Tay-Sachs disease (TSD), an autosomal recessive neurodegenerative condition, is the result of a deficiency of
beta-hexosaminidase A (
hex A). Heterozygotic individuals are screened by analysis for
hex A and
hex B activities; the percent of
hex A is the critical determinant of carrier vs noncarrier status. Most laboratories use a heat-inactivation assay that exploits the differential thermolability of the
isoenzymes. However, we have found a reciprocal relation between the apparent leukocyte
hex A activity and the amount of the sample used in the assay; i.e., a significant increase in the percent of
hex A activity with decreasing amounts of sample. Three sets of data indicate that this phenomenon was caused by an effect on the
hex B isoenzyme and not on
hex A. This variation in
hex A activity with sample amount was not observed when a
hex A-specific substrate was used. This phenomenon was also not seen in assays of leukocytes from carriers for
Sandhoff disease, a condition associated with a reduction in the amount of
hex B. Finally, when leukocytes from a TSD homozygote, containing almost no
hex A, were analyzed, marked increases in the percent of
hex A were observed with decreasing sample concentrations. These data indicate that misdiagnoses could result from variations in sample concentrations used for TSD carrier testing and support the view that the leukocyte concentrations used for these assays should be standardized.