Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North Americans

The diagnosis of hereditary fructose intolerance (HFI) presents a difficult challenge that often involves procedures of high risk to the patient. A relatively noninvasive method that involves molecular analysis of common alleles would offer a decided advantage. The molecular defects in the aldolase B gene were studied in 31 HFI subjects (23 pedigrees, 47 apparently independent alleles) from the United States and Canada. We screened for the three most common European alleles by direct hybridization of allele-specific oligodeoxyribonucleotides (ASOs) to portions of the aldolase B gene that were amplified by PCR. Fifty-five percent of mutant North American alleles were A149P (ala149 → pro), the most common mutation in the European population. The other two alleles, A174D (ala174 → asp) and N334K (asn334 → lys), represent 11 and 2% of North American alleles, respectively. Nine patients, representing 32% of independent alleles studied, had an HFI allele that was not of this common missense class. This North American allele distribution is significantly different from that in Europe, where 13% of HFI alleles are not of this type. Preliminary screening of amplified DNA with this set of ASOs indicated that 80% of symptomatic HFI patients can be identified in the American population by this simple genetic test.