A fatal form of juvenile epilepsy affects pedigree dogs of the Parson Russell Terrier breed

A genetic discovery links mitochondrial dysfunction to the onset of severe, even fatal, epilepsy in Parson Russell Terrier puppies just a few months old. This is the first description of this new neurodegenerative disorder of the canine brain. Researchers at the University of Helsinki investigated very specific cases of severe epilepsy in Parson Russell Terrier puppies. Aged 6 to 12 weeks, affected dogs suddenly develop acute epileptic seizures that progress rapidly, sometimes become continuous, and do not respond to treatment. The animals then die within a few hours or must be euthanized. Histopathology of brain tissue revealed extensive neuronal necrosis affecting the gray matter throughout the brain. Intraneuronal mitochondrial accumulation, as well as an accumulation of β-amyloid and generalized neurodegeneration—typical of human Alzheimer’s disease—were also observed. Such accumulation is surprising in such young dogs. Using nearly 30,000 samples collected across Europe from 374 different dog breeds, the researchers were able to identify the culprit. Affected puppies have a genetic defect in the PITRM1 gene that causes the loss of two amino acids in the PITRM1 enzyme, preventing it from functioning normally. This enzyme plays an important role in mitochondrial function and, therefore, in energy metabolism. It acts as a mitochondrial cleaner, breaking down unwanted protein fragments as well as harmful amyloid-β. If PITRM1 does not function properly, the accumulation of these substances in the mitochondria disrupts their function. Neurons are particularly sensitive to disruptions in cellular respiration—which takes place in the mitochondria—which explains the early neurodegeneration observed in affected puppies whose mitochondria are blocked. In humans, mutations in this same PITRM1 gene also cause neurodegeneration, resulting in spinocerebellar ataxia associated with psychiatric and cognitive abnormalities. Although the human form of the disease progresses more slowly, the clinical presentation and underlying mechanisms are similar. Few human cases have been diagnosed to date, but the existence of a spontaneous canine model could improve our understanding of the disease and the care of patients. The results obtained in dogs so far confirm the essential role of PITRM1 in neuronal survival and reinforce the link between mitochondrial dysfunction and neurodegeneration. To date, this genetic mutation has been identified only in the Parson Russell Terrier breed, and only 5% of pedigree dogs of this breed are recessive carriers. The study’s findings will directly benefit the animals, as the genetic tests developed will soon be made available to breeders to identify asymptomatic carriers and prevent them from breeding, thereby ensuring that no more puppies are born with this new neurodegenerative disorder.