Epilepsy, mitochondrial dysfunction, neurodegeneration

Gene: PITRM1

Transmission: Autosomal recessive

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.

Mutation: Deletion, PITRM1 gene; c.175_180 del, p.(L59_S60 del), chr.2.

Medical system: Neurological

Breeds: Parson Russell Terrier

Age of onset of symptoms: 6-12 weeks.

A disease phenotype involving severe progressive epileptic seizures was observed in puppies from an extended inbred pedigree of European Parson Russell Terriers.  Seizures were characterized by anxious behavior, sudden head movements, facial spasms, repeated eye blinking, and excessive salivation.  Seizures progressed rapidly to status epilepticus and the death of the animal.  Molecular studies revealed a mutation within the PITRM1 gene which codes for a peptidase enzyme involved in mitochondrial energy production and in neuronal survival.  The mutation, when homozygote (M/M) resulted in the epileptic seizures seen clinically and in the neurodegeneration with amyloid beta protein accumulation within neurons seen on pathology.  Carrier animals (M/N) were clinically normal.  DNA studies on a total of 791 Parson Russell Terriers revealed carrier frequencies of between 5.2% and 17%.  The mutation was not found in other breeds tested.  Use of a DNA test to identify carrier animals will be useful in eliminating the disease and eventually the mutation from the Parson Russell Terrier breed.

References:

OMIA link: [2324-9615]

Cocostîrc V, Paștiu AI, Pusta DL. (2023) An overview of canine inherited neurological disorders with known causal variants.  Animals (Basal) 13(22):3568.  [pm/38003185]

Hytönen MK, Sarviaho R, Jackson CB, et al. (2021) In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration. Hum Genet 140:1593-1609. [pubmed/33835239]

Contributed by:  Anne Denoncourt and Nick Manseau, Class of 2028, Faculty of Veterinary Medicine, University of Montreal. (Translation DWS).