New approach in the diagnosis and therapy of hyperphenylalaninemia

Bettocchi, Ilaria (2012) New approach in the diagnosis and therapy of hyperphenylalaninemia , [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze mediche generali e scienze dei servizi: progetto n. 1 "Medicina materno-infantile e dell'età evolutiva e fisiopatologia della funzione sessuale", 24 Ciclo. DOI 10.6092/unibo/amsdottorato/4593.
Documenti full-text disponibili:
Documento PDF (Italiano) - Richiede un lettore di PDF come Xpdf o Adobe Acrobat Reader
Download (1MB) | Anteprima


Background. Phenylketonuria is the most prevalent inborn error of aminoacid metabolism. Is an autosomal recessive disorder. It results from mutations in the phenylalanine hydroxilase (PAH) gene. Phenotypes can vary from mild hyperphenylalaninemia to a severe phenylketonuria wich, if untreated, results in severe mental retardation. Thanks to neonatal screening programmes, early detection and promp dietetic intervention (phenylalanine restricted diet lifelong) has allowed to avoid neurocognitive complications. Recently, a new therapy is become widely used: the oral supplementation with the PAH cofactor (BH4), wich can alleviate the diet burden. Genotype-phenotype correlation is a reliable tool to predict metabolic phenotype in order to establish a better tailored diet and to assess the potential responsiveness to BH4 therapy. Aim Molecular analysis of the PAH gene, evaluation of genotype-phenotype correlation and prediction of BH4 responsiveness in a group of HPA patients living in Emilia Romagna. Patients and methods. We studied 48 patients affected by PAH deficiency in regular follow-up to our Metabolic Centre. We performed the molecular analysis of these patients using genomic DNA extracted from peripheral blood samples Results. We obtained a full genotipic characterization of 46 patients. We found 87 mutant alleles and 35 different mutations, being the most frequent IVS10-11 G>A (19.3%), R261Q (9.1%), R158Q (9.1%), R408Q (6.8%) and A403V (5.7%), including 2 new ones (L287, N223Y) ever described previously. Notably, we found 15 mutations already identified in BH4-responsive patients, according to the literature. We found 42 different genotipic combinations, most of them in single patients and involving a BH4-responsive mutation. Conclusion. BH4 responsiveness is shown by a consistent number of PAH deficient hyperphenylalaninemic patients. This treatment, combined with a less restricted diet or as monotherapy, can reduce nutritional complications and improve the quality of life of these patients.

Tipologia del documento
Tesi di dottorato
Bettocchi, Ilaria
Dottorato di ricerca
Scuola di dottorato
Scienze mediche e chirurgiche cliniche
Settore disciplinare
Settore concorsuale
Parole chiave
hyperphenylalaninemia BH4-responsiveness genotype phenotype
Data di discussione
2 Aprile 2012

Altri metadati

Statistica sui download

Gestione del documento: Visualizza la tesi