SCIENCE, MEDICINE AND PHENYLKETONURIA

Science addresses ignorance; medicine uses facts. The scientific appro ach to phenylketonuria (PKU) led to the discovery of its causes, both ultimate (allelic heterogeneity at the PAH locus) and proximate (dieta ry phenylalanine), the proximal phenotype (phenylalanine hydroxylase d eficiency), the associated metabolic phenotype and the major distal ph enotype (impaired cognitive development and neuropsychological functio n) for which the pathogenesis is still being investigated. By applying knowledge through newborn screening, early diagnosis and treatment, t he brain disease of PKU has been greatly ameliorated. The population a pproach, which converted incidence into cases, revealed genetic hetero geneity in hyperphenylalaninemia involving four other loci, controllin g cofactor (BH4) synthesis and recycling, and non-random geographic di stribution of mutant PAH alleles of which more than 170 were known in April 1994. Various mechanisms including founder effect, genetic drift , hypermutability and selection (perhaps) explain the polymorphic aggr egate frequency (approximate to 0.01) and spectrum of PKU mutations in human populations.