HYPERPHENYLALANINEMIA IN POLAND. MOLECULAR BASIS - CLINICAL IMPLICATIONS

M.Nowacka. C.Zekanowski, J.Bal, B.Cabalska,

Department of Pediatrics, Department of Genetics, National Research Institute of Mother and Child, Warsaw,Poland

OBJECTIVE : Hyperphenylalaninema is a recessive inherited metabolic disorder caused by deficiency of the hepatic phenylalanine hydroxylase (PAH) or its obligatory cofactor, tetrahydrobiopterin (BH4). It is heterogeneous disease both of the genotypic and phenotypic level. The aim of this study was to determine the mutations responsible for different forms ofhyperphenylalaninemia

METHODS: The study includes 115 patients with phenylalanine hydroxylase (PAH) deficiency and 4 patients with 6-pyruvoyl- tetrahydrobiopterin syntase (PTPS) deficiency. Differential diagnosis was confirmed by measuring the plasma phenylalanine concentration, tetrahydrobiopterin loading test and analysis of biopterin in urine. Diagnosis was verified by identification of mutations in the PAH and PTPS genes.

RESULTS: Among 54 patients with classic phenylketonuria the following mutations were found: R408W, R252W, R158Q, P281L, G272X, IVS10, IVS12,IVS4,IVS2 Mild phenylketonuria -18 patients -was connected with mutations: Y414C, R243Q, R241H, A104D, E390K. In the group of mild hyperfenylalaninemia- 43 patients, the following mild mutations were found : V245A, R297H, A300S, I306V, T380M, A403V. In the group with PTPS deficiency three novel mutations: E35G, N36K and F100V were identified. In one patient with mild form of disease mutation D136V was identified in both PTPS alleles.

RESULTS: Genotyping in HPA confirms the diagnosis and offers the possibility of predicting the phenotype early even in newborn period.