In other species: domestic cat , 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: Probably autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2023

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.

Molecular basis: Bullock et al. (2023): "A whole genome sequence generated with DNA from the affected [Doberman Pinscher] dog contained a likely causal, homozygous missense variant in MAN2B1 that predicted an Asp104Gly amino acid substitution that was unique among whole genome sequences from over 4000 dogs. A lack of detectable α-mannosidase enzyme activity confirmed a diagnosis of a-mannosidosis."

Clinical features: Bullock et al. (2023): A "7-month-old Doberman Pinscher dog presented with progressive neurological signs and brain atrophy suggestive of a hereditary neurodegenerative disorder. The dog was euthanized due to the progression of disease signs."

Pathology: Bullock et al. (2023): "Microscopic examination of tissues [from the affected Doberman Pinscher] ... revealed massive accumulations of vacuolar inclusions in cells throughout the central nervous system, suggestive of a lysosomal storage disorder. ... In addition to the vacuolar inclusions characteristic of α-mannosidosis, the dog exhibited accumulations of autofluorescent intracellular inclusions in some of the same tissues. The autofluorescence was similar to that which occurs in a group of lysosomal storage disorders called neuronal ceroid lipofuscinoses (NCLs). As in many of the NCLs, some of the storage bodies immunostained strongly for mitochondrial ATP synthase subunit c protein. This protein is not a substrate for α-mannosidase, so its accumulation and the development of storage body autofluorescence were likely due to a generalized impairment of lysosomal function secondary to the accumulation of α-mannosidase substrates. ... In addition to storage body accumulation, glial activation indicative of neuroinflammation was observed in the brain and spinal cord of the proband."

Breed: Doberman Pinscher (Dog) (VBO_0200442).
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: