The mutations in Ashkenazi Jews with adult G_M2 gangliosidosis, the adult form of Tay-Sachs disease

The adult form of Tay-Sachs disease, adult G_M2 gangliosidosis, is an autosomal recessive disorder that results from mutations in the a chain of β-hexosaminidase A. This disorder, like infantile Tay-Sachs disease, is more frequent in the Ashkenazi Jewish population. A point mutation in the α-chain gene was identified that results in the substitution of Gly ²⁶⁹ with Ser in eight Ashkenazi adult G_M2 gangliosidosis patients from five different families. This amino acid substitution was shown to depress drastically the catalytic activity of the a chain after expression in COS-1 cells. All ofthese patients proved to be compound heterozygotes of the allele with the Gly to Ser change and one of the two Ashkenazi infantile Tay-Sachs alleles. These findings will aid in the diagnosis and understanding of β-hexosaminidase A deficiency disorders.