Genetic testing of hyperphenylalaninemias

Irma Dianzani, Luisa De Sanctis, Marco Spada, Alberto Ponzone

Research output: Contribution to journalArticlepeer-review


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 ( and http:/

Original languageEnglish
Pages (from-to)71-82
Number of pages12
JournalMinerva Biotecnologica
Issue number2
Publication statusPublished - Jun 2000


  • Biopterin analogous and derivates
  • Metabolism, inborn errors
  • Phenylalanine
  • Phenylketonuria

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology


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