OMIA 000578-9615 : Krabbe disease in Canis lupus familiaris

In other species: domestic cat , sheep , Rhesus monkey

Possibly relevant human trait(s) and/or gene(s) (MIM number): 245200 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1996

Cross-species summary: Also known as globoid cell leukodystrophy (GLD), galactosylceramide lipidosis, galactocerebrosidase deficiency, GALC deficiency, globoid cell leukoencephalopathy, galactosylceramide beta-galactosidase deficiency. A lysosomal storage disease in which there is a buildup (storage) of myelin, due to the lack of the enzyme galactosylceramidase (galactocerebrosidase), whose task is to break down myelin into its constituent molecules. Characterised by weakness progressing to paralysis.

Species-specific name: globoid cell leukodystrophy

Species-specific symbol: GLD

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Victoria et al. (1996) identified the cause of this disorder, in both West Highland White terriers and Cairn terriers, as a base substitution (A to C transversion) at position 473 of the cDNA for galactocerebriosidase (GALC), resulting in an amino acid substitution (tyrosine to serine) at position 158 in the peptide. They have developed a PCR genotyping test which is being used within both breeds, to identify carriers.

In an Irish Setter family, McGraw and Carmichael (2006) identified a 78 bp insertion in the same gene as the causative mutation.

Clinical features: Clinical signs are usually apparent in affected dogs by 4-6 weeks of age (Corado et al., 2020). Affected dogs initially present with tremors and pelvic limb weakness which then progresses to pelvic limb ataxia as well as thoracic limb dysmetria, followed by tetraparesis and then eventually hind limb paralysis (Corado et al., 2020). Other clinical signs may include a wide-based stance, hypermetria, generalised incoordination and muscle atrophy (Bradbury et al., 2018). [IT thanks DVM student Sharna Allison, who provided the basis of this contribution in April 2022]

Pathology: This disease results in extensive characteristic white matter demyelination, globoid cell infiltration and low leukocyte galactosylceramidase activity (Fletcher et al., 2010). Demyelination usually begins in the spinal cord, peripheral nerves and hindbrain before progressing to the cerebellum (Fletcher et al., 2010). Histopathological changes in GLD-affected dogs include reactive astrocytosis and microglial activation (Fletcher et al., 2010). Psychosine, a GALC substrate, is believed to be responsible for cell death in GLD (Corado et al., 2020). [IT thanks DVM student Sharna Allison, who provided the basis of this contribution in April 2022]

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

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
GALC galactosylceramidase Canis lupus familiaris 8 NC_051812.1 (59589663..59531522) GALC Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
953 Irish Setter Krabbe disease GALC insertion, gross (>20) Naturally occurring variant CanFam3.1 8 g.59294611_59294612insN[78] c.790_791insN[78] NM_001003238.1; NP_001003238.1; the 78 bp insertion includes a 16-bp insertion site duplication and a 62 bp U4 snRNA-derived sequence; the downstream reading frame is preserved (for sequence details see McGraw et al., 2006) 2006 16490723
51 Cairn Terrier West Highland White Terrier Krabbe disease GALC missense Naturally occurring variant CanFam3.1 8 g.59311801T>G c.473A>C p.(Y158S) NM_001003238.1; NP_001003238.1 1996 8661004 Genomic coordinates in CanFam3.1 provided by Robert Kuhn

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2022 Hordeaux, J., Jeffrey, B.A., Jian, J., Choudhury, G.R., Michalson, K., Mitchell, T.W., Buza, E.L., Chichester, J., Dyer, C., Bagel, J., Vite, C.H., Bradbury, A.M., Wilson, J.M. :
Efficacy and safety of a Krabbe disease gene therapy. Hum Gene Ther :, 2022. Pubmed reference: 35333110. DOI: 10.1089/hum.2021.245.
2021 Feltri, M.L., Weinstock, N.I., Favret, J., Dhimal, N., Wrabetz, L., Shin, D. :
Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy. Glia 69:2309-2331, 2021. Pubmed reference: 33851745. DOI: 10.1002/glia.24008.
2020 Corado, C.R., Pinkstaff, J., Jiang, X., Galban, E.M., Fisher, S.J., Scholler, O., Russell, C., Bagel, J.H., ODonnell, P.A., Ory, D.S., Vite, C.H., Bradbury, A.M. :
Cerebrospinal fluid and serum glycosphingolipid biomarkers in canine globoid cell leukodystrophy (Krabbe disease). Mol Cell Neurosci 102:103451, 2020. Pubmed reference: 31794880. DOI: 10.1016/j.mcn.2019.103451.
Story, B.D., Miller, M.E., Bradbury, A.M., Million, E.D., Duan, D., Taghian, T., Faissler, D., Fernau, D., Beecy, S.J., Gray-Edwards, H.L. :
Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7:80, 2020. Pubmed reference: 32219101. DOI: 10.3389/fvets.2020.00080.
2018 Bradbury, A.M., Rafi, M.A., Bagel, J.H., Brisson, B.K., Marshall, M.S., Pesayco Salvador, J., Jiang, X., Swain, G.P., Prociuk, M.L., ODonnell, P.A., Fitzgerald, C., Ory, D.S., Bongarzone, E.R., Shelton, G.D., Wenger, D.A., Vite, C.H. :
AAVrh10 gene therapy ameliorates central and peripheral nervous system disease in canine globoid cell leukodystrophy (Krabbe disease). Hum Gene Ther 29:785-801, 2018. Pubmed reference: 29316812. DOI: 10.1089/hum.2017.151.
2016 Bongarzone, E.R., Escolar, M.L., Gray, S.J., Kafri, T., Vite, C.H., Sands, M.S. :
Insights into the pathogenesis and treatment of Krabbe disease. Pediatr Endocrinol Rev 13 Suppl 1:689-96, 2016. Pubmed reference: 27491217.
Bradbury, A.M., Bagel, J.H., Jiang, X., Swain, G.P., Prociuk, M.L., Fitzgerald, C.A., O'Donnell, P.A., Braund, K.G., Ory, D.S., Vite, C.H. :
Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe's disease). J Neurosci Res 94:1007-17, 2016. Pubmed reference: 27638585. DOI: 10.1002/jnr.23838.
Karumuthil-Melethil, S., Gray, S.J. :
Immunological considerations for treating globoid cell leukodystrophy. J Neurosci Res 94:1349-58, 2016. Pubmed reference: 27638617. DOI: 10.1002/jnr.23874.
2015 Graziano, A.C., Cardile, V. :
History, genetic, and recent advances on Krabbe disease. Gene 555:2-13, 2015. Pubmed reference: 25260228. DOI: 10.1016/j.gene.2014.09.046.
2010 Fletcher, JL., Williamson, P., Horan, D., Taylor, RM. :
Clinical signs and neuropathologic abnormalities in working Australian Kelpies with globoid cell leukodystrophy (Krabbe disease). J Am Vet Med Assoc 237:682-8, 2010. Pubmed reference: 20839990. DOI: 10.2460/javma.237.6.682.
Monaldi, A., Martínez Munera, A.M. :
Globoid leukodystrophy in a West Highland terrier. / Leucodistrofia de células globoides en un westy. Argos—Informativo Veterinario 158:38-41, 2010.
2008 Beltran, E., Matiasek, L.A., De Risio, L., Mellersh, C., Platt, S.R. :
Globoid cell leukodystrophy in a litter of kelpies with episodic cerebellar disease Journal of Veterinary Internal Medicine 22:723 only, 2008.
Capucchio, MT., Prunotto, M., Lotti, D., Valazza, A., Galloni, M., Dore, B., Pregel, P., Amedeo, S., Catalano, D., Cornaglia, E., Schiffer, D. :
Krabbe's disease in two West Highland White terriers. Clin Neuropathol 27:295-301, 2008. Pubmed reference: 18808060.
2006 McGraw, RA., Carmichael, KP. :
Molecular basis of globoid cell leukodystrophy in Irish setters. Vet J 171:370-2, 2006. Pubmed reference: 16490723. DOI: 10.1016/j.tvjl.2004.10.019.
2000 McGowan, J.C., Haskins, M., Wenger, D.A., Vite, C. :
Investigating demyelination in the brain in a canine model of globoid cell leukodystrophy (Krabbe disease) using magnetization transfer contrast: Preliminary results Journal of Computer Assisted Tomography 24:316-321, 2000. Pubmed reference: 10752900.
Wenger, D.A. :
Murine, canine and non-human primate models of Krabbe disease Molecular Medicine Today 6:449-451, 2000. Pubmed reference: 11074371.
1999 Wenger, D.A., Victoria, T., Rafi, M.A., Luzi, P., Vanier, M.T., Vite, C., Patterson, D.F., Haskins, M.H. :
Globoid cell leukodystrophy in cairn and West Highland white terriers Journal of Heredity 90:138-142, 1999. Pubmed reference: 9987921.
1998 Cozzi, F., Vite, C.H., Wenger, D.A., Victoria, T., Haskins, M.E. :
MRI and electrophysiological abnormalities in a case of canine globoid cell leucodystrophy Journal of Small Animal Practice 39:401-405, 1998. Pubmed reference: 9741878.
1996 Victoria, T., Rafi, M.A., Wenger, D.A. :
Cloning of the canine GALC cDNA and identification of the mutation causing globoid cell leukodystrophy in West Highland White and Cairn Terriers Genomics 33:457-462, 1996. Pubmed reference: 8661004. DOI: 10.1006/geno.1996.0220.
1994 Poncelet, L., Heimann, M., Coignoul, F., Balligand, M. :
Globoid cell leucodystrophy in seven West Highland White Terrier pups Annales de Medecine Veterinaire 138:513-519, 1994.
1988 Vicini, D.S., Wheaton, L.G., Zachary, J.F., Parker, A.J. :
Peripheral nerve biopsy for diagnosis of globoid cell leukodystrophy in a dog. J Am Vet Med Assoc 192:1087-90, 1988. Pubmed reference: 3372337.
1985 Suzuki, K., Suzuki, K. :
Genetic galactosylceramidase deficiency (globoid cell leukodystrophy, Krabbe disease) in different mammalian species. Neurochem Pathol 3:53-68, 1985. Pubmed reference: 3895053.
1983 Luttgen, P.J., Braund, K.G., Storts, R.W. :
Globoid cell leucodystrophy in a Basset hound. Journal of Small Animal Practice 24:153-160, 1983.
1979 Bjerkas, I. :
Hereditary leukodystrophy in Dalmatian dogs in Norway Norsk Veterinaertidsskrift 91:167-170, 1979.
1976 Yunis, E.J., Lee, R.E. :
The morphologic similarities of human and canine globoid leukodystrophy American Journal of Pathology 85:99-114, 1976. Pubmed reference: 970445.
1975 Johnson, G.R., Oliver, J.E., Selcer, R. :
Globoid cell leukodystrophy in a Beagle Journal of the American Veterinary Medical Association 167:380-384, 1975. Pubmed reference: 1158775.
1974 Boysen, B.G., Tryphonas, L., Harries, N.W. :
Globoid cell leukodystrophy in the Bluetick Hound dog. I. Clinical manifestations Canadian Veterinary Journal 15:303-308, 1974.
1973 Zaki, F.A., Kay, W.L. :
Globoid cell leukodystrophy in a Miniature Poodle Journal of the American Veterinary Medical Association 163:248-250, 1973. Pubmed reference: 4721757.
1971 Fletcher, T.F., Lee, D.G., Hummer, R.F. :
Ultrastructural features of globoid cell leukodystrophy in the dog American Journal of Veterinary Research 32:177-181, 1971. Pubmed reference: 5099954.
Howell, J.McC., Palmer, A.C. :
Globoid cell leukodystrophy in two dogs Journal of Small Animal Practice 12:633-642, 1971. Pubmed reference: 5167788.
Kurtz, H.J., Fletcher, T.F. :
Peripheral neuropathy and central nervous system lesions in canine globoid-cell leukodystrophy (Krabbe's disease). S D J Med 24:5-6 passim, 1971. Pubmed reference: 4327663.
Suzuki, Y., Suzuki, K. :
Krabbe's globoid cell leukodystrophy: deficiency of galactocerebrosidase in serum, leukocytes, and fibroblasts Science 171:73-75, 1971. Pubmed reference: 5538703.
1970 Suzuki, K. :
Ultrastructural study of experimental globoid cells Laboratory Investigation 23:612-619, 1970. Pubmed reference: 5484847.
1966 Fletcher, T.F., Kurtz, H.J., Low, D.G. :
Globoid cell leukodystrophy (Krabbe type) in the dog. J Am Vet Med Assoc 149:165-172, 1966. Pubmed reference: 5950438.
1963 Fankhauser, R., Luginbuhl, H., Hartley, W.J. :
Leukodystrophie vom Typus Krabbe beim Hund. Schweiz Arch Tierheilkd 105:10, 1963.

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  • Created by Frank Nicholas on 08 Jun 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 03 Sep 2012
  • Changed by Frank Nicholas on 27 Aug 2016
  • Changed by Imke Tammen2 on 21 Apr 2022