Globoid Cell Leukodystrophy (Krabbe Disease)

 

Gene: GALC

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.

Mutations:

Terrier mutation: Substitution, GALC gene; c.473A>C, p.(Y158S), exon5

Setter mutation: Insertion, GALC gene; c.790_791 ins. 78 nt

Medical system: Neuromuscular, lysosomal storage disease

Breeds: American Staffordshire Terrier/Amstaff, Cairn Terrier, Irish Setter, West Highland White Terrier

Age of onset of symptoms: 3 to 6 months

Globoid cell leukodystrophy (Krabbe Disease) is a central nervous system lysosomal storage disorder.  This disease is characterized by the loss of myelin fibers which are essential for the proper conduction of nerve impulses.  In affected animals, a defect in the enzyme galactocerebrosidase results in disrupted recycling of galactocerebrosides, required for the normal function of myelin. Galactocerebrosides accumulate in cells and over time the cells are no longer able to produce myelin.  Affected puppies show various neurological symptoms such as tremor, muscle weakness, balance problems, behavioral changes, jerky movements, incoordination, diminished muscle tone and reduced reflexes.  They have slower growth than their normal littermates and show symptoms such as incoordination in the hind legs as early as 3 to 6 months of age.  This condition progresses rapidly leading to blindness, paralysis and eventual death before the age of 12 months.  Affected puppies are usually euthanized for humanitarian reasons before the disease reaches its terminal stages.

 

References:

OMIA link: [0578-9615]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Feltri ML, Weinstock NI, Favret J, et al. (2021) Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy. Glia 69:2309-2331.  [pubmed/33851745]

McGraw RA, Carmichael KP. (2006) Molecular basis of globoid cell leukodystrophy in Iris setters. Vet Journal 171:370-372. [pubmed/16490723]

Wenger DA, Victoria T, Rafi MA, et al. (1999) Globoid cell leukodystrophy in cairn and West Highland white terriers. J Hered. 90(1):138-42. [pubmed/9987921]

Victoria T, Rafi MA, Wenger DA. (1996) Cloning of the canine GALC cDNA and identification of the mutation causing globoid cell leukodystrophy in West Highland White and Cairn Terriers. Genomics 33L457-462. [pubmed/8661004]