GENETIC TESTING - PART II 

Minerva Biotecnologica 2000 June;12(2):71-82

Copyright © 2000 EDIZIONI MINERVA MEDICA

language: English

Genetic testing of hyperphenylalaninemias

Dianzani I. ¹, De Sanctis L. ², Spada M. ², Ponzone A. ²

¹ Dipartimento di Scienze Mediche, Università del Piemonte Orientale, Novara, Italy; ² Dipartimento di Scienze Pediatriche, Università di Torino, Torino, Italy

Primary hyper­phe­ny­la­lan­i­ne­mi­as (HPAs) ­share a bio­chem­i­cal phe­no­type char­ac­ter­ized by phen­y­lal­a­nine (Phe) plas­ma lev­els high­er ­than 2 mg/dl. They are ­caused by a ­defect in the Phe hydrox­y­lat­ing ­system (phen­y­lal­a­nine hydrox­y­lase, PAH) or in the bio­syn­the­sis or regen­er­a­tion ­system of the PAH cofac­tor, tet­ra­hy­dro­bi­op­te­rin (BH4). Four enzymat­ic ­defects deter­mine BH4 defi­cien­cy: gua­no­sine tri­phos­phate cyclo­hy­dro­lase (­GTPCH-1), 1,6-pyru­voyl tet­rah­ydrop­te­rin syn­thase (­PTPS), dihy­drop­ter­i­dine reduc­tase (­DHPR) and pte­rin-4a-car­bi­nol­a­mine dehy­dra­tase (PCD) defi­cien­cy. BH4 defi­cien­cies are char­ac­ter­ized not ­only by HPA but ­also by deple­tion of dop­a­mine and serot­o­nin, ­whose bio­syn­the­sis ­needs ­this cofac­tor. Besides men­tal retar­da­tion, ­found in all HPAs, the dif­fer­ent meta­bol­ic impair­ment ­explains the neu­ro­log­i­cal symp­toms in BH4 defi­cien­cies. Neonatal screen­ing pro­grams ­allow to sus­pect a pri­mary HPA, but the ulti­mate diag­no­sis is ­obtained by apply­ing sequen­cial­ly spe­cif­ic ­tests. The ­genes respon­sible for all ­these dis­or­ders ­have ­been iden­ti­fied, the rel­e­vant muta­tions ­have ­been ­described, a gen­o­type-phe­no­type cor­re­la­tion has ­been ­revealed and a treat­ment ­able to pre­vent men­tal retar­da­tion in PKU and to ­reduce the ­main symp­toms in BH4 defi­cien­cies is avail­able. Clinical and molec­u­lar ­data of pri­mary HPAs are includ­ed in two data­bas­es (­http://­data.mch.­mcgill.ca/­pahdb/ and ­http:/www.­unizh.ch/­blau/bh4.­html).