• Ikue HataEmail author
  • Miori Yuasa
  • Yuko Isozaki


Phenylketonuria (PKU) is an amino acid metabolic disorder caused by the congenital deficiency of phenylalanine hydroxylase (PAH), in which an increased blood phenylalanine (Phe) concentration leads to severe neurological disorders. Tetrahydrobiopterin (BH4) is a cofactor of PAH; therefore, congenital disorders arising from defects in BH4 synthesis or recycling systems also cause hyperphenylalaninemia. In the cases where hyperphenylalaninemia is detected by screening of newborns, amino acid analysis, pterin analysis, and BH4 loading test are required for the diagnosis. PAH is encoded by the PAH gene and exists as a dimer or tetramer. In response to the Phe concentration in blood, the structure of PAH change to its activated form, which is stabilized by BH4. As Phe is a large neutral amino acid (LNAA), it competes with other LNAAs for a transporter in the blood-brain barrier. Insufficient levels of non-Phe LNAAs in the central nervous system are supposed to reduce the synthesis of proteins essential for proper brain development and function. PAH variants have been identified in all exons, and many of them are located in exon 6 and 7. The frequency of PAH variants is specific to people residing in different regions of the world. The severity of PKU phenotype and BH4 responsiveness can be predicted by genotype to some extent. A Phe-restricted diet to maintain blood Phe levels within the recommended range is the principal means of managing PKU. The required total protein intake is supplied by a Phe-free formula. BH4 administration may improve the daily Phe tolerance in BH4-responsive mild PKU. The efficacy and safety of enzyme-replacement therapy using phenylalanine ammonia lyase, LNAAs supplementation, glycomacropeptide, and gene therapy have been investigated. In pregnant women with PKU, hyperphenylalaninemia affects the growth and neurological development of the fetus; therefore, planned pregnancy preceded by Phe-restricted diet is recommended. Patients with PKU treated appropriately can achieve normal intellectual ability. Both tyrosine hydroxylase and tryptophan hydroxylase require BH4 as a common cofactor. Hence, in patients with BH4 deficiency, dysfunction of tyrosine hydroxylase and tryptophan hydroxylase cause deficiencies of catecholamine and serotonin. Administration of L-dopa and 5-hydroxytryptophan, which are neurotransmitter precursors, is required to prevent neurological symptoms in addition to BH4 therapy.


Phenylketonuria Phenylalanine Phenylalanine hydroxylase Tetrahydrobiopterin BH4 deficiency 


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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Faculty of Medical SciencesUniversity of FukuiFukuiJapan

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