Thermal activation of hexosaminidase A in a genetic compound with Tay-Sachs disease

Increase in total hexosaminidase activity has been observed during heat treatment of serum and leukocyte specimens from a 1-year-old boy with cherry-red spot and severe and progressive mental and motor deterioration. The activity increased 40% in the first 40-70 min of incubation at 50 degrees C and pH 4.3, but declined thereafter and was only slightly above the initial activity in the final 2-3 h of incubation. Heat treatment of specimens from family members revealed very reduced rates of inactivation of hexosaminidase in the proband's father and some paternal relatives, whereas those of the mother and some maternal relatives were indistinguishable from those of Tay-Sachs carriers. Mixing experiments with enzyme preparations from the proband, normal controls and patients with Tay-Sachs disease resulted in additive values and did not support the possibility of inhibitor- or activator-related defect. Fractionation of heat-treated samples by ion exchange chromatography and electrophoresis, as well as examination of the separated fractions for their thermostability, have shown that hexosaminidase A is the activated component and hexosaminidases B, I1 and I2 are not affected. These findings suggest that the patient is a genetic compound and the apparent thermal activation is probably due to formation of hexosaminidase A from altered alpha-subunits produced by the paternal mutant alpha-allele and beta-subunits produced by the normal beta-alleles.