J Pediatr Biochem 2016; 06(01): 019-024
DOI: 10.1055/s-0036-1582250
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Neurological Involvement in Tetrahydrobiopterin Deficiency

Italia Mascaro
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
,
Ferdinando Ceravolo
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
,
Stefania Ferraro
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
,
Daniela Procopio
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
,
Francesca Falvo
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
,
Michele Grisolia
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
,
Giuseppina Leone
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
,
Vincenzo Salpietro
2  Department of Pediatrics, University of Messina, Messina, Italy
3  Institute of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, United Kingdom
,
Agata Polizzi
4  National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
,
Martino Ruggieri
5  Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
,
Daniela Concolino
1  Department of Medical and Surgical Sciences, Pediatric Unit, Department of Pediatrics, University “Magna Graecia,” Catanzaro, Italy
› Author Affiliations
Further Information

Publication History

02 December 2015

15 January 2016

Publication Date:
26 April 2016 (eFirst)

Abstract

Tetrahydrobiopterin (BH4) is a natural and essential cofactor for the enzymatic hydroxylation of phenylalanine (Phe) and tyrosine (Tyr), and for two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Five separate genetic conditions affecting BH4 synthesis or recycling have been identified so far, including deficiency in (1) 6-pyruvoyltetrahydropterin synthase; (2) dihydropteridine reductase; (3) GTP cyclohydrolase I; (4) sepiapterin reductase; and (5) pterin-4α-carbinolamine dehydratase. These disorders cause hyperphenylalaninemia and impaired synthesis of serotonin and dopamine since tyrosine hydroxylase and neuronal tryptophan hydroxylase require BH4 and serotonin/dopamine products (5-hydroxytryptophan and L-dopa). All these five genetic conditions can be identified by newborn screening procedures due to elevated blood levels of Phe (with the sole exception of sepiapterin reductase deficiency). BH4 loading tests and measurement of neurotransmitter metabolites, pterins, and folates in cerebrospinal fluid can add further important information on disease severity. Untreated patients develop a complex neurological phenotype, which includes Parkinson-like features, brain degeneration, and early death. The gold standard treatment of severe disorders of BH4 metabolism is based on replacement therapy with BH4, 5-hydroxytryptophan, L-dopa, and carbidopa, with the addition, in certain cases, of folinic acid supplements and pramipexole. Dopamine agonists can improve L-dopa therapy, making treatment easier, relieving symptoms, stabilizing clinical course, and possibly ameliorating long-term outcomes. The outcome of patients with disorders of biopterin synthesis can be favorable, with either normal or near-normal cognition, and with some residual neurological symptoms usually manifesting diurnal variation, that is, worst when patients become tired or when the dosage or interval for medications is inadequate.