CHARACTERIZATION OF 2 STOP CODON MUTATIONS IN THE GALACTOSE-1-PHOSPHATE URIDYLTRANSFERASE GENE OF 3 MALE GALACTOSEMIC PATIENTS WITH SEVERE CLINICAL MANIFESTATION

Classical galactosemia, which is caused by deficiency of galactose-1-p hosphate uridyltransferase, is characterized by acute problems of hepa tocellular dysfunction, sepsis, cataracts and failure to thrive. Galac tose limitation reverses these symptoms immediately; however, the long -term complications, such as mental retardation and ovarian failures a re major problems in most of these patients. In order to investigate t he molecular basis for phenotype variation in galactosemia, we have sc reened the most common mutation in the GALT gene, Q188R. We have furth er examined those patients who are heterozygous for Q188R or negative for this mutation by SSCP analysis and direct sequencing. In three mal e patients, we have identified, for the first time, two stop-codon mut ations in the GALT gene, G212X (exon 7) and E340X (exon 10). Two patie nts of 8 and 28 years of age, respectively, who are compound heterozyg otes for Q188R and G212X, have severe mental retardation and their gen eral clinical condition is more severe than that of patients with miss ense mutations. The third patient, who is 8 years of age and who is ho mozygous for E340X, the N314D polymorphism and a silent substitution L 218L, presents with a relatively normal physical and mental condition to date.