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The effects of sapropterin on urinary monoamine metabolites in phenylketonuria.

Abstract：

BACKGROUND:Sapropterin dihydrochloride (BH4, tetrahydrobiopterin) can lower plasma phenylalanine (Phe) concentrations for a subset of patients with phenylketonuria (PKU), an inborn error of metabolism. Studies suggest that monoamine neurotransmitter concentrations are low in PKU patients. Sapropterin functions as a cofactor for hydroxylases specific to Phe, tyrosine, and tryptophan metabolism, pathways essential for catecholamine and serotonin synthesis. OBJECTIVE:The objective of this study is to determine the impact of sapropterin on monoamine neurotransmitter status in patients with PKU. DESIGN:58 PKU subjects were provided 20 mg/kg of sapropterin for 1 month. Those who responded with at least a 15% decrease in plasma Phe received sapropterin for 1 year, while Non-responders discontinued it. After an additional 3 months, Responders who demonstrated increased Phe tolerance and decreased medical food dependence were classified as Definitive, whereas Responders unable to liberalize their diet without compromising plasma Phe control were identified as Provisional. At study visits, patients provided blood for plasma amino acids, 3-day diet records, and 12-hour urine samples analyzed for epinephrine (E), dopamine (DA), dihydroxyphenylacetate (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3MT), serotonin (5HT), and 5-hydroxyindole acetic acid (5HIAA) using HPLC with electrochemical detection. RESULTS:Compared with healthy non-PKU controls, subjects with PKU had significantly lower baseline concentrations of DA, HVA, 3MT, 5HT, and 5HIAA (p < 0.001 for all). Medical food protein intake had a direct association with DA, HVA, 5HT, and 5HIAA during the study (p < 0.05 for all), while plasma Phe had an inverse association with these markers (p < 0.01 for all). DOPAC was also associated with plasma Phe throughout the year (p = 0.035), although not at baseline. Patients with PKU had a significant increase in HVA (p = 0.015) after 1 month of sapropterin. When stratifying by Responder and Non-Responder status, significance of HVA increase in Non-responders (p = 0.041) was confirmed, but not in Responders (p = 0.081). A declining trend in urinary 5HIAA, significant only after controlling for plasma Phe (p = 0.019), occurred for Definitive Responders during the 1-year study. CONCLUSION:Urinary monoamine concentrations are low in patients with PKU and are influenced by oral sapropterin and medical food intake, highlighting the importance of these therapies to neurotransmitter metabolism in phenylketonuria.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Douglas TD,Jinnah HA,Bernhard D,Singh RH

doi

10.1016/j.ymgme.2013.04.017

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

243-50

issue

3

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(13)00144-3

journal_volume

109

pub_type

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