, Volume 32, Issue 1, pp 22-26

Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria

Purchase on Springer.com

$39.95 / €34.95 / £29.95*

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access



The value of genotyping to identify tetrahydrobiopterin-responsive (BH4-responsive) patients with phenylalanine hydroxylase (PAH) deficiency is a matter of debate.


We reviewed 250 cases of patients with PAH deficiency, using published data from 198 cases and unpublished data from 52 cases of patients attending our own clinic. Patients underwent analyses for BH4 load and genetic mutations. Partial and full BH4 responses were defined as a 10–29% decrease and a ≥30% decrease from baseline in blood phenylalanine levels, respectively. BH4-responsive alleles were identified from BH4-responsive patients as either homozygous for a specific allele or compound heterozygous for that allele with a null mutation.


Most inconsistencies between observed genotype and BH4 response were associated with mutations in the regulatory domain of PAH (p.R68S, p.I65T, p.L48S and p.F39C), where 20/62 alleles (32.2%) were non-responsive. In the catalytic domain (mutations p.Y414C, p.R261Q, p.E390G, p.A300S, p.R241C, p.A403V and p.V388M), only 8/125 alleles (6.4%) were non-responsive. Seven patients had a genotype with two BH4-responsive alleles resulting in no response or only a partial response to BH4. Ten patients had identical genotypes but inconsistent responses in BH4 load.


These results show that BH4 non-responsiveness is associated with genotype. However, patients with mutations in the regulatory domain show inconsistent results. In patients with two responsive alleles, non-responsiveness may be related to negative inter-allelic complementation. In patients with the same genotype and inconsistent results for BH4 load, external factors such as intestinal absorption of BH4, catabolic conditions or other genetic factors may be responsible. Further in vitro studies are necessary to clarify the genotype–phenotype correlation in patients with BH4-responsive PKU.

Communicating editor: Nenad Blau
Competing interests: F. K. Trefz is a member of the scientific advisory board for PKU supported by Merck Serono International S.A., Geneva, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany).
Presented at the International Conference on Tetrahydrobiopterin, PKU, and NOS, 23–28 March 2008, St Moritz, Champfér, Switzerland