Adult GM2 gangliosidosis is a rare autosomal recessive disease with widely varying neurological and psychiatric manifestations. It is caused by marked deficiency, but not total absence, of beta-hexosaminidase (Hex) A, due to a single base change in the alpha-subunit gene of Hex, resulting in a substitution of Ser for Gly at position 269 in the alpha-subunit of the enzyme. The same mutation was identified in all investigated patients, most of whom are Ashkenazi Jews. Among previously studied non-Jewish patients of unrelated families this mutation appears either homozygously or in compound heterozygosity with an unidentified alpha-subunit mutation, whereas all Ashkenazi patients are compound heterozygotes. In all but one of them the other mutation is one of the Ashkenazi infantile Tay-Sachs alleles, while in one 76-year-old woman with very mild neurological symptoms, it is an unidentified alpha-subunit mutation. At present, the little correlation that seems to exist between these different genotypes and the severity of the disease poses a serious dilemma for genetic counselors.