In other species: domestic cat

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 230000 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 (Dog) (VBO_0200497).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: