BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations
Introduction
In Phenylketonuria (PKU, OMIM 261600), deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH) impairs the conversion of phenylalanine (Phe) into tyrosine (Tyr), resulting in strongly increased blood Phe concentrations and normal to slightly reduced blood Tyr concentrations. Left untreated, especially high blood Phe concentrations have been associated with classical PKU symptomatology: severe mental retardation, seizures, and depressive and anxiety disorders. Neonatal screening and immediate institution of a Phe-restricted diet aim to reduce the blood Phe concentrations as early as possible. Moreover, in some PKU patients, blood Phe concentrations respond to treatment with tetrahydrobiopterin (BH4), primarily by its activities as cofactor and natural chaperone for PAH [1], [2]. These current treatment strategies can prevent severe mental retardation, but outcome remains suboptimal. Even early diagnosed and continuously treated PKU patients show impaired neuropsychological functioning and are prone to depressive and anxiety problems [3].
These neuropsychological impairments may at least in part be related to a cerebral deficiency of dopamine and serotonin [4], [5]. This consideration is in line with previous data in living and deceased PKU patients, showing reduced dopaminergic and serotonergic metabolites in CSF as well as decreased catecholamine and serotonin concentrations in the brain [6], [7]. Moreover, increased blood prolactin concentrations have been observed at increasing blood Phe concentrations [8], indicating reduced brain concentrations of its natural inhibitor dopamine [9].
BH4 is not only a cofactor for hepatic PAH, but is also involved in cerebral neurotransmission by its cofactor and/or chaperone activities for Tyr hydroxylase, tryptophan hydroxylase, and nitric oxide synthase [10], [11], while BH4 is known to cross the blood–brain barrier (BBB) [11]. Therefore, it is hypothesized that BH4 may improve cerebral functioning beyond its effect through lowering blood Phe concentrations in BH4-responsive PKU patients. This hypothesis is substantiated by fMRI investigations in PKU patients showing improved neural activation after 4 weeks of BH4 treatment (20 mg/kg) even when blood Phe concentrations had not decreased [12]. To investigate whether BH4 might increase cerebral dopamine concentrations beyond its effect through lowering blood phenylalanine concentrations, this study compared blood prolactin in relation to blood phenylalanine concentrations in BH4-responsive PKU patients, who were subsequently treated without and with BH4.
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Patients
In total, data of 9 BH4-responsive PKU males were collected retrospectively of whom both values of blood prolactin concentrations without and with BH4 treatment could be retrieved. Female patients were excluded because of too much possible variation by confounders. BH4-responsiveness was defined as ≥ 30% decrease of blood Phe concentrations during the 48-hour loading test and/or having a genotype with at least one DNA mutation suggesting BH4 responsiveness. Patients received BH4 treatment at
Patient and biochemical characteristics
Patient characteristics of BH4-responsive PKU patients who were subsequently treated without and with BH4 are shown in Table 1. Of one patient, DNA analysis has not revealed any PAH mutations thus far. BH4 deficiency has been excluded biochemically and with the use of DNA analysis, while, clinically, this patient does not show any signs suggestive of BH4 deficiency. Further investigations are currently being performed.
In total, 45 measurements were obtained from 9 patients. Of these, 16 samples
Discussion
To investigate whether BH4 might improve brain dopamine concentrations beyond an effect through lowering blood Phe concentrations, this study compared blood prolactin in relation to blood Phe concentrations in BH4-responsive PKU males who were subsequently treated without and with BH4. Three main findings could be distinguished. Firstly, blood prolactin concentrations positively correlated to blood Phe concentrations. Secondly, blood prolactin concentrations were significantly lower when using
Conclusion
In conclusion, this study suggests that BH4 treatment may increase cerebral dopamine concentrations at least in some PKU patients, beyond its effect through lowering blood Phe concentrations. Such a possible effect may be dose-dependent. Therefore, it can be hypothesized that high-dose BH4 treatment might improve neuropsychological functioning in both BH4-responsive and BH4-unresponsive PKU patients by improving cerebral neurotransmitter concentrations. The present study, however, was
References (28)
- et al.
The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency
Mol. Genet. Metab.
(2004) - et al.
Tetrahydrobiopterin for patients with phenylketonuria
Lancet
(2007) - et al.
Phenylketonuria
Lancet
(2010) - et al.
Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses
Mol. Genet. Metab.
(2010) The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain
Brain Res.
(1972)- et al.
The role of 6R-tetrahydrobiopterin in the nervous system
Prog. Neurobiol.
(2000) - et al.
The effects of tetrahydrobiopterin (BH4) treatment on brain function in individuals with phenylketonuria
Neuroimage Clin.
(2013) - et al.
Large daily fluctuations in plasma tyrosine in treated patients with phenylketonuria
Am. J. Clin. Nutr.
(1996) - et al.
TIDAL WAVES: network mechanisms in the neuroendocrine control of prolactin release
Front. Neuroendocrinol.
(2014) - et al.
The effects of sapropterin on urinary monoamine metabolites in phenylketonuria
Mol. Genet. Metab.
(2013)
Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvoyltetrahydropterin synthase knockout mice
J. Biol. Chem.
Tetrahydrobiopterin and PKU: into the future
J. Pediatr.
Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker
J. Pediatr.
The neurochemistry of phenylketonuria
Eur. J. Pediatr.
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