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  • Updated 05.25.2019
  • Released 02.17.1994
  • Expires For CME 05.25.2022

GM2 gangliosidoses

Introduction

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 (58). Bernard Sachs later described the clinical findings and noted the enlarged pyramidal neurons in this disorder, which he called "familial amaurotic idiocy" (52). 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 (33). 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 (56). The enzymatic defect in Tay-Sachs disease, a deficiency of the lysosomal enzyme beta-hexosaminidase A, was identified in 1969 (45). Deficiency of beta-hexosaminidase A and B became known as “Sandhoff disease” (53). 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 (08; 12). Knowledge about the molecular genetic aspects of the beta-hexosaminidase enzymes began after HEXA was cloned by Myerowitz and associates (43) and was further advanced when the HEXA and HEXB genomic structures were characterized (49; 48).

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