopathologic examination of the spinal cord is necessary for definitive diagnosis. Noninflammatory axonal and myelin degeneration is present at all levels of the spinal cord, being most severe in the dorsal lateral funiculus within the middle to caudal thoracic region. Segmental axonal and myelin degeneration, endoneurial fibrosis, hypomyelinated fibers and secondary demyelination are present in peripheral nerves. Axon cylinder vacuolization is characteristic (Coates et al., 2010).

Prevalence: In an extensive project, Zeng et al. (2014) genotyped 33,747 dogs representing 222 breeds for both known mutant alleles, namely c.52T and c.118A. They concluded that "the SOD1:c.118A allele is widespread and common among privately owned dogs whereas the SOD1:c.52T allele is rare and appears to be limited to Bernese Mountain Dogs." Full details are available in the paper. Mizukami et al. (2016) reported the frequency of the c.118A allele as 0.008 in 500 Border collies in Japan. Regarding the insertion reported by Turba et al. (2107), these authors reported that "The allele containing the insertion was highly prevalent in Hovawart dogs, accounting for the 26.6% of allele frequency. The insertion was also found in other unrelated breeds such as Rough Collies and Standard Poodles." Santos et al. (2020) genotyped 97 German Shepherd dogs for the SOD1:c.118G>A mutation using a PCR/RFLP test. The dogs were located in Brazil and had no clinical signs of degenerative myelopathy at the time of sampling. They “observed genotype frequencies (with 95% confidence interval) of: 0.758 (0.672-0.844), 0.242 (0.156-0.328) and 0.000 (0.000-0.000) for "GG", "AG" and "AA" genotypes, respectively.” Maki et al. (2022) genotyped 541 German Shepherd Dogs (GSD) registered with the Japanese GSD Registration Society from 2000 to 2019, for the SOD1:c.118G>A likely causal variant (omia.variant:36). They reported "330 G/G dogs (61%), 184 G/A dogs (34%), and 27 A/A dogs (5%), indicating a frequency of the mutant allele of 0.220". For each of the seven A/A dogs over 10 years old (this being an adult-onset disease), the owners reported "DM-related clinical signs, indicating a clinical progression rate of 100%".

Control: Due to the high frequency of the causative mutation in Boxers and Pembroke Welsh Corgis, in these breeds it is not practical to exclude carriers from breeding, so it is recommended that carriers be bred to noncarriers. Breeding of affected dogs of any breed should be avoided.

Genetic testing: Investigating the "many discordant findings between the parental and the offspring genotypes found by different laboratories" in testing for the c.118G>A variant, Turba et al. (2017) discovered "An insertion of 54 nucleotides [in the SOD1 gene] composed of a poly-T stretch and 15 nucleotides containing the duplication of the exon 2-intron 2 junction was . . . responsible for the partial mismatch of the reverse primer used for a direct sequencing assay. The mismatch hampered the amplification of the corresponding allele and caused an evident drop-out effect. The insertion is in complete linkage disequilibrium with the c.118G allele." Santos et al. (2020) identified “a deletion of one “T” in the position 26540247 described as ENSCAFG00000008859:g.26540247del … located in the intron 1 of the SOD1 gene. … Although the role of the ENSCAFG00000008859:g.26540247del on structure and expression of SOD1 (and consequently its relationship with CDM) was not investigated in this study, its location does not suggest that it can influence the expression of the studied disease.” However, this variant prevented in a small number of dogs adequate genotyping of the SOD1:c.118G>A in the PCR-RFLP test used in this study.

Breeds: Alaskan Husky (Dog) (VBO_0200015), Alaskan Malamute (Dog) (VBO_0200017), American Eskimo Dog (Dog) (VBO_0200046), American Water Spaniel (Dog) (VBO_0200059), Australian Cattle Dog (Dog) (VBO_0200088), Australian Shepherd (Dog) (VBO_0200095), Beagle (Dog) (VBO_0200131), Belgian Shepherd Dog (Dog) (VBO_0200144), Belgian Shepherd Dog, Malinois (Dog) (VBO_0200147), Bernese Mountain Dog (Dog) (VBO_0200161), Bloodhound (Dog) (VBO_0200175), Border Collie (Dog) (VBO_0200193), Borzoi (Dog) (VBO_0200197), Boxer (Dog) (VBO_0200210), Briard (Dog) (VBO_0200234), Canaan Dog (Dog) (VBO_0200274), Cardigan Welsh Corgi (Dog) (VBO_0200290), Cavalier King Charles Spaniel (Dog) (VBO_0200309), Chesapeake Bay Retriever (Dog) (VBO_0200326), Chinese Crested (Dog) (VBO_0200345), Collie (Dog) (VBO_0200375), Collie Rough (Dog) (VBO_0200376), Coton de Tulear (Dog) (VBO_0200389), Czechoslovakian Wolfdog (Dog) (VBO_0200402), Dalmatian (Dog) (VBO_0200427), Doberman Pinscher (Dog) (VBO_0200442), English Mastiff (Dog) (VBO_0200492), English Springer Spaniel (Dog) (VBO_0200497), French Bulldog (Dog) (VBO_0201455), German Shepherd Dog (Dog) (VBO_0200577), Golden Retriever (Dog) (VBO_0200610), Great Pyrenees (Dog) (VBO_0200629), Hovawart (Dog) (VBO_0200674), Irish Setter (Dog) (VBO_0200702), Jack Russell Terrier (Dog) (VBO_0200724), Kerry Blue Terrier (Dog) (VBO_0200764), Komondor (Dog) (VBO_0200779), Kuvasz (Dog) (VBO_0200793), Labrador Retriever (Dog) (VBO_0200800), Newfoundland (Dog) (VBO_0200938), Norwich Terrier (Dog) (VBO_0200962), Nova Scotia Duck Tolling Retriever (Dog) (VBO_0200964), Pembroke Welsh Corgi (Dog) (VBO_0200995), Poodle, Miniature (Dog) (VBO_0201051), Poodle, Standard (Dog) (VBO_0201056), Pug (Dog) (VBO_0201089), Puli (Dog) (VBO_0201102), Rat Terrier (Dog) (VBO_0201125), Rhodesian Ridgeback (Dog) (VBO_0201135), Romanian Mioritic Shepherd Dog (Dog) (VBO_0201141), Rottweiler (Dog) (VBO_0201143), Saint Bernard (Dog) (VBO_0201160), Samoyed (Dog) (VBO_0201174), Shetland Sheepdog (Dog) (VBO_0201217), Shiloh Shepherd (Dog) (VBO_0201226), Siberian Husky (Dog) (VBO_0201233), Soft Coated Wheaten Terrier (Dog) (VBO_0201260), Staffordshire Bull Terrier (Dog) (VBO_0201296), Tamaskan Dog (Dog) (VBO_0201334), Tenterfield Terrier (Dog) (VBO_0201342), Tibetan Terrier (Dog) (VBO_0201353), Weimaraner (Dog) (VBO_0201401), Welsh Terrier (Dog) (VBO_0201412), White Swiss Shepherd Dog (Dog) (VBO_0201423), Wire Fox Terrier (Dog) (VBO_0201424).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated genes: