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Canine Mendelian disease record

Inflammatory Myopathy (Discovered in the Dutch Shepherd Dog; SLC25A12-related)

Inflammatory Myopathy (Discovered in the Dutch Shepherd Dog; SLC25A12-related). Autosomal recessive. Observed in 0 of 266 breeds tested in the Sniff Atlas, with measured variant frequencies drawn from 242,665 dogs (Donner 2023). Whether a dog carrying this variant is at risk depends on the disease’s inheritance pattern; outcome also depends on penetrance, modifiers, and environment. The frequencies below describe variant prevalence, not confirmed disease incidence.

OMIA identifier
OMIA:002294-9615
Autosomal recessive
Linked gene
SLC25A12
Human counterpart
In humans, this gene is SLC25A12. OMIM 603667 In people, SLC25A12 rarely tolerates loss-of-function variation (gnomAD v4.1 constraint, LOEUF 0.53), a sign it does important, dosage-sensitive work. In people, variants in the SLC25A12 gene have conflicting classifications in ClinVar, and none is expert-reviewed. The evidence is unsettled, not that variants here are benign.
Source dataset
Sniff Atlas v1.0.1 / DOI
The human connection

A model of human developmental and epileptic encephalopathy, 39

Dogs with this condition carry a change in SLC25A12. In people, changes in the same gene cause developmental and epileptic encephalopathy, 39. That makes affected dogs a naturally-occurring model of the human disease, and it is part of why studying dogs moves medicine forward for everyone. It does not mean your dog has the human disease. It means the two share an underlying biology.

In people, the disease is described as: A rare mitochondrial substrate carrier disorder characterized by severe muscular hypotonia, seizures (with or without episodic apnea) beginning in the first year of life, and arrested psychomotor development (affecting mainly motor skills). Severe spasticity with hyperreflexia has also been reported. Global cerebral hypomyelination is a characteristic imaging feature of this disease.

In humans it is also called: DEE39, EIEE39, AGC1 deficiency, epileptic encephalopathy, early infantile, 39.

MONDO:0013056 OMIM 612949

Mapped from OMIA via the human disease's OMIM entry to the Mondo Disease Ontology (Monarch Initiative, CC-BY 4.0). Sniff renders this as a model-of link; the canine disease remains the subject of this page.

About this disease

From OMIA's curated record

Documented in OMIA (Online Mendelian Inheritance in Animals). This describes the disease as recorded in the published literature, not a prediction for any individual dog. As of 2026-06-03.

Summary

CDMC

Clinical features

Shelton et al. (2019) reported in Dutch Shepherd dogs with the p.L349P variant: "Five related Dutch Shepherd dogs with progressive muscle weakness and generalized muscle atrophy beginning at 3 to 9 months of age were euthanized by 2 years of age. Clinical signs included muscle tremors, pelvic limb stiffness, weakness progressing to inability to walk, and severe muscle atrophy. Serum CK activity was moderately elevated (ranging from 800–2,500 IU/L (reference values <200 IU/L) in all affected dogs, indicating myofiber damage. As far as could be determined, affected dogs did not have behavioral abnormalities or seizure activity, interacted with littermates and other dogs, and were visual with no ocular abnormalities noted. As myopathic changes predominated, extensive evaluations by a veterinary neurologist for central nervous system disease or by an ophthalmologist for ocular disease were not performed." Christen et al. (2022) reported in 4 Nova Scotia Duck Tolling Retrievers with the p.P446L variant: "Age of onset of neurological signs was between 10 weeks and 6 months. Clinical abnormalities were restricted to the neuromuscular system in all four dogs. Neurological examination showed generalized ataxia and hypermetria, which was more pronounced in the pelvic limbs in all four dogs. Intentional head tremor was present in one dog. In two dogs, generalized neuromuscular weakness became apparent after 1 month, characterized by exercise intolerance, episodic collapse, stiff gait, and bunny hopping. Hopping was delayed in four limbs in three dogs, menace responses were absent in one dog, and decreased withdrawal reflexes were found in four limbs of three dogs." ... "Blood examination showed increases in serum creatine kinase concentrations in all four dogs (between 3 and 25 times greater than the upper reference limit). An EMG showed mild spontaneous activity in peripheral limb muscles. MRI of the brain in the same dog showed bilateral symmetrical lesions in the cerebellum and multifocal lesions in the masticatory muscles."

Molecular genetics

Shelton et al. (2019): "After filtering these protein-coding homozygous variants against a dog genetic variant database . . . only one was unique to the sequenced case; a leucine to proline mutation (chr36:g.16,219,219A>G; c.1046T>C; p.L349P) within the SLC25A12 gene." SLC25A12 encodes the solute carrier family 25 member 2, a mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle. Shelton et al. (2019) demonstrated that recombinant mutant SLC25A12 showed a strong impairment of transport activity compared to the wildtype protein. "As a result of this impaired transport, mitochondrial redox becomes more oxidizing with fewer reducing equivalents imported into the mitochondria via NADH. MAS defects lead to progressive intramitochondrial oxidation as NADH/NAD+ and NADPH/NADP+ ratios fall. The fall in intramitochondrial NADH/NAD+ ratio results in a highly oxidizing and proinflammatory muscle milieu. This is in contrast to the primary disorders of oxidative phosphorylation like complex I and complex IV deficiency leading to Leigh Syndrome, in which the mitochondria cannot consume the NADH that comes in and the intramitochondrial NADH/NAD+ ratio rises." (Shelton et al. 2019) Christen et al. (2022) studied two litters of Nova Scotia Duck Tolling Retrievers, in which a total of four puppies were affected by a phenotype designated as cerebellar degeneration-myositis complex (CDMC). Whole genome sequencing of an affected dog at 29.1x coverage and comparison to 565 control genomes revealed 6 homozygous and 88 heterozygous private protein-changing variants. The authors identified a homozygous missense variant in SLC25A12 as the most likely candidate for the observed neurologic/neuromuscular phenotype. The identified variant was Chr36:16,504,064G>A (UU_Cfam_GSD_1.0 assembly) or XM_038584842.1:c.1337C>T or XP_038440770.1:(p.Pro446Leu). Genotypes at this variant showed the expected co-segregation with the phenotype in the available families and were perfectly associated with the disease phenotype in independently collected cohorts of 380 European and 153 North American Nova Scotia Duck Tolling Retrievers. The mutant allele frequencies in the European and North American cohorts were 3.6% abd 1.3%, respectively.

Pathology

Shelton et al. (2019): "Histopathology of muscle biopsies confirmed an inflammatory myopathy and immune-mediated, infectious and dystrophic disorders were considered." Christen et al. (2022): "Muscle and nerve biopsies showed a fiber-invasive lymphohistiocytic myositis without evidence of intracellular infectious agents on histology and tissue PCR. The only other abnormality seen on postmortem examination was severe cerebellar nuclear degeneration. Based on the available clinical and diagnostic findings, we tentatively termed the phenotype of the four affected dogs cerebellar degeneration—myositis complex (CDMC)."

History

Shelton et al. (2019): "This report is the first description of a SLC25A12 variant resulting in an inflammatory myopathy in any species and reveals a complex pattern of metabolomic changes associated with this variant."

Human analog

OMIA links this condition to its human counterpart in OMIM (Mendelian Inheritance in Man), the place to read across to the deeper human literature for the same biology.

Disease · OMIM 612949 Gene · OMIM 603667

Source: OMIA (Nicholas, Tammen & the Sydney Informatics Hub), entry OMIA:002294-9615, doi:10.25910/2AMR-PV70 (CC-BY 4.0).

The evidence

Published references

The peer-reviewed papers behind this disease, curated by OMIA. Starred entries are OMIA-designated landmark papers.

  2. Phenotypic and genetic aspects of hereditary ataxia in dogs. · J Vet Intern Med · 2023 · PMID 37341581

References curated by OMIA (Nicholas, Tammen & the Sydney Informatics Hub), doi:10.25910/2AMR-PV70 (CC-BY 4.0). Full list at the OMIA entry.

Your breed

See what Inflammatory Myopathy (Discovered in the Dutch Shepherd Dog; SLC25A12-related) looks like in your dog's breed.
Variant frequency by breed

Observed only in small-sample breeds

Maximum variant frequency per breed across variants in the Donner 2023 cohort, with . The list below is split into well-sampled breeds (n ≥ 50 tested) and small-sample breeds (n < 50, where the Wilson CI typically spans more than 20 percentage points and frequencies should not be compared directly to the well-sampled entries). Frequencies are population-level, not per-litter or per-line.

Scope of this record

Scope

This record carries the breed-level carrier frequencies from the Donner 2023 cohort. Penetrance data (the fraction of at-risk dogs that develop the phenotype) is not yet quantified for this disease in the Sniff Atlas v1.0.1. The OMIA entry is the authoritative reference for the clinical phenotype, inheritance pattern, and gene assignment.

Predicted disease relevance at the per-dog level is UNPROVEN. The variant frequency is measured; phenotype outcome depends on penetrance, environment, and modifier loci. Consult a veterinarian for clinical interpretation.

How to cite this record

Citations

If you use this record in published work, cite the Sniff Atlas (the published dataset that carries the breed-level carrier frequencies) and the upstream sources:

  • Sniff Atlas v1.0.1 for the per-breed carrier frequencies:

    Gehring, M. (2026). Sniff Atlas v1.0.1. Zenodo. https://doi.org/10.5281/zenodo.20566358. CC-BY 4.0.

  • OMIA for the disease definition, inheritance, and gene assignment:

    Nicholas, F. W., & Tammen, I. (2024). OMIA. Sydney Informatics Hub, The University of Sydney. https://doi.org/10.25910/2AMR-PV70. Entry: OMIA:002294-9615.

  • Donner et al. 2023 for the breed × variant carrier-frequency cohort:

    Donner, J., Freyer, J., Davison, S., Anderson, H., Blades, M., Honkanen, L., et al. (2023). Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs. PLOS Genetics, 19(2), e1010651. https://doi.org/10.1371/journal.pgen.1010651.

Full citation formats (BibTeX, RIS, CITATION.cff) at sniff.world/cite.

Related

Related

Last updated
Sources: Sniff Atlas v1.0.1 · OMIA OMIA:002294-9615 · Donner et al. 2023 · gnomAD v4.1 (Karczewski 2020) · ClinVar (Landrum 2018)