OMIA 000396-9615 : Fucosidosis, alpha in Canis lupus familiaris

In other species: domestic cat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 230000

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1996

Species-specific description: Alpha fucosidosis is a lysosomal disease characterized by severe, progressive neurological degeneration. Affected dogs usually die or are euthanized by 3-4 years of age. There is a test available. Therapeutic methods are under investigation.

History: The first reports of this disorder in dogs were by Hartley et al. (1992) and Littlewood et al. (1992).

Mapping: CFA2

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Skelly et al. (1996) identified a 14-bp deletion at the 3' end of exon 1 of the canine gene for alpha-L-fucosidase, in dogs affected with fucosidosis, causing a frameshift which results in 25 novel codons followed by two premature stop codons. Using the same strategy, Occhiodora and Anson (1996) reported the same mutation in an Australian colony of the same breed.

Clinical features: Affected dogs appear clinically normal until around 4-6 months of age, when behavioral signs are first noticeable. Signs include progressive ataxia, proprioceptive dysfunction, change in temperament, dysphagia, dysphonia, loss of learned behavior, muscle wasting, and apparent blindness. Affected dogs usually die or are euthanized by 3-4 years of age (Skelly et al., 1996, Fletcher et al., 2011). Bone marrow transplantation therapy slowed progression and decreased severity of clinical signs, but only if performed at an early age (Taylor et al., 1992).

Pathology: Affected animals are deficient in both forms of alpha-L-fucosidase, and are unable to completely degrade complex oligosaccharides. Therefore, they accumulate fucose-containing oligosaccharides and glycopeptides in lysosomes, which appear as vacuoles in histologic section. Heterozygous animals have about 50% of normal fucosidase activity (Abraham et al., 1984, Skelly et al., 1996). Lysosomal storage disturbs normal extracellular traffic and activates microglia, which causes the inflammatory response. Vacuolation and inflammation of neurons in the frontal cortex occurs by 2 months of age, before clinical signs become apparent. Chronic neuroinflammation can cause secretion of tumor necrosis factor alpha, which is a pro-apoptotic cytokine. This causes neuronal loss (Fletcher et al., 2011).

Prevalence: This disorder has been reported in ESSP in UK, Australia and USA.

Control: Relatives of affected dogs should be tested. Breeding of affected or carrier dogs is not recommended.

Genetic testing: There is a test available.

Breed: English Springer Spaniel.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
FUCA1 fucosidase, alpha-L- 1, tissue Canis lupus familiaris 2 NC_006584.3 (75665473..75677087) FUCA1 Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
English Springer Spaniel Fucosidosis, alpha FUCA1 deletion, small (<=20) a 14-bp deletion at the 3' end of exon 1 1996 8730282

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.
2016 Fletcher, J.L., Taylor, R.M. :
Therapy Development for the Lysosomal Storage Disease Fucosidosis using the Canine Animal Model. Pediatr Endocrinol Rev 13 Suppl 1:697-706, 2016. Pubmed reference: 27491218.
2012 Sewell, A.C., Haskins, M.E., Giger, U. :
Dried blood spots for the enzymatic diagnosis of lysosomal storage diseases in dogs and cats. Vet Clin Pathol 41:548-57, 2012. Pubmed reference: 23121383. DOI: 10.1111/j.1939-165x.2012.00485.x.
2011 Fletcher, J.L., Kondagari, G.S., Wright, A.L., Thomson, P.C., Williamson, P., Taylor, R.M. :
Myelin genes are downregulated in canine fucosidosis. Biochim Biophys Acta 1812:1418-26, 2011. Pubmed reference: 21683140. DOI: 10.1016/j.bbadis.2011.06.001.
Kondagari, G.S., King, B.M., Thomson, P.C., Williamson, P., Clements, P.R., Fuller, M., Hemsley, K.M., Hopwood, J.J., Taylor, R.M. :
Treatment of canine fucosidosis by intracisternal enzyme infusion. Exp Neurol 230:218-26, 2011. Pubmed reference: 21575633. DOI: 10.1016/j.expneurol.2011.04.019.
Kondagari, G.S., Ramanathan, P., Taylor, R. :
Canine fucosidosis: a neuroprogressive disorder. Neurodegener Dis 8:240-51, 2011. Pubmed reference: 21282938. DOI: 10.1159/000322541.
Kondagari, G.S., Yang, J., Taylor, R.M. :
Investigation of cerebrocortical and cerebellar pathology in canine fucosidosis and comparison to aged brain. Neurobiol Dis 41:605-13, 2011. Pubmed reference: 21056668. DOI: 10.1016/j.nbd.2010.10.026.
2000 Bielicki, J., Muller, V., Fuller, M., Hopwood, J.J., Anson, D.S. :
Recombinant canine alpha-l-fucosidase: expression, purification, and characterization. Mol Genet Metab 69:24-32, 2000. Pubmed reference: 10655154. DOI: 10.1006/mgme.1999.2947.
1999 Skelly, B.J., Sargan, D.R., Winchester, B.G., Smith, M.O., Herrtage, M.E., Giger, U. :
Genomic screening for fucosidosis in English Springer Spaniels American Journal of Veterinary Research 60:726-729, 1999. Pubmed reference: 10376901.
1998 Holmes, N.G., Acheson, T., Ryder, E.J., Binns, M.M. :
A PCR-based diagnostic test for fucosidosis in English Springer Spaniels Veterinary Journal 155:113-114, 1998.
1997 Ferrara, M.L., Occhiodoro, T., Fuller, M., Hawthorne, W.J., Teutsch, S., Tucker, V.E., Hopwood, J.J., Stewart, G.J., Anson, D.S. :
Canine fucosidosis - a model for retroviral gene transfer into haematopoietic stem cells Neuromuscular Disorders 7:361-366, 1997. Pubmed reference: 9267851.
1996 Occhiodoro, T., Anson, D.S. :
Isolation of the canine alpha-l-fucosidase cDNA and definition of the fucosidosis mutation in English Springer Spaniels Mammalian Genome 7:271-274, 1996. Pubmed reference: 8661697.
Skelly, B.J., Sargan, D.R., Herrtage, M.E., Winchester, B.G. :
The molecular defect underlying canine fucosidosis Journal of Medical Genetics 33:284-288, 1996. Pubmed reference: 8730282.
Smith, M.O., Wenger, D.A., Hill, S.L., Matthews, J. :
Fucosidosis in a family of American-bred English Springer Spaniels Journal of the American Veterinary Medical Association 209:2088-2090, 1996. Pubmed reference: 8960193.
1992 Ferrara, M.L., Taylor, R.M., Stewart, G.J. :
Age at Marrow Transplantation Is Critical for Successful Treatment of Canine Fucosidosis Transplantation Proceedings 24:2282-2283, 1992. Pubmed reference: 1413057.
Keller, C.B., Lamarre, J. :
Inherited Lysosomal Storage Disease in an English Springer Spaniel Journal of the American Veterinary Medical Association 200:194-195, 1992. Pubmed reference: 1559875.
Occhiodoro, T., Hopwood, J.J., Morris, C.P., Anson, D.S. :
Correction of alpha-L-Fucosidase Deficiency in Fucosidosis Fibroblasts by Retroviral Vector-Mediated Gene Transfer Human Gene Therapy 3:365-369, 1992. Pubmed reference: 1525209. DOI: 10.1089/hum.1992.3.4-365.
Taylor, R.M., Farrow, B.R.H., Stewart, G.J. :
Amelioration of Clinical Disease Following Bone Marrow Transplantation in Fucosidase-Deficient Dogs American Journal of Medical Genetics 42:628-632, 1992. Pubmed reference: 1609845. DOI: 10.1002/ajmg.1320420439.
1989 Kretz, K.A., Darby, J.K., Willems, P.J., Obrien, J.S. :
Characterization of Ecori Mutation in Fucosidosis Patients - A Stop Codon in the Open Reading Frame Journal of Molecular Neuroscience 1:177-180, 1989. Pubmed reference: 2642067.
Taylor, R.M., Martin, I.C.A., Farrow, B.R.H. :
Reproductive abnormalities in canine fucosidosis Journal of Comparative Pathology 100:369-380, 1989. Pubmed reference: 2760271.
Taylor, R.M., Stewart, G.J., Farrow, B.R.H., Healy, P.J. :
The Effect of Bone Marrow-Derived Cells on Lysosomal Enzyme Activity in the Brain After Marrow Engraftment Transplantation Proceedings 21:3822-3823, 1989. Pubmed reference: 2530677.
1988 Barker, C.G., Herrtage, M.E., Shanahan, F., Winchester, B.G. :
Fucosidosis in English Springer Spaniels: results of a trial screening programme Journal of Small Animal Practice 29:623-630, 1988.
Barker, C., Dell, A., Rogers, M., Alhadeff, J.A., Winchester, B. :
Canine alpha-L-fucosidase in relation to the enzymic defect and storage products in canine fucosidosis. Biochem J 254:861-8, 1988. Pubmed reference: 3196299.
Taylor, R.M., Farrow, B.R.H. :
Fucosidosis Comparative Pathology Bulletin 20:2-4, 1988.
Taylor, R.M., Farrow, B.R., Stewart, G.J., Healy, P.J., Tiver, K. :
The clinical effects of lysosomal enzyme replacement by bone marrow transplantation after total lymphoid irradiation on neurologic disease in fucosidase deficient dogs. Transplant Proc 20:89-93, 1988. Pubmed reference: 3278467.
1987 Taylor, R.M., Farrow, B.R., Stewart, G.J., Healy, P.J., Tiver, K. :
Lysosomal enzyme replacement in neural tissue by allogenic bone marrow transplantation following total lymphoid irradiation in canine fucosidosis Transplantation Proceedings 19:2730-2734, 1987. Pubmed reference: 3547950.
1986 Taylor, R.M., Farrow, B.R., Stewart, G.J. :
Correction of enzyme deficiency by allogeneic bone marrow transplantation following total lymphoid irradiation in dogs with lysosomal storage disease (fucosidosis). Transplant Proc 18:326-9, 1986. Pubmed reference: 3515668.
Taylor, R.M., Farrow, B.R., Stewart, G.J., Healy, P.J. :
Enzyme replacement in nervous tissue after allogeneic bone-marrow transplantation for fucosidosis in dogs. Lancet 2:772-4, 1986. Pubmed reference: 2876234.
1985 Alroy, J., Ucci, A.A., Warren, C.D. :
Human and canine fucosidosis: a comparative lectin histochemistry study. Acta Neuropathol 67:265-71, 1985. Pubmed reference: 4050341.
Friend, S.C., Barr, S.C., Embury, D. :
Fucosidosis in an English springer spaniel presenting as a malabsorption syndrome. Aust Vet J 62:415-20, 1985. Pubmed reference: 3833197.
Herrtage, M.E., Palmer, A.C., Blakemore, W.F. :
Canine fucosidosis [a letter] Veterinary Record 117:451-452, 1985. Pubmed reference: 4071939.
1984 Abraham, D., Blakemore, W.F., Dell, A., Herrtage, M.E., Jones, J., Littlewood, J.T., Oates, J., Palmer, A.C., Sidebotham, R., Winchester, B. :
The enzymatic defect and storage products in canine fucosidosis Biochemical Journal 222:25-33, 1984. Pubmed reference: 6477509.
Healy, P.J., Farrow, B.R., Nicholas, F.W., Hedberg, K., Ratcliffe, R. :
Canine fucosidosis: a biochemical and genetic investigation. Res Vet Sci 36:354-9, 1984. Pubmed reference: 6463379.
1983 Kelly, W.R., Clague, A.E., Barns, R.J., Bate, M.J., MacKay, B.M. :
Canine alpha-L-fucosidosis: a storage disease of Springer Spaniels Acta Neuropathologica 60:9-13, 1983. Pubmed reference: 6880626.
1982 Hartley, W.J., Canfield, P.J., Donnelly, T.M. :
A suspected new canine storage disease. Acta Neuropathol 56:225-32, 1982. Pubmed reference: 7072491.
Littlewood, J.D., Herrtage, M.E., Palmer, A.C. :
Neuronal storage disease in English spriner spaniels Veterinary Record 112:86-87, 1982.

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