GM2 gangliosidosis in Burmese cats

Gangliosidoses are a class of inherited diseases known as „lysosomal storage diseases".

Lysosomes are the digestive system of the cell and responsible for breaking down complex chemicals so that they can be recycled.

GM2 gangliosidoses are progressive, fatal neuropathic lysosomal storage disease resulting from a deficiency of β-N-acetylhexosaminidase activity and causes accumulation of GM2 gangliosides in brain tissue.

There are several types of mutations that cause gangliosidoses in various cat breeds. The first signs of the gangliosidoses are tremors of head and hind limbs, unsteady gait, wide stance and inappropriate falling. The onset and rate of progression of clinical signs vary with the specific type of mutation. GM2 in Burmese cats has an early onset with severe signs by 3 months. Late signs include complete loss of hind limb use, blindness or epileptic like seizures. The kittens of Burmese cats affected by GM2 hardly survive for 6 months.

In Burmese cat breeds, 15 base pairs deletion was revealed that includes splice acceptor site of intron 11. If the mutation is present, it generates incorrect splicing of RNA, removal of exon 12 from mRNA and a premature stop codon. In addition, this deletion activates new splice acceptor sites in RNA generating new transcripts which are not present in healthy cats (Bradbury et al., 2009).

GM2 is an autosomal recessive disorder. The disease affects cats with P/P (positive / positive) genotype only. Cats with P/N (positive /negative) genotype are clinically without any symptoms. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended.

The lysosomal enzyme critical for the development of GM2 is β-N-acetylhexosaminidase, responsible for removal of the end of N-acetyl-galaktosamine from GM2 ganglioside. The functional hexosaminidase activity requires for its correct function coordinated action of three various proteins, non-hydrolytic GM2 activator and two hydrolytic sub-units a and b. The sub-units may combine to form the two major hexosaminidase isozymes, each with different substrate specificity -- HexB (bb) and HexA(ab). The defect of one out of three necessary proteins causes one type of GM2 gangliosidosis. The AB-variant is caused by non-functional GM2 activator, the B-variant by non-functional a-subunit and 0-variant is caused by non-functional b-subunit.

References:
A. M. Bradbury et al.: Neurodegenerative lysosomal storage disease in European Burmese cats with hexosaminidase b-subunit deficiency, Molecular Genetics and Metabolism, 2009