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  • Updated 03.15.2023
  • Released 02.17.1994
  • Expires For CME 03.15.2026

GM2 gangliosidoses



The GM2 gangliosidoses are a group of lysosomal storage diseases characterized by a defect in ganglioside metabolism due to a deficiency of the catabolic enzyme beta-hexosaminidase. This leads to accumulation of GM2 ganglioside within the lysosome. Full catabolic activity of beta-hexosaminidase requires interaction of three molecules: the A and B subunits of gangliosides and the GM2 activator protein, which functions as a cofactor for the enzyme. Each of these molecules are encoded by a different gene, but defects in any of these three can cause GM2 gangliosidoses. Three diseases have been described, corresponding to mutations in one of these three genes: Tay-Sachs disease (caused by beta-hexosaminidase A deficiency, OMIM 272800), Sandhoff disease (caused by beta-hexosaminidase B deficiency, OMIM 268800), and the AB variant (deficiency of the GM2 activator protein, OMIM 272750). Although the precise pathophysiology in each disease state varies, the clinical presentation and course of progressive neurologic decline is nearly identical among the three types. Each subtype can be further characterized by age of onset (infantile, late infantile, juvenile, and adult-onset phenotypes), which corresponds to residual enzyme activity. New treatments for GM2 gangliosidosis are being explored through clinical trials and preclinical models.

Key points

• Tay-Sachs disease and Sandhoff disease are lysosomal storage disorders.

• Tay-Sachs disease is caused by a deficiency of beta-hexosaminidase A.

• Sandhoff disease is caused by a deficiency of beta-hexosaminidase A and B.

• Carrier detection in at risk populations is successful for prevention.

• A gene therapy clinical trial is underway for infantile-onset GM2 gangliosidosis.

Historical note and terminology

The first clinical description of what is now known as GM2 gangliosidosis occurred in 1881, when British ophthalmologist Warren Tay described a peculiar bright-red macula in a child with developmental delay. Bernard Sachs later described the clinical findings and noted enlarged pyramidal neurons in this disorder, which he called "familial amaurotic idiocy." It was the ophthalmologist who also examined Sachs’s patient who termed the description, “cherry-red macula.”

In the 1930s, Ernst Klenk discovered gangliosides within the postmortem brain tissues of patients with “amaurotic idiocy” (52). It was not until 1969 that accumulation of ganglioside within the brain was found to be secondary to deficiency of the lysosomal enzyme beta-hexosaminidase A (42). Myerowitz and colleagues isolated the cDNA clone containing the coding sequence for beta-hexosaminidase A in 1985. The HEXA and HEXB genomic structures were characterized in 1987 (39; 48; 47).

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