Molecular Analysis of the Inheritance of Phenylketonuria and Mild Hyperphenylalaninemia in Families with Both Disorders

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Abstract
Clinical phenylketonuria and mild hyperphenylalaninemia represent two different phenotypes of phenylalanine hydroxylase deficiency. To determine the genetic relation between these two phenotypes, we studied two families in which one member had phenylketonuria and other members had mild hyperphenylalaninemia. We identified Restriction-Fragment Length polymorphisms that differentiated the four phenylalanine hydroxylase alleles in each family. Phenylketonuria and mild hyperphenylalaninemia were found to be allelic; certain pairs of alleles induced the more severe phenylketonuria phenotype, and other pairs induced the less severe hyperphenylalaninemia phenotype. Several of the alleles that were identified can contribute to either phenylketonuria or mild hyperphenylalaninemia. These results demonstrate that there are multiple and distinct mutations in the phenylalanine hydroxylase gene, with different levels of severity, and that various combinations of the mutant alleles can result in different phenotypes of the metabolic disorders of hyperphenylalaninemia. (N Engl J Med 1986; 314:1276–80.)