Metabolic studies on two patients with nonhepatic tyrosinemia using deuterated tyrosine loads

Metabolic studies on two patients with defects in the tyrosine oxidation pathway are reported. Serum tyrosine was greatly elevated in both patients (1.37 and 1.52 mmol/liter, respectively) and both excreted large quantities of p-hydroxyphenylacetic acid, p-hydroxyphenyllactic acid, and p-hydroxyphenylpyruvic acid. Deuterated tyrosine loads were administered to both patients, before and after lowering of the serum tyrosine concentration by dietary treatment, and to a normal adult control subject. In one patient the excretion of the deuterated (D2)-tyrosine load was more than 300 times that found in the control subject whether the test was done at high or low serum tyrosine level and the pattern of metabolites indicated a persistent defect in p-hydroxyphenylpyruvic acid oxidase. Enzyme assays on needle liver biopsy supported this finding. In the second patient excretion of the D2 label was 300 times that of the control at high serum tyrosine levels, but only 5 times normal at low serum tyrosine levels. This finding was interpreted as indicating substrate inhibition of p-hydroxyphenylpyruvic acid oxidase. The primary defect has not been established in this patient, but the findings are compatible with a defect in hepatic-soluble tyrosine aminotransferase.