CHARACTERIZATION OF UNUSUAL HEXOSAMINIDASE-A (HEX-A) DEFICIENT HUMAN MUTANTS

Abstract

Two families with unusual hexosaminidase A (HEX A) mutations are described. In one, the proband had the Tay-Sachs disease phenotype with considerable HEX A activity. In the 2nd, the proband was phenotypically normal with absent HEX A activity. Activities using ganglioside GM2 as substrate demonstrate markedly reduced activities in the 1st case and half-normal activities in the 2nd. Pedigree analysis indicate the presence of 2 different mutations. In the 1st, the proband appears to be an allelic compound HEX A 2-4 where mutation HEX A 4 leads to a diminution of HEX A activity against GM2 but not for the synthetic substrate, 4-methylumbelliferyl-.beta.-D-N-acetylglucosaminide, with HEX A 2 being the Tay-Sachs disease (or similar) mutation. In the 2nd family, the proband is an allelic compound HEX A 2-5 where mutation HEX A 5 leads to a diminution of HEX A activity against the synthetic substrate, 4-methylumbelliferyl-.beta.-D-N-acetyl-glucosaminide, but not for GM2. The presence of either mutation will lead to false-negative (HEX A 4) or false-positive (HEX A 5) assignments of heterozygosity or homozygosity for GM2 gangliosidosis when synthetic substrates are employed. In both families, GM2 N-acetyl-.beta.-D-galactosaminidase activity in fibroblasts was an accurate determinant of phenotype.