Phenylketonuria and BH4 Deficiencies

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