GM2 gangliosidoses

The GM2 gangliosidoses are a group of related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This enzyme catalyzes the biodegradation of fatty acid derivatives known as gangliosides. The diseases are better known by their individual names.

Beta-hexosaminidase is a vital hydrolytic enzyme, found in the lysosomes, that breaks down lipids. When beta-hexosaminidase is no longer functioning properly, the lipids accumulate in the nervous tissue of the brain and cause problems. Gangliosides are made and biodegraded rapidly in early life as the brain develops. Except in some rare, late-onset forms, the GM2 gangliosidoses are fatal.

All three disorders are rare in the general population. Tay-Sachs disease has become famous as a public health model because an enzyme assay test for TSD was discovered and developed in the late 1960s and early 1970s, providing one of the first "mass screening" tools in medical genetics. It became a research and public health model for understanding and preventing all autosomal genetic disorders.

Tay-Sachs disease, AB variant, and Sandhoff disease might easily have been defined together as a single disease, because the three disorders are associated with failure of the same metabolic pathway and have the same outcome. Classification and naming for many genetic disorders reflects history, because most diseases were first observed and classified based on biochemistry and pathophysiology before genetic diagnosis was available. However, the three GM2 gangliosidoses were discovered and named separately. Each represents a distinct molecular point of failure in a subunit that is required for activation of the enzyme.

Tay-Sachs disease
Tay-Sachs disease is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. The disease results from mutations on chromosome 15 in the HEXA gene encoding the alpha-subunit of the lysosomal enzyme beta-N-acetylhexosaminidase A. The most common form, infantile Tay-Sachs disease, is usually fatal by early childhood.

Sandhoff disease
Sandhoff disease is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. The disease results from mutations on chromosome 5 in the HEXB gene, critical for the lysosomal enzymes beta-N-acetylhexosaminidase A and B. Sandhoff Disease is clinically indistinguishable from Tay-Sachs Disease. The most common form, infantile Sandhoff disease, is usually fatal by early childhood.

AB variant
GM2-gangliosidosis, AB variant is a rare, autosomal recessive metabolic disorder that causes progressive destruction of nerve cells in the brain and spinal cord. Mutations in the GM2A gene cause AB variant. The GM2A gene provides instructions for making a protein called the GM2 activator. This protein is a cofactor that is required for the normal function of beta-hexosaminidase A. The disease is usually fatal by early childhood.