Association between Minihaplotypes and Mutations at the Phenylalanine Hydroxylase Locus in Latvian Phenylketonuria Patients

Phenylketonuria (PKU; OMIM 261600) is one of the most common inborn errors of metabolism in Caucasians, with a frequency of 1 : 10 000 newborns in Europe. It is an autosomal recessive trait caused by a deficiency of hepatic phenylalanine hydroxylase (PAH; 1 phenylalanine 4-monooxygenase, EC 1.14.16.1), the main clinical signs of which are impaired cognitive development and function (Eisensmith et al., 1995a; Scriver et al., 1995). PAH catalyses the irreversible hydroxylation of phenylalanine (Phe) to tyrosine. Deficiency of this enzyme results in a high concentration of Phe and its metabolites, such as phenylpyruvate, phenyllactate, and phenylacetate, collectively known as phenylketones, which are neurotoxic, particularly during the first years of life (Nyhan et al., 2005; Albrecht et al., 2009). The neurotoxicity effect was suggested by a Norwegian physician and biochemist, Asbjörn Fölling, in 1934 and was later substantiated by George Jervis in 1947 (Jervis, 1947).