HETEROZYGOUS CARRIERS OF PHENYL- KETONURIA DETECTED BY PHENYLALANINE TOLERANCE TESTS

The molecule whose dysfunction is responsible for the hereditary disease of phenylketonuria is the liver enzyme concerned with the oxidation of phenylalanine. Inactivity of this enzyme results in the high blood levels of phenylalanine, the excretion of phenylpyruvic acid, and mental deficiency. Genetic studies have established this condition to be completely recessive, and no related mental or biochemical abnormalities have been found in the heterozygous parents or siblings of the patients. Pauling’s introduction of the term “molecular disease” suggests, however, that the fraction of enzyme stemming from the abnormal gene in the heterozygotes should be defective. This prediction is supported by the present findings from phenylalaninetolerance tests that known heterozygotes of phenylketonuria have lower capacities for metabolizing phenylalanine than do normal people. Plasma levels of L-phenylalanine were determined one, two, and four hours after oral doses of 0.1 g. of L-phenylalanine per kg. body weight, given after an overnight fast, in 19 heterozygous individuals (parents of proved phenylketonuric patients) and an equal number of normal adult controls. L-phenylalanine was measured by a modification of the bacterial decarboxylase method of Udenfriend and Cooper. The fasting plasma phenylalanine levels taken before the test in all individuals were within the range of 0.03 to 0.16 μmol/ml. The phenylalanine levels in the heterozygotes during the test were on the average about twice that of 190 Yi-Yung Hsia, Driscσll, Troll and Knox (648) the controls at each of the hourly intervals. The distinction between the groups was particularly clear at the fourth hour, and by comparison of the area under the tolerance curve. The test was repeated on several individuals from each group with highly reproducible results. Table 1. Plasma L-Phenylalanine Levels after L-Phenylalanine Ingestion. Values given are the means + the standard deviation, and the ranges, in μmols per ml. of plasma, found in 19 adult controls and 19 parents (heterozygotes) of known phenylketonuric patients. Hours after Dose 2