Ashkenazi-Jewish and non-Jewish adult G_M2 gangliosidosis patients share a common genetic defect

The adult form of Tay-Sachs disease, adult G_M2 gangliosidosis, is an autosomal recessive neurological disorder caused by a partial deficiency of β-hexosaminidase A. We had previously identified, in Ashkenazi-Jewish adult G_M2 gangliosidosis patients, a Gly²⁶⁹→Ser mutation in the β-hexosaminidase α-subunit. All of the Ashkenazi patients were found to be compound heterozygotes with an allele containing the Gly²⁶⁹→Ser mutation together with one of the Ashkenazi infantile Tay-Sachs alleles. We have now found the same Gly²⁶⁹→Ser mutation in six adult G_M2 gangliosidosis patients from four different non-Jewish families. Genomic DNA from three of the patients, two of whom were brothers, exhibited a hybridization pattern consistent with homozygosity for the Gly²⁶⁹→Ser mutation. The remaining non-Jewish patients were compound heterozygotes of the Gly²⁶⁹→Ser mutation together with an unidentified α-subunit mutation. The results demonstrate that individuals homozygous for the Gly²⁶⁹→Ser change can be clinically affected. The same Gly²⁶⁹→Ser mutation in both the Ashkenazi and non-Jewish patients may be the result of a common ancestor, given that the ancestry of these non-Jewish patients, like the Ashkenazim, can be traced to eastern Europe.