GM2-gangliosidosis is a group of neurological disorders resulting from 
genetically defective catabolism, and consequent abnormal accumulation, of 
GM2-ganglioside. Three major types are distinguished: the B variant (Tay-Sachs 
disease), the O variant (Sandhoff disease), and the AB variant, caused by 
genetic abnormalities in the genes coding for the beta-hexosaminidase alpha- or 
beta-subunit, or the GM2-activator protein, respectively. A number of gene 
abnormalities responsible for Tay-Sachs disease have already been identified and 
the correlation between the beta-hexosaminidase alpha gene abnormality and the 
clinical phenotype has been explained in many cases. In the severest phenotype 
of Tay-Sachs disease (infantile form), mRNA of beta-hexosaminidase alpha subunit 
is not produced or is unstable such as in French Canadian patients or in Jewish 
patients with infantile Tay-Sachs disease, or the polypeptide does not have any 
catalytic activities because of the alteration of glycosylation such as the 
mutation of Glu482-to-Lys found in a Italian patient or the altered structure of 
polypeptide. The mutation identified in a large majority of the Japanese 
infantile Tay-Sachs disease patients, which is a G-to-T substitution at 3'-end 
of intron 5, generates a short mRNA with complete skipping of exon 6 and a 
polypeptide lacking 34 amino acids is generated but catalytically inactive. On 
the other hand, some active alpha beta dimers must be generated in patients with 
milder phenotypes of Tay-Sachs disease such as Gly269-to-Ser mutation in an 
adult form. Some of the mutations appear in high frequency among certain ethnic 
groups such as Ashkenazi Jewish patients and French Canadians.(ABSTRACT 
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