EVALUATION of IRON INTAKE UPON BLASMA - PHENYLALANINE LEVELS in PHENYLKETONURIA PATIENTS in 3 YEARS LONGITUDINAL RANDOMIZED STUDY

Introduction: Phenylketonuria (PKU) (OMIM 261600) is an autosomal recessive congenital metabolic disease with an average of about 1:10,000 newborns, characterized by Phe accumulation in the body due to deficiency of the PAH, Most cases (98%) of PKU/HPA result from mutations in the phenylalanine hydroxylase (PAH) gene which locates on the chromosom e 12q24.1, that lead to deficient or absent activity PAH enzyme (EC 1.14.16.1). The remaining cases (2%) arise due to a block in the metabolism of Tetrahydrobiopterin (BH4) the PAH cofactor. Normal blood levels of Phe are <120 mmol/L, Based on blood Phe concentrations, PAH deficiency can be classified into classic PKU (Phe >1200 μmol/L), mild PKU (Phe = 600-1200 μmol/L) and mild Hyperphenylalaninemia (MHP) (Phe = 120 - <600 μmol/L). High concentration of Phe in blood (>360 μmol/L) at neonatal age, could lead to irreversible brain damage, but it can be prevented by early diagnosis, thanks to newborn screening and initiation of Phe-restricted diets.

The main source of natural nutrients, especially Iron (Fe), Vitamin B12 (vit B12), and Vitamin D (vit D) in normal children's diet are foods containing proteins; so, its restriction in the dietary management of PKU can lead to essential element's deficiency, anaemia, irreversible neurological defects and failure to thrive. Nowadays, these elements can be supplemented through special diet therapy. Diagnosis of HPA is made based on an elevated blood Phe concentration on a repeat blood sample confirmed genetically. The upper reference limit for Phe in whole blood or plasma in neonates is 120 μmol/L(9). All patients, at newborn screening, with plasma Phe levels, of more than 360 μmol/L, must initiate restricted low and controlled Phe diet therapy (RLCPDT) as early as possible to prevent above mentioned complications. The dietary scheme includes also other supplementations of Docosahexaenoic acid (DHA), vitamins, and other nutrients. Fe is not yet considered a recommended supplementation to PKU patients although most of our patients are supplanted with this micronutrient due to the finding of anaemia. the investigators noted that the patients supplanted with iron have consequentially reduced Phe plasma levels. This may be conceded with the fact that the investigators realized this study to confirm the relation of Iron supplementation with P-Phe levels.

The PAH enzyme is tetrameric and contains three major domains including a regulatory, a small tetramerization and a catalytic domain that contains the active site that includes a ferrous iron (Fe) prosthetic group bound to three charged aminoacid residues. So that PAH enzyme performs its hydroxylation function correctly, it requires the presence of iron, oxygen, and a cofactor, Tetrahydrobiopterin (BH4) to hydroxylase Phe in Tyr.

Based on these structural and functional considerations, it is hypothesized that iron supplementation in PKU patients can enhance the activity of the PAH enzyme, consequently reducing their blood levels of Phe. At the researcher's consciousness this study is the first to be applied to PKU human patients.

Lectures studies regarding iron and PKU: J. L. Bodley, revealed a high incidence of low stores of iron in 53 low-phenylalanine diet PKU patients in a retrospective study. These findings suggest that the current dietary management of PKU is associated with an increased risk for low iron store depletion.