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.

List of contents

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

Summary

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.

Product details

• Authors: Nena Blau, Nenad Blau, Alberto Burlina, Alberto B Burlina, Alberto B. Burlina, Barbara Burton, Barbara K e Burton, Barbara K. Burton, Clair Cannet, Claire Cannet
• Assisted by: Nena Blau (Editor), Nenad Blau (Editor)
• Publisher: UNI-MED, Bremen
• Languages: English
• Product format: Hardback
• Released: 13.11.2021
• EAN: 9783837416015
• ISBN: 978-3-8374-1601-5
• No. of pages: 136
• Dimensions: 173 mm x 11 mm x 248 mm
• Weight: 381 g
• Illustrations: 34 Abb.
• Series: UNI-MED Science; TA270
• Subjects: Natural sciences, medicine, IT, technology > Medicine > Clinical medicine; Angeborene Krankheiten und Störungen, BH4 Deficiencies, blood phenylalanine, Phenylketonuria