In patients with phenylketonuria (PKU), blood phenylalanine concentration during childhood is the major determinant of cognitive outcome. Thanks to newborn screening and early dietary therapy, individuals with PKU no longer experience intellectual disability. Nevertheless, some do not achieve their full potential. The establishment of uniform guidelines and improved management for PKU can lead to optimal outcomes in this metabolic disorder.Since in 1999 it has been shown that some patients with PKU respond to the administration of tetrahydrobiopterin (BH4; sapropterin dihydrochloride) by lowering blood phenylalanine concentrations, that these patients can be treated with sapropterin dihydrochloride. Enzyme substitution therapy with phenylalanine ammonia lyase (PAL) is a promising new option, along with diet and sapropterin, to reduce Phe levels and improve the clinical outcome of subjects with PKU. Gene therapy is another new approach which remains to be evaluated in upcoming studies. It has been also shown that patient's genotype determines the phenotype and helps in predicting BH4 responsiveness.In the 4th edition of this textbook past, present, and future efforts related to PKU and BH4 deficiencies are discussed. The reviews and scientific contributions in this book provide professionals, the patients, and their families to understand PKU within a biochemical, neurological and psychological context.

1.History, epidemiology and classification of PKU131.1.Historical background131.2.Epidemiology151.3.Classification and nomenclature of PKU152.The phenylalanine hydroxylating system182.1.Phenylalanine hydroxylase (PAH)182.1.1.The phenylalanine hydroxylase system182.1.2.Tetrahydrobiopterin202.1.3.DNAJC12, a HSP40 co-chaperon of PAH223.PKU due to phenylalanine hydroxylase deficiency253.1.Physical characteristics of patients with PKU253.2.Neurocognitive deficits in PKU253.3.Candidate clinical mechanisms of neurocognitive deficits283.4.Rationale for lifelong treatment of PKU to minimise neurological damage303.5.Non-cerebral manifestations of (treated) PKU303.6.Maternal PKU303.7.Assessment of a patient with PKU314.Tetrahydrobiopterin deficiencies384.1.Overview384.2.Clinical features384.2.1.General clinical symptoms384.2.2.Symptoms related to specific defects394.3.Developmental outcomes415.Diagnosis of hyperphenylalaninaemias435.1.Newborn screening435.1.1.History of newborn screening435.1.2.Screening methods445.1.3.General issues relating to screening455.2.Differential diagnosis of PKU455.2.1.Disorders of BH4 synthesis and recycling (BH4 deficiency)455.2.2.BH4-responsive HPA/PKU486.Dietary management of PKU556.1.Aims of dietary management556.2.Initiation of dietary therapy556.3.Management guidelines566.4.Monitoring566.5.Delivery of treatment by the healthcare team576.6.Transition of care576.7.Application of dietary management576.8.Optimising growth and nutritional outcome626.9.Patient/caregiver education626.10.Gaining and maintaining dietary adherence626.11.Pregnancy and breastfeeding666.12.Alternative treatment options667.Pharmacologic management of PKU with sapropterin dihydrochloride (BH4)717.1.The phenomenon of BH4 responsiveness717.1.1.Introduction to sapropterin/BH4717.1.2.Therapeutic indications for sapropterin717.1.3.Administering sapropterin727.1.4.Pharmacokinetics of sapropterin737.2.Therapeutic profile of sapropterin in general populations of patients with PKU737.2.1.Clinical efficacy737.2.2.Tolerability and safety in general populations of patients with PKU767.2.3.Neurophysiologic outcomes767.2.4.Quality of life777.3.Sapropterin in special populations of patients with PKU777.3.1.Children777.3.2.Pregnant women777.3.3.Patients with well-controlled blood Phe787.4.Adherence to sapropterin787.5.Future developments788.Enzyme substitution therapy in PKU828.1.Rationale for enzyme replacement therapy within the management of PKU828.2.Human studies of pegvaliase839.Gene therapy for PKU889.1.Experimental gene therapy for PKU using the classical PKU mouse model889.2.Overview of (planned) clinical trials8810.Management of tetrahydrobiopterin (BH4) deficiencies9110.1.Overview9110.2.First-line treatment9210.2.1.Dietary treatment9210.2.2.Tetrahydrobiopterin (sapropterin dihydrochloride)9410.2.3.L-Dopa with or without carbidopa/benserazide9410.2.4.5-Hydroxytryptophan9410.2.5.Folinic acid9410.3.Second-line pharmacologic treatment9510.3.1.Dopamine agonists9510.3.2.Monoamine oxidase inhibitors (MAOI; selegiline and rasagiline)9510.4.Third-line treatment9510.4.1.Chronic drug treatments9510.4.2.Acute drug treatments9510.4.3.Drugs to avoid in BH4 disorders9610.5.Information from the BIODEF database9611.US phenylalanine hydroxylase deficiency diagnosis and management guideline9811.1.Introduction9811.2.Elements of the ACMG guideline9911.2.1.Evidence Review9911.2.2.Recommended Phe Level9911.2.3.General recommendations9911.3.Future issues10112.European guidelines for the diagnosis and management of patients withphenylketonuria10312.1.Introduction and background10312.2.Overview of key recommendations10313.Genetics of PKU and DNAJC12 deficiency10913.1.Mendelian inheritance10913.2.PAH genotype and severity of PKU11013.2.1.Locations of variations in the PAH gene11013.2.2.The PKU phenotype and severity of hyperphenylalaninaemia11013.2.3.PAH genotype and BH4-sensitive PKU11213.3.Genotypes associated with DNAJC12 deficiency11414.Genetics of BH4 deficiencies11714.1.Overview11714.2.GTP cyclohydrolase I (GCH1)11714.3.6-Pyruvoyl-tetrahydropterin synthase (PTS)11814.4.Dihydropteridine reductase (QDPR)11814.5.Sepiapterin reductase (SPR)11914.6.Pterin-4a-carbinolamine dehydratase (PCBD1)11915.Metabolomics research in Phenylketonuria (PKU)12115.1.Background12115.2.General problems in metabolomic analysis12115.3.Application of metabolomics studies in PKU research12216.Resources for patients and their families12616.1.International PKU societies12616.2.National PKU societies12616.3.Online information sources13316.4.Manufacturers and/or suppliers of special foods for use in PKU13416.5.Books13417.Abbreviations135Index136