Genetic basis - GCL is caused by mutations in the GALC (galactocerebrosidase) gene, which encodes a lysosomal enzyme necessary for myelin maintenance in the nervous system. In Irish Setters, a specific 78 base pair insertion mutation (c.790_791insN) has been identified in GALC that results in an abnormal, inactive protein. The disease is inherited in an autosomal recessive pattern, meaning two copies of the mutated gene (one from each parent) are needed for a dog to be affected. Carrier dogs have one copy of the mutation but appear healthy; they can pass the mutant gene to offspring.
Pathophysiology - The GALC enzyme deficiency impairs degradation of galactocerebroside, a lipid critical to myelin sheaths of nerve cells. Accumulation of toxic metabolites like psychosine leads to progressive demyelination and death of nerve cells, causing neurological dysfunction. Symptoms usually begin between 6 and 22 weeks of age. Dogs initially seem healthy but develop tremors, muscle weakness, poor coordination, and paralysis as nerves deteriorate.
Complications - Neurological clinical signs including tremors, limb weakness, vision loss, seizures, and progressive paralysis. The disease progresses rapidly and is invariably fatal, usually leading to humane euthanasia by 1 year of age. No effective treatment or cure exists.
Why This Matters to Breeders and Vets - For breeders, testing allows breeding decisions that prevent puppies from inheriting this fatal neurological disease, improving welfare and breed health. Veterinarians use genetic and clinical knowledge to aid in diagnosis, advise owners, and manage expectations for affected dogs. Understanding autosomal recessive inheritance assists with genetic counseling and responsible breeding to keep breeds healthy.