GM2 Gangliosidosis (GM2A gene)

GM2 gangliosidosis is a lysosomal deposition disease that results in the accumulation of GM2 gangliosides in various tissues, leading to progressive deterioration of the nervous system affecting coordination and movement ability. The genetic variant responsible is found in the GM2A gene encoding the GM2 activator protein required for the degradation of GM2 ganglioside.

Symptoms

GM2 gangliosidosis presents in cats around 14 months of age, initially with symptoms of motor incoordination and an exaggerated startle response to high-pitched noises. With disease progression, gait difficulties, ataxia and intention tremors develop. In advanced stages, cats may become blind and experience feeding difficulties.

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.

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, or Tay-Sachs disease type AB, is a lysosomal storage disease caused by deficiency of the activator protein GM2A, essential for the degradation of GM2 ganglioside in cells. The alpha and beta subunits of beta-N-acetylhexosaminidase and GM2 activator protein are involved in the catabolism of GM2 ganglioside. If any of these three participants is defective, GM2 ganglioside accumulates in the lysosomes, causing progressive and incurable deterioration of the central nervous system. This disease occurs in several forms depending on the gene affected: variant B (deficiency of the alpha subunit of beta-N-acetylhexosaminidase), variant 0 (deficiency of the beta subunit of beta-N-acetylhexosaminidase), and variant AB (deficiency of the activator protein GM2A). The AB variant, identified in affected feline models, is characterized by a 4-base pair deletion (c.516_519del) in the GM2A gene, affecting the crucial hydrophobic binding capacity of the activator protein.

Most affected breeds

Not specified

Bibliography

Martin DR, Cox NR, Morrison NE, et al. Mutation of the GM2 activator protein in a feline model of GM2 gangliosidosis. Acta Neuropathol. 2005 Nov