GM2 activator deficiency, also known as GM2 gangliosidosis AB variant is caused due to biallelic pathogenic variants in the GM2A gene. The GM2A gene encodes the GM2 activator protein- a 22-kDa glycoprotein that is an essential cofactor for functional activity of β-hexosaminidase A.

The GM2 activator protein binds to GM2 gangliosides to form a complex, which then subsequently binds to β-hexosaminidase A, ultimately resulting in enzymatic hydrolysis of GM2 ganglioside GM3 ganglioside. Thus, a defective GM2 activator protein leads to failure of GM2 ganglioside degradation, ensuing in their abnormal accumulation, particularly in the neuronal cells and spinal cord.

To date, 14 individuals have been reported with GM2 activator deficiency. Most of them have been infantile form with onset of symptoms between four months to one year of age. Recently, few cases with juvenile onset and a single case of adult onset has been reported.

The mode of inheritance of GM2A is autosomal recessive. Thus, parents of an affected child are presumed to be heterozygous (carrier) for the variant in the GM2A gene. Hence, molecular testing is recommended in the parents to confirm the heterozygous status. If parental carrier status is confirmed, each sib of the affected child has a 25% chance of being affected, 50% chance of being an asymptomatic heterozygote/carrier and 25% chance of inheriting neither of the pathogenic variants.
Heterozygotes or carriers are asymptomatic and do not develop any clinical manifestations of the disease.