Early studies suggested that African American children (AA) with galactosemia developed fewer symptoms than white galactosemic children (W). The biochemical and molecular basis for this disparity has not been clarified. Galactosemia is caused by deficiency of galactose-1-phosphate uridyl transferase (GALT). In this study, GALT activity was measured in the RBC and WBC of 10 W and 8 AA. WBC activities were measured because WBC unlike RBC make GALT protein and may therefore more accurately reflect GALT activity in other tissues. GALT protein content was determined by Western blot. Mutational analysis of the gene was undertaken to determine the presence of Q188R (common mutation) and S135L (found only in AA) alleles. S135L was present in 9/16 AA alleles.

RBC activity was similar (p=0.61) in W vs AA (0.26 +/- 0.28 vs 0.33 +/- 0.25); (normal 17-26 umol/h/g Hgb) and no correlation of RBC activity with genotype was observed. WBC GALT activity was not statistically different in W vs AA. However, S135L homozygotes (n=4) had significantly greater WBC activity(13 +/- 6) vs Q188R homozygotes (2 +/- 2; p=0.011, n=4) or all other genotypes(1 +/- 2; p<0.001, n=8). Compound heterozygotes (S135L/X) had intermediate activity (3 +/- 4, n=4). The S135L allele, prevalent in AA, appears to confer about 5% of normal GALT activity in WBC. GALT protein was undetectable in RBC or WBC by Western blot except for the WBC with 1 or 2 S135L alleles where it was reduced but readily detectable. The data suggest that the protein encoded by the S135L allele is unstable being detectable in WBC which are short-lived but not in RBC which survive months. The S135L GALT mutation appears to be responsible for milder symptoms in a subset of AA by coding for a protein with decreased stability in WBC (and, by inference, in other tissues where the protein functions). 6 of 8 AA in this study were not homozygous for S135L and therefore race alone should not be used to predict galactose tolerance or long-term prognosis. Molecular analysis is indicated in guiding management in African Americans with galactosemia.