In other species: dog , taurine cattle , goat , sheep , domestic guinea pig

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 248500 (trait) , 609458 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009561: alpha-mannosidosis

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1997

Cross-species summary: A lysosomal storage disease in which there is a buildup (storage) of mannose-rich compounds, due to the lack of the enzyme alpha-mannosidase, whose task is to cleave mannose from such compounds. Clinical signs include ataxia, head tremor, aggression, and finally paralysis and death.

Species-specific description: Alpha-mannosidosis is a lysosomal storage disease characterized by accumulation of mannose-rich oligosaccharides in lysosomes. Clinical signs include neurological deficits, skeletal deformities, growth retardation, gingival hyperplasia, and corneal and lenticular opacities. Affected cats are deficient in the lysosomal hydrolase alpha-mannosidase, which is necessary for the degradation of glycoproteins. In the absence of sufficient alpha-mannosidase, mannose-rich oligosaccharides accumulate intracellularly. Upon histopathologic examination, vacuolated neurons, glial cells, and endothelial cells are present throughout the central nervous system. The mode of inheritance is autosomal recessive. The causative mutation is a 4 base pair deletion in the gene coding for lysosomal alpha-mannosidase. There is a test available to detect the mutation. Siblings of affected cats should be tested. Breeding of affected or carrier cats is not recommended. Edited by Mark Haskins, VMD, PhD

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Berg et al. (1997) identified a causative variant as a 4-base-pair deletion in the gene coding for lysosomal alpha-mannosidase, resulting in "a frame shift from codon 583 and premature termination at codon 645". This variant is specific to Persian cats and was not found in Domestic Longhair cat with alpha-mannosidosis. According to the variant nomencalture of the years 2013 this variant corresponds to c.1749_1752delCCAG or p.Q584Afs.

Clinical features: Cats with alpha-mannosidosis have severe neurological deficits, tremors, loss of balance, nystagmus, hearing loss, synovitis, dorsoventral narrowing of the palpebral fissure, hydrocephalus, skeletal deformities, growth retardation, gingival hyperplasia, and corneal and lenticular opacities. Without treatment, life expectancy is about six months (Abkowitz et al., 2009, Vite et al., 2001). Urinary oligosaccarides can be detected by thin-layer chromatography.

Pathology: Affected cats are deficient in the lysosomal hydrolase alpha-mannosidase, which is necessary for the degradation of glycoproteins. In the absence of sufficient alpha-mannosidase, mannose-rich oligosaccharides accumulate intracellularly. Upon histopathologic examination, vacuolated neurons, glial cells, and endothelial cells are present throughout the central nervous system. The centrum semiovale and the cerebellar white matter appear to be deficient in myelin. There are fewer Purkinje cells and granular neurons than normal in the cerebellum (Vite et al., 2001).

Control: Siblings of affected cats should be tested. Breeding of affected or carrier cats is not recommended.

Genetic testing: There is a test available to detect the mutation.

Breeds: Domestic Longhair, Domestic Shorthair, Persian (Cat) (VBO_0100188).
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: