Genetic testing of hyperphenylalaninemias

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).