Discrimination of heterozygotes for phenylketonuria, persistent hyperphenylalaninemia and controls by phenylalanine loading

Abstract

Hyperphenylalaninemia commonly is the result of an autosomal recessively inherited deficiency of the liver enzyme, phenylalanine hydroxylase [1,2]. Classical phenylketonuria (PKU) is caused by absent activity of this enzyme. Persistent hyperphenylalaninemia (PHP), the most common of the non-PKU variants of hyperphenylalaninemia, is secondary to a significant, although not total, deficiency of phenylalanine hydroxylase activity [l]. Determination of PKU heterozygous individuals would be very useful for providing accurate genetic counseling. for siblings, offspring, spouses and other relatives of PKU patients. However, since direct assay of enzyme activity requires liver biopsy [l], several methodologies have been devised to assess carrier status in this disorder [3-151. Most of these methods are based on the evaluation of phenylalanine (P) and/or tyrosine (T) blood levels as a means of classifying individuals as carriers or noncarriers for PKU. In fact, the development of oral P loading tests for carrier detection was first described thirty years ago [3]. Some of the most widely used methods to date are based on the analysis of P and T blood levels following an oral [3-5,7] or intravenous [8,9] P load or a deuterated P load [lo]. Several investigators have evaluated P and T levels in midday, semifasting blood [11,13] or in samples obtained after an overnight fast [12]. Discriminant analysis was used in some of the loading studies to evaluate the data [ll-131. A number of factors have been shown to modify P or T metabolism and thus complicate heterozygote detection [16,17] including oral contraceptives, pregnancy, age, sex and obesity.