Hyperekplexia, startle disease, GLRA1-related

Gene: GLRA1

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, GLRA1 gene; 36 bp deletion within intron1-2 and exon2, chromosome 4.

Breed: Miniature Australian Shepherd

Medical system: Neurologic

Age of onset of symptoms: By 6 weeks.

Glycine is a major inhibitory neurotransmitter found in the central nervous system. Hyperekplexia, also known as Startle Disease, is a rare autosomal recessive neurological disorder seen in humans and in animals including the dog that is caused by disruption of glycine neurotransmission within the spinal cord and brain stem.

Hyperekplexia was diagnosed in a litter of Miniature Australian Shepherds from Finland. Clinical symptoms included an exaggerated startle response involving stiff, stilted gait, dyspnea and occasionally falling over. The startle response could be triggered by auditory stimulation. DNA analysis identified a homozygous deletion within the GLRA1 gene; this gene codes for a glycine receptor subunit protein implicated in synaptic glycine recycling. The asymptomatic parents of the affected animals were heterozygous carriers of the mutation. Mutations in the GLRA1 gene are a known cause of hyperekplexia in humans. Analysis of 127 unrelated European Miniature Australian Shepherds revealed a carrier frequency of 4.7%, while no mutant alleles were found when testing 45 Miniature American Shepherds, a closely related breed. Further DNA testing, of both European and North American animals of both breeds is now warranted. Veterinarians and breeders of Miniature Australian Shepherds and Miniature American Shepherds should be aware of this disease and should use DNA tests to identify carrier animals and selective breeding to eliminate the disease.

The SLC6A5 gene is another gene involved in glycine neurotransmission. This gene codes for a glycine transporter molecule that binds glycine within the synaptic cleft and recycles it to presynaptic vesicles. Mutations in the SLC6A5 gene will also cause hyperekplexia in dogs.