A hypothesis on the biochemical mechanism of BH(4)-responsiveness in phenylalanine hydroxylase deficiency.

Abstract:

:We describe six children with tetrahydrobiopterin (BH(4)) responsive phenylalanine hydroxylase (PAH) deficiency. All patients carry two mutant alleles in the PAH gene. Cofactor deficiency was excluded. The effect of BH(4) administration was studied by correlating different oral BH(4) doses with plasma phenylalanine levels under defined protein intake. Our results indicate that oral BH(4) supplementation may be used as long-term treatment for individuals with BH(4)-responsive PAH deficiency, either without or in combination with a less restrictive diet. Previous in vitro studies have demonstrated that BH(4) inhibits PAH tetramers but activates PAH dimers. This may indicate, that BH(4)-responsiveness results from BH(4) induced stabilization of mutant PAH dimers. In addition, interindividual differences in the cellular folding apparatus may determine the tertiary structure and the amount of mutant PAH dimers and hence may account for divergent BH(4)-responsiveness reported for the same PAH genotype.

journal_name

Amino Acids

journal_title

Amino acids

authors

Steinfeld R,Kohlschütter A,Ullrich K,Lukacs Z

doi

10.1007/s00726-002-0354-0

subject

Has Abstract

pub_date

2003-07-01 00:00:00

pages

63-8

issue

1

eissn

0939-4451

issn

1438-2199

journal_volume

25

pub_type

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