Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: A semi-mechanistically-based, nonlinear mixed-effect modeling

Trefz, Friedrich K.; Lichtenberger, Olaf; Blau, Nenad; Muntau, Ania C.; Feillet, François; Bélanger-Quintana, Amaya; Spronsen, Francjan van; Munafo, Alain

doi:10.1016/j.ymgme.2015.01.013

Cited by 7 publications

(5 citation statements)

References 35 publications

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“…The theoretical frequency of BH4-sensitive genotypes is 17–79% in Europe, and the gradient is directed from the northeast to the southwest, and roughly coincides with the frequency of the p.Arg408Trp pathogenic variant: the minimum proportion of respondents was in the Baltic countries, the maximum in Spain [9]. There were more than 57% responders to the treatment in a Western European study that studied BH4 sensitivity in newborns [12]. It was obvious that the percentage of respondents in Russia was closer to the Eastern European values.…”

Section: Resultsmentioning

confidence: 99%

Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia

et al. 2019

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Phenylalanine hydroxylase (PAH) deficiency is responsible for most cases of phenylketonuria (PKU). Furthermore, numerous studies on BH4-sensitive PAH deficiency have been conducted. To date, BH4, a cofactor of PAH, has not been used to treat PKU in Russia.Genotype data of patients with PKU can be used to predict their sensitivity to BH4 therapy. A cohort of 2579 patients with PKU from Russia was analyzed for 25 common PAH gene mutations using custom allele-specific multiplex ligation-dependent probe amplification-based technology. A mutation detection rate of 84.1% chromosomes was accomplished. Both pathogenic alleles were identified in 73.1% of patients. The most frequent pathogenic variants were p.Arg408Trp (50.9%), p.Arg261Gln (5.3%), p.Pro281Leu (3.5%), IVS12+1G>A (3.1%), IVS10-11G>A (2.6%), and p.Arg158Leu (2.4%). The exact boundaries of a PAH exon 5 deletion were defined as EX5del4154ins268 (c.442-2913_509+1173del4154ins268). Severe phenotypes prevailed in the cohort, and classical PKU was observed in 71.8% cases. Due to the genotype-based prediction, 55.9% of the probands were non-responders to the BH4-treatment, and 20.2% were potential responders. Analysis of genotype data is useful to predict BH4 response in PKU patients. The high rate of non-responders among Russian patients was due to the high allele frequency of severe PAH mutations.

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Section: Resultsmentioning

confidence: 99%

Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia

et al. 2019

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“…Blau et al [ 470 ] and Singh et al [ 450 ] published protocols for BH4 loading tests. The 24 h test in newborns can detect BH4-deficiencies in addition to BH4-responsiveness in PAH patients [ 473 ]. The arbitrary responsiveness definition of a > 30% reduction in blood Phe appears to be a good compromise between sensitivity and specificity for the initial screening test.…”

Section: Treatment In Specific Patient Groupsmentioning

confidence: 99%

The complete European guidelines on phenylketonuria: diagnosis and treatment

Wegberg

MacDonald

Ahring

et al. 2017

Orphanet J Rare Dis

598

885

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Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

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“…In these cases, BH 4 appeared to be working as a pharmacological chaperone to restore dysfunctional PAH to more normal function (52). Kuvan ® , marketed by BioMarin Pharmaceuticals in the USA, is the name of the pharmacological form of BH 4 ; it is reported as effective in lowering Phe levels for ~30% of PKU affected individuals for whom it has been tried (53). Much research has been directed at determining which genotypes are likely to respond to BH 4 , with varying results (e.g.…”

Section: Bh4 Acting As a Pharmacological Chaperonementioning

confidence: 99%

New protein structures provide an updated understanding of phenylketonuria

Jaffe

2017

Molecular Genetics and Metabolism

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Phenylketonuria (PKU) and less severe hyperphenylalaninemia (HPA) constitute the most common inborn error of amino acid metabolism, and is most often caused by defects in phenylalanine hydroxylase (PAH) function resulting in accumulation of Phe to neurotoxic levels. Despite the success of dietary intervention in preventing permanent neurological damage, individuals living with PKU clamor for additional non-dietary therapies. The bulk of disease-associated mutations are PAH missense variants, which occur throughout the entire 452 amino acid human PAH protein. While some disease-associated mutations affect protein structure (e.g. truncations) and others encode catalytically dead variants, most have been viewed as defective in protein folding/stability. Here we refine this view to address how PKU-associated missense variants can perturb the equilibrium among alternate native PAH structures (resting-state PAH and activated PAH), thus shifting the tipping point of this equilibrium to a neurotoxic Phe concentration. This refined view of PKU introduces opportunities for the design or discovery of therapeutic pharmacological chaperones that can help restore the tipping point to healthy Phe levels and how such a therapeutic might work with or without the inhibitory pharmacological chaperone BH4. Dysregulation of an equilibrium of architecturally distinct native PAH structures departs from the concept of “misfolding”, provides an updated understanding of PKU, and presents an enhanced foundation for understanding genotype/phenotype relationships.

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Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: A semi-mechanistically-based, nonlinear mixed-effect modeling

Cited by 7 publications

References 35 publications

Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia

Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia

The complete European guidelines on phenylketonuria: diagnosis and treatment

New protein structures provide an updated understanding of phenylketonuria

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