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Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype.

Abstract：

:Tetrahydrobiopterin (BH4) responsiveness in patients with mutations in the phenylalanine hydroxylase (PAH) gene is a recently recognized subtype of hyperphenylalaninemia characterized by a positive BH4 loading test. According to recent estimates, this phenotype may be quite common, suggesting that a large group of individuals may benefit from BH4 substitution, eliminating the need of life-long dietary restrictions. This underscores the importance of identifying BH4-responsive patients in each population, establishing the association with specific PAH mutations. In this work, we describe the results of a pilot study performed with 31 Spanish PAH-deficient patients subjected to a BH4 loading test. Overall, 11/31 (37%) showed a positive response with a 30% decrease in blood Phe levels 8 h after the BH4 challenge, and three additional patients, considered slow responders, showed this decrease only after 12-16 h. We report for the first time a patient homozygous for a splicing mutation with a slow response, suggesting an effect of BH4 supplementation on PAH gene expression. Most of the responsive patients belong to the mild hyperphenylalaninemia (MHP) or mild phenylketonuria phenotypic groups. In MHP patients we report for the first time the results of parallel single Phe doses confirming the utility of these analyses for a better evaluation of the response. Genotype analysis confirms the involvement in the response of specific mutations (D415N, S87R, R176L, E390G, and A309V) present in hemizygous patients, and provide relevant information for the discussion of the potential mechanisms underlying BH4 responsiveness.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Desviat LR,Pérez B,Bèlanger-Quintana A,Castro M,Aguado C,Sánchez A,García MJ,Martínez-Pardo M,Ugarte M

doi

10.1016/j.ymgme.2004.06.007

subject

Has Abstract

pub_date

2004-09-01 00:00:00

pages

157-62

issue

1-2

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(04)00158-1

journal_volume

83

pub_type

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