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- A novel neurodegenerative disorder in Great Pyrenees
A novel neurodegenerative disorder in Great Pyrenees
Human genetics 2023
Kari J. Ekenstedt, Katie M. Minor, G. Diane Shelton, James J. Hammond, Andrew D. Miller, Susan M. Taylor, Yanyun Huang & James R. Mickelson
Background
A novel neurodegenerative disorder in Great Pyrenees dogs has been identified, resembling the human condition autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). ARSACS is a progressive neurodegenerative disease caused by mutations in the SACS gene, resulting in cerebellar ataxia, spasticity, and peripheral neuropathy. This study aims to characterize the clinical, histopathological, and genetic features of this disorder in dogs, providing the first large animal model of ARSACS.
Methods
The study employed a multi-faceted approach including pedigree analysis, clinical and postmortem examinations, genome-wide association studies (GWAS), and Sanger sequencing. The discovery cohort included 32 dogs, with tissue samples obtained from affected dogs for histological analysis. Sequencing focused on identifying variants in the SACS gene.
Results
A 4-base pair deletion in the SACS gene was found in affected dogs, leading to a truncated sacsin protein missing critical domains essential for its chaperone function. Clinically, affected dogs displayed early-onset cerebellar ataxia, spasticity, progressive limb weakness, and eventual paresis, with most euthanized by 4-7 years. Histopathology revealed severe cerebellar Purkinje cell loss, degeneration of spinal cord white matter, and peripheral neuropathy. The identified deletion segregated perfectly with disease status in the cohort, confirming autosomal recessive inheritance.
Limitations
The sample size is relatively small, with limitations in the genetic diversity of the study population. Furthermore, findings are specific to Great Pyrenees dogs, and additional breeds were not evaluated for this mutation.
Conclusions
This study establishes a 4-base pair deletion in the SACS gene as the cause of a novel neurodegenerative disorder in Great Pyrenees dogs, mirroring human ARSACS. This canine model offers a valuable system for studying ARSACS pathophysiology and potentially testing therapeutic approaches.
Comparison of T2 sagittal midline images of the brain of affected and non-affected Great Pyrenees. a T2 sagittal image of affected Great Pyrenees at 1 year of age. On midline cross-section, the cerebellum is small with increased fluid present between the folia (arrow). The caudal aspect of the cerebellum is flattened with a larger compensatory cerebellomedullary cistern (arrowhead). b Normal T2 sagittal image of the brain of a 3 year old Great Pyrenees. On midline cross-section, the cerebellum (arrow) is round and fills the dorsal portion of the caudal fossa. The cerebellomedullary cistern (arrowhead) is larger in this breed compared to many other breeds, but smaller than that of the affected dog
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