Phenylketonuria: Old disease, new approach to treatment

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Abstract
If one were to construct a fantasy about a human genetic disease for which all is known and a cure available, phenylketonuria (PKU) is likely to come to mind. In what other genetic disorder have the following been accomplished: characterization and mapping of the relevant gene (1, 2); identification of the mutations (3); determination of enzyme structure and functional sites (4); identification of the clinical (5) and biochemical characteristics (6); correlations of genotype with phenotype (7); prenatal diagnosis (8); recognition of the teratogenic risks in the maternal condition (9); development of treatment that prevents mental retardation (10); production of an animal model that mimics the biochemical phenotype and expresses much of the clinical phenotype (11); and, as if these were not enough, establishment of newborn screening for the disease so that virtually all affected individuals in the developed world receive preventive treatment (12)? It is an astounding story, the standard to which all genetic disease is held. Nevertheless, there is another side to the story. To prevent mental retardation, affected individuals must maintain a strict and difficult diet, probably for life (13). This requirement can so alter the normal lifestyle that dietary compliance and its concomitant metabolic control too often suffer, the result being clinical complications such as reduced cognitive abilities (14), neuropsychological dysfunction (15), and emotional disturbance (16, 17). Less than optimal metabolic control during pregnancy produces offspring with birth defects (18). Consequently, less onerous treatment for PKU is sorely needed, and the paper by Sarkissian et al. published in this issue of the Proceedings (19) suggests that this might not be far away. They show that the blood phenylalanine concentration in the phenylalanine hydroxylase (PAH)enu2 mouse model of human PKU can be reduced substantially by the administration of phenylalanine ammonia lyase (PAL), a nonmammalian …