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GM2 Gangliosidosis Type 2 (HEXB gene, Domestic Shorthair)

GM2 Gangliosidosis Type 2 (HEXB gene, Domestic Shorthair)

GM2 gangliosidosis is a lysosomal deposition disease that results in the accumulation of GM2 gangliosides in various tissues, leading to progressive neuromuscular deterioration and growth retardation. The genetic variant responsible is found in the HEXB gene encoding the hexosaminidase enzyme responsible for the degradation of GM2 ganglioside.

Symptoms

GM2 gangliosidosis presents in cats at around 6 to 8 weeks of age. Early symptoms include mild tremors that progress to coordination problems. Affected cats have severe problems moving and eating. In addition, they often suffer weight loss and progression of the neurological disease usually leads to euthanasia at around 4 months of age.

Disease Management

There is currently no effective treatment for feline GM2 gangliosidosis. Treatment focuses on alleviating symptoms and improving the patient`s quality of life. Studies are underway to evaluate adeno-associated viral vectors for the treatment of feline gangliosidosis, however, further research is still required.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the cat, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected cat must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between cats carrying genetic variants that may cause disease, even if they do not show symptoms, is not recommended.

Technical report

GM2 gangliosidosis type 2, known as Sandhoff disease, is a lysosomal storage disorder caused by deficiency of the enzyme beta-N-acetylhexosaminidase, which is essential for the degradation of GM2 ganglioside in cells. This catabolism process involves the alpha and beta subunits of beta-N-acetylhexosaminidase and the GM2 activator protein. When any of these three components is defective, GM2 ganglioside accumulates in lysosomes, leading to progressive and incurable deterioration of the central nervous system. The disease occurs in several forms depending on the gene affected: variant B (beta-N-acetylhexosaminidase alpha subunit deficiency), variant 0 (beta-N-acetylhexosaminidase beta subunit deficiency), and variant AB (GM2A activator protein deficiency). Variant 0 corresponds to GM2 gangliosidosis type 2 and different variants have been identified in various breeds. In the domestic short-haired cat, a 25 base pair inversion (c.1467_1491inv) was identified at the 3` end of the HEXB gene, which introduces a premature stop codon and causes a significant decrease in protein levels.

Most affected breeds

Domestic Shorthair Cat

Bibliography

Bradbury AM, Peterson TA, Gross AL, et al. AAV-mediated gene delivery attenuates neuroinflammation in feline Sandhoff disease. Neuroscience. 2017 Jan 6