MAJOR MILESTONES IN THE HISTORY OF PHENYLKETONURIA
(excerpt from the volume Aminoacidopatii: aspecte genetice, biochimice și clinice, authors: Romana Vulturar și Mircea Cucuianu, Ed. Casa Cărții de Știință, 2011)
In the 1930s, phenylketonuria (PKU) emerged increasingly clearly as a disease associated with mental retardation and a biochemical profile altered from normal; this profile was explained by the Norwegian physician and biochemist Asbjörn Fölling in 1934 and the British physician Penrose in 1935 by a homozygous mutant phenotype for a condition transmitted according to Mendelian law of autosomal recessive type. As a result, heterozygotes are asymptomatic with normal intelligence, hyperphenylalninemia, i.e. phenylketonuria and mental retardation occurring only in homozygotes. The name "phenylketonuria" was given by Penrose and Quastel in 1937 to link the disease to the metabolic phenotype. In the 1940s, Dr Penrose presented the characteristics and hypotheses of phenylketonuria to the University of London; this is considered an important moment in the early research into the disease.
In the 1950s, hepatic phenylalanine hydroxylase (PAH) enzyme activity was shown to be deficient in PKU patients (Jervis, 1953), and Bickel et al. in 1954, Woolf et al. in 1955, and Armstrong and Tyler in 1955 showed that the metabolic phenotype in PKU could be treated by a phenylalanine-restricted diet, with the potential to prevent mental retardation. As mentioned, phenylketonuria provided a new model for the medical approach to hereditary diseases.
In the 1960s, a simple laboratory test was developed that meets the requirements of a "screening" for newborns (Guthrie and Susi, 1963); this program was expanded worldwide to allow early diagnosis and the institution of therapy to prevent mental retardation in PKU patients. Thus, PKU became a prototype for population-based genetic "screening" (National Academy of Sciences, Committee for the Study of Inborn Errors of Metabolism, 1975) with importance in public health programs.
In the 1970s, Danks et al. noted the description of patients who fell into the form of the disease called "malignant hyperphenylalaninemia". The work of Kaufman S. ("Phenylalanine hydroxylation cofactor in phenylketonuria", in Science 1958, 12, 128(3337):1506-8 and "The structure of Phenylalanine hydroxylation cofactor", in Proc. Natl. Acad. Sci. USA, 1963, 50:1085) on the importance of the catalytic cofactor required for phenylalanine hydroxylation. The discovery of this new form of PKU revealed the presence of abnormalities affecting both the synthesis and recycling pathways of BH4. Phenylketonuria is now regarded as "a symbol of human biochemical genetics".
In the 1980s, genetic advances made it possible to locate the PAH gene on chromosome 12 and catalogue it in the GenBank database. David Konecki et al. later obtained the complete sequence of the PAH gene.
In the 1990s, a PAH Mutation Analysis Consortium was formed and more than 520 types of mutations have been recorded to date. The PAH enzyme was also crystallised in the 1990s, and its structure (described at 2 Ǻ resolution) allows to explain the effects of some PAH gene mutations.
It has been shown that the corresponding PAH enzyme genotype is not a rigorous predictor for the clinical course of patients with phenylketonuria; in this regard, several factors that influence phenotypic variation in this disease have been identified, such as: interindividual variations in intestinal absorption, hepatic uptake of phenylalanine from the diet, its rate of incorporation into proteins, the rate of phenylalanine crossing blood-brain barrier structures, mutations affecting tetrahydrobiopetrin (which is a cofactor, also protecting the PAH enzyme from proteolytic degradation), and interactions of the PAH gene with other genes.
