Phenylketonuria and BH4 Deficiencies

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 PKU13 1.1.Historical background13 1.2.Epidemiology15 1.3.Classification and nomenclature of PKU15 2.The phenylalanine hydroxylating system18 2.1.Phenylalanine hydroxylase (PAH)18 2.1.1.The phenylalanine hydroxylase system18 2.1.2.Tetrahydrobiopterin20 2.1.3.DNAJC12, a HSP40 co-chaperon of PAH22 3.PKU due to phenylalanine hydroxylase deficiency25 3.1.Physical characteristics of patients with PKU25 3.2.Neurocognitive deficits in PKU25 3.3.Candidate clinical mechanisms of neurocognitive deficits28 3.4.Rationale for lifelong treatment of PKU to minimise neurological damage30 3.5.Non-cerebral manifestations of (treated) PKU30 3.6.Maternal PKU30 3.7.Assessment of a patient with PKU31 4.Tetrahydrobiopterin deficiencies38 4.1.Overview38 4.2.Clinical features38 4.2.1.General clinical symptoms38 4.2.2.Symptoms related to specific defects39 4.3.Developmental outcomes41 5.Diagnosis of hyperphenylalaninaemias43 5.1.Newborn screening43 5.1.1.History of newborn screening43 5.1.2.Screening methods44 5.1.3.General issues relating to screening45 5.2.Differential diagnosis of PKU45 5.2.1.Disorders of BH4 synthesis and recycling (BH4 deficiency)45 5.2.2.BH4-responsive HPA/PKU48 6.Dietary management of PKU55 6.1.Aims of dietary management55 6.2.Initiation of dietary therapy55 6.3.Management guidelines56 6.4.Monitoring56 6.5.Delivery of treatment by the healthcare team57 6.6.Transition of care57 6.7.Application of dietary management57 6.8.Optimising growth and nutritional outcome62 6.9.Patient/caregiver education62 6.10.Gaining and maintaining dietary adherence62 6.11.Pregnancy and breastfeeding66 6.12.Alternative treatment options66 7.Pharmacologic management of PKU with sapropterin dihydrochloride (BH4)71 7.1.The phenomenon of BH4 responsiveness71 7.1.1.Introduction to sapropterin/BH471 7.1.2.Therapeutic indications for sapropterin71 7.1.3.Administering sapropterin72 7.1.4.Pharmacokinetics of sapropterin73 7.2.Therapeutic profile of sapropterin in general populations of patients with PKU73 7.2.1.Clinical efficacy73 7.2.2.Tolerability and safety in general populations of patients with PKU76 7.2.3.Neurophysiologic outcomes76 7.2.4.Quality of life77 7.3.Sapropterin in special populations of patients with PKU77 7.3.1.Children77 7.3.2.Pregnant women77 7.3.3.Patients with well-controlled blood Phe78 7.4.Adherence to sapropterin78 7.5.Future developments78 8.Enzyme substitution therapy in PKU82 8.1.Rationale for enzyme replacement therapy within the management of PKU82 8.2.Human studies of pegvaliase83 9.Gene therapy for PKU88 9.1.Experimental gene therapy for PKU using the classical “PKU” mouse model88 9.2.Overview of (planned) clinical trials88 10.Management of tetrahydrobiopterin (BH4) deficiencies91 10.1.Overview91 10.2.First-line treatment92 10.2.1.Dietary treatment92 10.2.2.Tetrahydrobiopterin (sapropterin dihydrochloride)94 10.2.3.L-Dopa with or without carbidopa/benserazide94 10.2.4.5-Hydroxytryptophan94 10.2.5.Folinic acid94 10.3.Second-line pharmacologic treatment95 10.3.1.Dopamine agonists95 10.3.2.Monoamine oxidase inhibitors (MAOI; selegiline and rasagiline)95 10.4.Third-line treatment95 10.4.1.Chronic drug treatments95 10.4.2.Acute drug treatments95 10.4.3.Drugs to avoid in BH4 disorders96 10.5.Information from the BIODEF database96 11.US phenylalanine hydroxylase deficiency diagnosis and management guideline98 11.1.Introduction98 11.2.Elements of the ACMG guideline99 11.2.1.Evidence Review99 11.2.2.Recommended Phe Level99 11.2.3.General recommendations99 11.3.Future issues101 12.European guidelines for the diagnosis and management of patients with phenylketonuria103 12.1.Introduction and background103 12.2.Overview of key recommendations103 13.Genetics of PKU and DNAJC12 deficiency109 13.1.Mendelian inheritance109 13.2.PAH genotype and severity of PKU110 13.2.1.Locations of variations in the PAH gene110 13.2.2.The PKU phenotype and severity of hyperphenylalaninaemia110 13.2.3.PAH genotype and BH4-sensitive PKU112 13.3.Genotypes associated with DNAJC12 deficiency114 14.Genetics of BH4 deficiencies117 14.1.Overview117 14.2.GTP cyclohydrolase I (GCH1)117 14.3.6-Pyruvoyl-tetrahydropterin synthase (PTS)118 14.4.Dihydropteridine reductase (QDPR)118 14.5.Sepiapterin reductase (SPR)119 14.6.Pterin-4a-carbinolamine dehydratase (PCBD1)119 15.Metabolomics research in Phenylketonuria (PKU)121 15.1.Background121 15.2.General problems in metabolomic analysis121 15.3.Application of metabolomics studies in PKU research122 16.Resources for patients and their families126 16.1.International PKU societies126 16.2.National PKU societies126 16.3.Online information sources133 16.4.Manufacturers and/or suppliers of special foods for use in PKU134 16.5.Books134 17.Abbreviations135 Index136