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Globoid Cell Leukodystrophy (GALC gene, Irish Setter)

Globoid Cell Leukodystrophy (GALC gene, Irish Setter)

Globoid cell leukodystrophy, also known as Krabbe disease, is a rare genetic disorder that affects the nervous system and results in a loss of myelin, the protective coating that surrounds nerve fibers in the central nervous system.

Symptoms

In dogs, globoid cell leukodystrophy has been identified in some breeds, such as the West Highland White Terrier, the Cairn Terrier, the Beagle and the miniature Poodle. Symptoms of the disease in dogs can vary depending on the breed and age of onset. Symptoms usually appear in the first few months of life and generally include progressive weakness, incoordination and difficulty walking (ataxia), tremors, hearing and vision loss, behavioral changes and seizures.

Disease Management

There is currently no cure for globoid cell leukodystrophy in dogs. Treatment is primarily supportive and may include medications to control symptoms. The prognosis for affected dogs is poor and the disease generally progresses rapidly, leading to decreased quality of life and ultimately euthanasia.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

The disease is due to a deficiency of an enzyme called galactocerebrosidase, which is crucial for the breakdown of certain lipids in the brain. Lack of this enzyme leads to the accumulation of toxic substances in the nervous system, resulting in the destruction of myelin and disruption of normal nerve cell function. McGraw et al. studied a group of Irish Setter puppies that exhibited symptoms characteristic of Krabbe disease and showed a deficiency in galactocerebrosidase activity. These researchers identified a mutation in the GALC gene, specifically the c.790_791insN[78] insertion, which was different from that previously found in Terrier dogs with Krabbe disease. The c.790_791insN[78] variant causes the insertion of 78 additional base pairs in the GALC gene sequence (encoding galactocerebrosidase), resulting in a protein that is larger than normal and non-functional.

Most affected breeds

Australian Kelpie
Basset Hound
Beagle
Bluetick Hound
Cairn Terrier
Dalmatian
Irish Setter
Miniature Poodle
Rottweiler
West Highland White Terrier

Bibliography

Bongarzone ER, Escolar ML, Gray SJ,et al. Insights into the Pathogenesis and Treatment of Krabbe Disease. Pediatr Endocrinol Rev. 2016 Jun;13 Suppl 1:689-96.

McGraw RA, Carmichael KP. Molecular basis of globoid cell leukodystrophy in Irish setters. Vet J. 2006 Mar;171(2):370-2.