GM2 gangliosidoses

Reuben Matalon MD PhD (Dr. Matalon of University of Texas Medical Branch has no relevant financial relationships to disclose.)
Lisvania M Delgado BS (Ms. Delgado of University of Texas Medical Branch has no relevant financial relationships to disclose.)
Kacey Hart BS (Ms. Hart of University of Texas Medical Branch has no relevant financial relationships to disclose.)
Raphael Schiffmann MD, editor. (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released February 17, 1994; last updated February 4, 2016; expires February 4, 2019

This article includes discussion of GM2 gangliosidoses, familial amaurotic idiocy, HEXA deficiency, HEXB deficiency, Sandhoff disease, Tay-Sachs disease, B variant of GM2 gangliosidoses, B1 variant of GM2 gangliosidoses, O variant of GM2 gangliosidoses, and AB variant of GM2 gangliosidoses. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

GM2 gangliosidoses are caused by beta-hexosaminidase deficiency. There are 2 major phenotypes: Tay-Sachs disease, caused by beta-hexosaminidase A deficiency, and Sandhoff disease, caused by beta-hexosaminidase A and B deficiency. In this article, the authors discuss approaches to the diagnosis and treatment of GM2 gangliosidosis. Different phenotypes require special diagnostic approaches. Different phenotypes require special diagnostic approaches. Treatment of GM2 gangliosidosis with substrate synthesis inhibition, enzyme replacement therapy with highly phosphomannosylated enzyme, and pharmacological chaperones are currently being investigated, and new chaperones have been added to the trials.

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 risk populations is successful in prevention.

Historical note and terminology

The first clinical description of what is now known as GM2 gangliosidosis occurred in 1881 when a British ophthalmologist, Warren Tay, described a peculiar bright-red macula in a child with mental and physical retardation (Tay 1881). Bernard Sachs later described the clinical findings and noted the enlarged pyramidal neurons in this disorder, which he called "familial amaurotic idiocy" (Sachs 1887). The ophthalmologist who examined Sachs' patient used the expression, “cherry-red macula.” The identification of a novel group of sialic acid–containing glycolipids in brains of these patients led to the initial biochemical understanding of Tay-Sachs disease (Klenk 1942). These acidic glycosphingolipids were called "gangliosides" because their highest concentrations in normal brain were found in ganglion cells. GM2 ganglioside is the primary ganglioside stored in Tay-Sachs disease (Svennerholm 1962). The enzymatic defect in Tay-Sachs disease, a deficiency of the lysosomal enzyme beta-hexosaminidase A, was identified in 1969 (Okada and O'Brien 1969). Deficiency of beta-hexosaminidase A and B became known as “Sandhoff disease” (Sandhoff et al 1968). The genes for each of the beta-hexosaminidase subunits were found to map to different chromosomes; the alpha subunit, encoded by HEXA, localizes to chromosome 15 and the beta subunit, encoded by HEXB, maps to chromosome 5 (Boedecker et al 1975; Chern et al 1977). Knowledge about the molecular genetic aspects of the beta-hexosaminidase enzymes began after HEXA was cloned by Myerowitz and associates (Myerowitz et al 1985) and was further advanced when the HEXA and HEXB genomic structures were characterized (Proia and Soravia 1987; Proia 1988).

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