Original Article
Tetrahydrobiopterin as an Alternative Treatment for Mild Phenylketonuria
N Engl J Med 2002; 347:2122-2132December 26, 2002
- Abstract
Background
Hyperphenylalaninemia is a common inherited metabolic disease that is due to phenylalanine hydroxylase deficiency, and at least half the affected patients have mild clinical phenotypes. Treatment with a low-phenylalanine diet represents a substantial psychosocial burden, but alternative treatments have not been effective.
Methods
To explore the therapeutic efficacy of tetrahydrobiopterin, we performed a combined phenylalanine–tetrahydrobiopterin loading test and analyzed the in vivo rates of [13C]phenylalanine oxidation in 38 children with phenylalanine hydroxylase deficiency (age range, 1 day to 17 years). We assessed whether responsiveness to tetrahydrobiopterin was associated with specific genotypes, and we mapped mutations using a structural model of the phenylalanine hydroxylase monomer.
Results
In 27 (87 percent) of 31 patients with mild hyperphenylalaninemia (10 patients) or mild phenylketonuria (21 patients), tetrahydrobiopterin significantly lowered blood phenylalanine levels. Phenylalanine oxidation was significantly enhanced in 23 of these 31 patients (74 percent). Conversely, none of the seven patients with classic phenylketonuria had a response to tetrahydrobiopterin as defined in this study. Long-term treatment with tetrahydrobiopterin in five children increased daily phenylalanine tolerance, allowing them to discontinue their restricted diets. Seven mutations (P314S, Y417H, V177M, V245A, A300S, E390G, and IVS4–5C→G) were classified as probably associated with responsiveness to tetrahydrobiopterin, and six mutations (A403V, F39L, D415N, S310Y, R158Q, and I65T) were classified as potentially associated. Four mutations (Y414C, L48S, R261Q, and I65V) were inconsistently associated with this phenotype. Mutations connected to tetrahydrobiopterin responsiveness were predominantly in the catalytic domain of the protein and were not directly involved in cofactor binding.
Conclusions
Tetrahydrobiopterin responsiveness is common in patients with mild hyperphenylalaninemia phenotypes. Responsiveness cannot consistently be predicted on the basis of genotype, particularly in compound heterozygotes.
Media in This Article
Figure 1
Blood Phenylalanine Concentrations before Phenylalanine Loading (Phe) and before and after Challenge with Tetrahydrobiopterin (BH4).Figure 4
Effect of Tetrahydrobiopterin (BH4) on Peripheral Phenylalanine Clearance and Oxidation Rates in the 38 Patients with Hyperphenylalaninemia.Article Activity
- Article
Hyperphenylalaninemia, a common inherited metabolic disease, was one of the first genetic disorders that could be treated.1 In most cases, hyperphenylalaninemia results from phenylalanine hydroxylase deficiency due to mutations in the phenylalanine hydroxylase gene.2 The associated phenotypes range in severity from classic phenylketonuria (Online Mendelian Inheritance in Man number 261600) to mild phenylketonuria and mild hyperphenylalaninemia. At least half of affected patients have one of the milder clinical phenotypes. Patients with both classic and mild phenylketonuria require lifelong dietary protein restriction to prevent neurologic sequelae and to ensure normal cognitive development, whereas patients with mild hyperphenylalaninemia may not require treatment.3 The highly restrictive diet is associated with a risk of nutritional deficiencies and represents a burden for the patients and their families. Therefore, a search for nondietary treatment alternatives has been encouraged.4
In approximately 50 genetic diseases of humans involving enzyme deficiencies, treatment with high doses of a cofactor can increase enzyme activity.5 Tetrahydrobiopterin is a natural cofactor of aromatic amino acid hydroxylases and nitric oxide synthase. Supplementation with this compound is an established treatment for the rare patients with hyperphenylalaninemia that is due to defects in the biosynthesis of tetrahydrobiopterin.6,7 However, more than 98 percent of patients with hyperphenylalaninemia have mutations in the phenylalanine hydroxylase gene, and they have elevated rather than decreased plasma concentrations of biopterin owing to the action of guanosine triphosphate cyclohydrolase I feedback regulatory protein.8 The therapeutic use of tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency had therefore not been considered.
Recently, however, individual patients with mutations in the phenylalanine hydroxylase gene have been shown to have a decrease in blood phenylalanine concentrations after tetrahydrobiopterin loading.9-13 Phenylalanine concentrations in the peripheral circulation, however, are governed by various genetic loci and modifying factors,1,14 and there is no evidence that the beneficial effect of tetrahydrobiopterin occurs at the level of phenylalanine hydroxylation. Therefore, we prospectively studied 38 children with phenylalanine hydroxylase deficiency in an effort to determine the frequency of sensitivity to tetrahydrobiopterin in these patients, whether tetrahydrobiopterin restores their oxidative capacity for phenylalanine, whether responsiveness to tetrahydrobiopterin is related to specific genotypes, and whether associated mutations map to distinct regions of the protein.
Methods
Patients
The study was conducted from December 2000 through December 2001 and was approved by the medical board of the Children's Hospital Research Center. We obtained written informed consent from the families of 38 children with various classes of hyperphenylalaninemia stratified according to the plasma phenylalanine concentration before treatment (normal, 30 to 120 μmol per liter): 10 patients had mild hyperphenylalaninemia (phenylalanine, less than 600 μmol per liter; age, 15 days to 10 years), 21 had mild phenylketonuria (phenylalanine, 600 to 1200 μmol per liter; age, 8 days to 17 years), and 7 had classic phenylketonuria (phenylalanine, more than 1200 μmol per liter; age, 1 day to 9 years). A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. We analyzed 7 patients during the newborn period and 31 at older ages. Five affected siblings from four families were included, because nongenetic factors are known to influence phenylalanine homeostasis. Mean daily phenylalanine tolerance was determined by calculating the dietary phenylalanine intake according to nutritional protocols.
Combined Phenylalanine and Tetrahydrobiopterin Loading Test
Phenylalanine loading was accomplished by having patients consume a meal containing 100 mg of phenylalanine per kilogram of body weight. One hour after the end of the meal the patients ingested 20 mg of tetrahydrobiopterin per kilogram (Schircks Laboratories). Blood phenylalanine concentrations were determined by electrospray ionization–tandem mass spectrometry before phenylalanine loading and before and 4, 8, and 15 hours after the tetrahydrobiopterin challenge. During the test period newborns were breast-fed, while older children received a standardized protein intake (10 mg of phenylalanine per kilogram) between six and eight hours after the challenge with tetrahydrobiopterin.
In Vivo Analysis of Phenylalanine Oxidation
The rate of phenylalanine oxidation was determined twice (on two different days) in each child — once without treatment and once during treatment with tetrahydrobiopterin (10 mg per kilogram over a 24-hour period). The tests were performed after a four-hour fast in infants and an overnight fast in older children. A total of 6 mg per kilogram of L-[1-13C]phenylalanine (Euriostop), dissolved in a 25 percent dextrose solution (2 mg per milliliter), was given orally. Breath samples were subsequently collected over a period of 180 minutes and stored in evacuated glass tubes until analysis by isotope-ratio mass spectrometry (deltaS, Thermoquest). The recovery of carbon-13 in breath samples was calculated as described by Treacy et al.,15 assuming a total carbon dioxide production of 300 mmol per hour per square meter of body-surface area.16,17 The amount of labeled carbon dioxide formed was expressed as the cumulative percentage of the dose administered as a function of time. The validity of results in newborns might be influenced by the diet or by the fact that breath sampling is more challenging than in older subjects. The base-line percentage of carbon-13 measured at time 0, however, did not differ significantly between newborns and older children. Values were considered to be below the limit of detection when the signal intensity of the atom excess (expressed as a percentage at time t, obtained by subtraction of the mean base-line value) did not allow sufficient distinction from atmospheric carbon-13 dioxide. On average, fewer than 1 of 27 consecutive measurements of carbon dioxide obtained during the 180 minutes of individual testing was uninterpretable in older children and fewer than 2 of 27 were uninterpretable in newborns, and these variations had a negligible influence on the final calculation. For the comparison among patients, we normalized the data by expressing individual results as a percentage of the mean value for the control group, which consisted of 12 healthy children (age, 2 days to 13 years).
Mutational Analysis
DNA was extracted from leukocytes according to standard protocols. Thirteen genomic fragments covering the entire coding sequence and the exon-flanking intronic sequences of the phenylalanine hydroxylase gene were amplified by the polymerase chain reaction followed by direct sequencing.18
Mapping of Phenylalanine Hydroxylase Gene Mutations
We constructed a model of the full-length, tetrahydrobiopterin-bound phenylalanine hydroxylase monomer from the crystal structures of several truncated forms19-22 by superimposing the catalytic domains using the tools provided by SWISS-MODEL/Swiss-Pdb Viewer.23
Results
Effects of Tetrahydrobiopterin on Blood Phenylalanine Levels and Rates of Phenylalanine Oxidation
Patients were classified as responsive to tetrahydrobiopterin when blood phenylalanine levels 15 hours after tetrahydrobiopterin challenge had decreased by more than 30 percent from the value obtained before the administration of tetrahydrobiopterin. An improvement in the rate of phenylalanine oxidation was considered to be significant when supplementation with tetrahydrobiopterin increased the individual normalized value by at least 15 percent. Tetrahydrobiopterin sensitivity was observed during the loading test in all 10 patients with mild hyperphenylalaninemia and in 17 of 21 patients with mild phenylketonuria (27 of 31, or 87 percent). Only four patients with mild phenylketonuria and all seven patients with classic phenylketonuria did not fulfill the criterion of responsiveness to tetrahydrobiopterin (Figure 1Figure 1
Blood Phenylalanine Concentrations before Phenylalanine Loading (Phe) and before and after Challenge with Tetrahydrobiopterin (BH4).). Some patients had a rapid decrease in phenylalanine resembling that seen in patients with defects in the synthesis of tetrahydrobiopterin, whereas others had a slow response, which reached a maximum 15 hours after the administration of the cofactor (data not shown).The basal cumulative recovery of labeled carbon dioxide reflected the various levels of residual phenylalanine oxidation and ranged from a mean (±SD) of 1.4±0.7 percent in the 7 patients with classic phenylketonuria to 3.0±1.4 percent in the 21 patients with mild phenylketonuria and to 4.8±1.8 percent in the 10 patients with mild hyperphenylalaninemia (mean value in 12 healthy controls, 8.3±2.8 percent). During treatment with tetrahydrobiopterin (10 mg per kilogram over 24 hours), the cumulative recovery of labeled carbon dioxide significantly increased in the same groups that had had a response to the loading test. The increase was more pronounced in those with mild phenylketonuria than in those with mild hyperphenylalaninemia (Figure 2AFigure 2
Effect of Short-Term Treatment with Tetrahydrobiopterin (BH4) on Phenylalanine Oxidation.). The curves of the fractional formation of labeled carbon dioxide deviated markedly from that of the normal-oxidation phenotype (Figure 2B). With cofactor treatment, the curves reverted toward normal in patients who had a response to tetrahydrobiopterin but remained unchanged in patients who did not have a response (Figure 2B).Before tetrahydrobiopterin treatment, all patients had blood phenylalanine concentrations above 200 μmol per liter and cumulative rates of recovery of labeled carbon dioxide below 7 percent, with considerable overlap between patients with a response and those without a response. After tetrahydrobiopterin treatment, the values in these two groups no longer overlapped (Figure 3Figure 3
Relation between the Cumulative Recovery of Labeled Carbon Dioxide during the 180 Minutes after the Ingestion of Labeled Phenylalanine and the Blood Phenylalanine Concentration before and after the Administration of Tetrahydrobiopterin (BH4), According to the Response to Tetrahydrobiopterin.).The degree of intersubject variability was large: tetrahydrobiopterin challenge reduced phenylalanine levels by 37 to 92 percent when blood values were compared before and 15 hours after the administration of tetrahydrobiopterin. In 23 of 27 patients with a response to tetrahydrobiopterin, blood phenylalanine concentrations decreased below 200 μmol per liter, whereas in 4 patients the response was moderate, and values were between 200 and 400 μmol per liter. In patients with no response, blood phenylalanine concentrations always exceeded 400 μmol per liter after tetrahydrobiopterin challenge. Tetrahydrobiopterin enhanced the oxidation rates of labeled phenylalanine by 10 to 91 percent and resulted in rates within the normal range in 22 of the 27 patients with a response to tetrahydrobiopterin. The remaining five patients had an improvement, but the rates did not reach the normal range. In 33 of 38 patients we observed full concordance between the two end points analyzed.
Values for individual patients and examples of notable imbalances in the effect of tetrahydrobiopterin are shown in Figure 4Figure 4
Effect of Tetrahydrobiopterin (BH4) on Peripheral Phenylalanine Clearance and Oxidation Rates in the 38 Patients with Hyperphenylalaninemia.. In four patients (Patients 2, 4, 7, and 26) who were responsive to tetrahydrobiopterin, the normalized increase in phenylalanine oxidation was in the range of 8 to 14 percent (data not shown) and therefore below our predefined level of significance. One patient with classic phenylketonuria (Patient 35) had a slight decrease in the blood phenylalanine concentration that did not fulfill the criterion of responsiveness, whereas the increase in the oxidation rate (24 percent) was significant. Notably, 7 of the 11 patients who did not meet the criterion of responsiveness in the loading test had a slight increase in the rate of phenylalanine oxidation (range, 2 to 14 percent) with short-term treatment with tetrahydrobiopterin.Long-Term Treatment with Tetrahydrobiopterin
The parents of five children with mild phenylketonuria (age, 4 to 14 years) provided written informed consent for their children to participate in a therapeutic trial replacing dietary phenylalanine restriction with the oral administration of tetrahydrobiopterin. Cofactor treatment at daily doses of 7.1 to 10.7 mg per kilogram for a mean of 207.0±51.3 days (range, 166 to 263) led to an increase in the mean daily phenylalanine tolerance, from 18.7±8.6 mg per kilogram (range, 8.5 to 30.0) before treatment to 61.4±27.9 mg per kilogram (range, 17.9 to 90.0) during treatment (P=0.04), with little effect on the mean blood concentrations of phenylalanine (366±120 μmol per liter during dietary treatment and 378±173 μmol per liter during cofactor treatment).
Identification and Mapping of Phenylalanine Hydroxylase Gene Mutations
In 37 of 38 patients, two mutant alleles were identified (Table 1Table 1
Genotypes in 38 Patients with Hyperphenylalaninemia, According to Whether They Were Responsive to Tetrahydrobiopterin.). We classified seven mutations (P314S, Y417H, V177M, V245A, A300S, E390G, and IVS4–5C→G) as probably responsible for responsiveness to tetrahydrobiopterin, because they were present in either the homozygous or a functional hemizygous state. Six additional mutations were potentially connected to tetrahydrobiopterin responsiveness because of considerable residual in vitro enzyme activity (A403V, F39L, D415N, R158Q, and I65T), as previously proposed,24 or (in the case of S310Y) because of a known severe mutation on the second allele. Four mutations (Y414C, L48S, R261Q, and I65V) were inconsistently associated with tetrahydrobiopterin responsiveness. Eight of 12 missense mutations connected to tetrahydrobiopterin responsiveness mapped to the catalytic domain, whereas 2 mapped to the regulatory domain and 2 to the tetramerization domain. None of them affected residues at the active site or amino acids that interacted directly with the cofactor (Figure 5Figure 5
Structural Localization of Phenylalanine Hydroxylase Missense Mutations.).Discussion
We present two lines of evidence that the metabolic phenotype of phenylalanine hydroxylase deficiency can be modified by pharmacologic doses of tetrahydrobiopterin. First, tetrahydrobiopterin loading led to normal or nearly normal blood phenylalanine concentrations in most patients with residual phenylalanine hydroxylase activity, suggesting that responsiveness to tetrahydrobiopterin is a common feature of mild hyperphenylalaninemia phenotypes. Second, tetrahydrobiopterin enhanced residual phenylalanine oxidative capacity in these patient groups.
Our findings suggest that the in vivo phenylalanine oxidation test can discriminate among classes of hyperphenylalaninemia of different severity. This observation is in accordance with data on the ability of the method to measure the dose effects of the phenylalanine hydroxylase gene.15 However, because of the multifactorial nature of hyperphenylalaninemia,25,26 the whole-body rate of phenylalanine oxidation is not a simple equivalent of phenylalanine hydroxylase activity. The decrease in blood phenylalanine concentrations was accompanied by a significant increase in phenylalanine oxidative capacity in the majority of patients who were identified as responsive to tetrahydrobiopterin. Taken together, these observations are consistent with the hypothesis that impaired phenylalanine hydroxylation is corrected by tetrahydrobiopterin therapy.
The extent of the fractional change in the disposal of phenylalanine did not always correspond to the change in phenylalanine oxidation — a finding not unexpected with respect to genetically determined enzyme deficiencies in general27 and phenylalanine hydroxylase deficiency in particular.26 We observed slow and rapid responses as well as differences in the time course and relative extent of formation of labeled carbon dioxide, suggesting that tetrahydrobiopterin may exert its effects through various mechanisms and with different degrees of efficacy. In addition to the proposal that high-dose tetrahydrobiopterin treatment may compensate for the decreased affinity of the mutant phenylalanine hydroxylase for tetrahydrobiopterin,28 other mechanisms need to be considered. Tetrahydrobiopterin treatment may up-regulate the expression of the phenylalanine hydroxylase gene,24 stabilize phenylalanine hydroxylase messenger RNA,29 facilitate the formation of functional phenylalanine hydroxylase tetramers, or protect a misfolded enzyme protein from proteolytic cleavage.30,31
The use of genotyping to predict the phenotype may present difficulties in the case of complex traits such as hyperphenylalaninemia,32 particularly in compound heterozygotes. We identified predominantly “mild” genotypes in the group of patients with a response to tetrahydrobiopterin, whereas most of the patients without a response had “severe” genotypes.2 The weight of the evidence of the association of distinct mutations with responsiveness to tetrahydrobiopterin varied. The Y414C mutation occurs in more than one clinical phenotype.33,34 We and others12 have identified this mutation in a functional hemizygous state in two patients with identical genotypes but discordant responses to tetrahydrobiopterin. This observation may be explained by the influences of modifying loci in hyperphenylalaninemia, since this trait is polygenic.1 In a homozygous state, and thus one in which homopolymeric tetramers are formed, the Y414C and the L48S mutations were reported to confer responsiveness to tetrahydrobiopterin.24,35 However, we detected these mutations in a functional hemizygous state in patients with classic phenylketonuria who had no response to tetrahydrobiopterin. Under these conditions, heteropolymerization may impede the formation of functional tetramers.
Our data confirm that most missense mutations associated with sensitivity to tetrahydrobiopterin are in the catalytic domain of the protein, but they do not map to residues at the active site and are not directly involved in cofactor binding.28 These mutations may affect interactions between domains in a monomer or influence residues in the dimer or tetramer interfaces,36 resulting in the misfolding of the protein and reduced enzyme activity. Tetrahydrobiopterin may act as a chemical chaperone and thus prevent misfolding.
In vitro expression analysis has been used to predict the functional effect in vivo of mutations in the phenylalanine hydroxylase gene.37-39 This type of analysis may result in the overestimation of phenylalanine hydroxylase activity in vitro,38 perhaps because such analyses have been carried out almost exclusively in the presence of high concentrations of natural or synthetic cofactors,2 thereby contributing to genotype–phenotype inconsistencies.33 Revised experimental protocols to assess the intrinsic severity of mutations should include a range of tetrahydrobiopterin concentrations.40
Since responsiveness to tetrahydrobiopterin cannot be predicted on the basis of pretreatment phenylalanine concentrations, we would suggest a new clinical classification: tetrahydrobiopterin-unresponsive hyperphenylalaninemia and tetrahydrobiopterin-responsive hyperphenylalaninemia, which includes tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and defects in the synthesis of tetrahydrobiopterin. A phenylalanine–tetrahydrobiopterin loading test with an extended observation period (at least 15 hours) can reliably and safely discriminate between patients with a response and patients without a response and ought to be performed in all patients with hyperphenylalaninemia to identify those who may benefit from tetrahydrobiopterin treatment. Our short-term study design does not exclude the possibility of subtle effects, which may become evident only after prolonged treatment even in some patients with classic phenylketonuria.
Our data suggest that long-term therapy with tetrahydrobiopterin could lead to an increase in phenylalanine tolerance. Cofactor treatment instead of a phenylalanine-restricted diet might be possible in many patients and would be expected to improve their quality of life substantially. Tetrahydrobiopterin treatment may also be helpful in cases of maternal phenylketonuria, since metabolic control, which is key to the prevention of serious adverse effects in the offspring,41 is difficult to maintain during pregnancy. However, the safety of tetrahydrobiopterin therapy during pregnancy has not been established. Worldwide, more than 350 patients with tetrahydrobiopterin deficiency have been treated with the cofactor.42 Some dose-dependent adverse reactions, including sleep disorders, polyuria, and loose stools, were reported in a safety evaluation.43
Several obstacles must be overcome before tetrahydrobiopterin treatment can be used routinely. First, tetrahydrobiopterin has not yet been approved for therapeutic use in most countries. Second, this compound is expensive. Third, dose-finding studies and clinical trials are needed to determine the bioavailability and long-term effects of tetrahydrobiopterin therapy in patients with phenylalanine hydroxylase deficiency.
In conclusion, we found that pharmacologic doses of tetrahydrobiopterin corrected impaired phenylalanine oxidation in the majority of patients with mild hyperphenylalaninemia phenotypes. Our findings have implications for the diagnostic workup and clinical classification of this defect as well as for therapeutic interventions. In the near future, in a large number of patients with hyperphenylalaninemia, cofactor treatment may obviate the need for the most burdensome dietary restrictions.
Supported by intramural funds from the Children's Research Center, University of Munich, Dr. von Hauner Children's Hospital.
We are indebted to the patients for their participation; to Florian Lagler, Esther Maier, Stephan Hiedl, Kathrin Vosberg, and Wolfgang Sperl for clinical care; to Katharina Dokoupil for nutritional advice; to Markus Phirrmann for assistance with the statistical analysis; to Berthold Koletzko and Dietrich Reinhardt for continuous support; to Nenad Blau for the measurement of pterins and the dihydropteridine reductase enzyme analysis; to Ralph Fingerhut and Bernhard Olgemöller for the measurement of phenylalanine; to Claudia Nevinny-Stickel and Ekkehard Albert for genotyping; to Barbara Paton, Debbie Stern, and Tricia LeVan for careful review of the manuscript; and to Alf Heger for his expert in silico skills. This article is part of an M.D. thesis to be submitted by Mr. Habich.
Source Information
From the Research Center, Department of Biochemical Genetics and Molecular Biology (A.C.M., W.R., M.H., A.A.R.), and the Department of Metabolic Disorders and Nutrition (H.D., B.H.), Dr. von Hauner Children's Hospital; and the Department of Clinical Chemistry and Clinical Biochemistry, Surgical Clinic (C.P.S.) — all at Ludwig Maximilians University, Munich, Germany.
Address reprint requests to Dr. Roscher at Dr. von Hauner Children's Hospital Research Center, Ludwig Maximilians University, Lindwurmstrasse 2a, D-80337 Munich, Germany, or at adelbert.roscher@kk-i.med.uni-muenchen.de.
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Citing Articles
1
S. Santos-Sierra, J. Kirchmair, A. M. Perna, D. Reiss, K. Kemter, W. Roschinger, H. Glossmann, S. W. Gersting, A. C. Muntau, G. Wolber, F. B. Lagler. (2012) Novel pharmacological chaperones that correct phenylketonuria in mice. Human Molecular Genetics
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Caroline Heintz, Heinz Troxler, Aurora Martinez, Beat Thöny, Nenad Blau. (2012) Quantification of phenylalanine hydroxylase activity by isotope-dilution liquid chromatography–electrospray ionization tandem mass spectrometry. Molecular Genetics and Metabolism
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Aleš Hnízda, Vojtěch Jurga, Kateřina Raková, Viktor Kožich. (2011) Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. Journal of Inherited Metabolic Disease
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Monica Cerreto, Paola Cavaliere, Carla Carluccio, Felice Amato, Adriana Zagari, Aurora Daniele, Francesco Salvatore. (2011) Natural phenylalanine hydroxylase variants that confer a mild phenotype affect the enzyme's conformational stability and oligomerization equilibrium. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1812:11, 1435-1445
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Christineh N. Sarkissian, Tse Siang Kang, Alejandra Gámez, Charles R. Scriver, Raymond C. Stevens. (2011) Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria. Molecular Genetics and Metabolism 104:3, 249-254
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Maureen Humphrey, Judy Nation, Ivan Francis, Avihu Boneh. (2011) Effect of tetrahydrobiopterin on Phe/Tyr ratios and variation in Phe levels in tetrahydrobiopterin responsive PKU patients. Molecular Genetics and Metabolism 104:1-2, 89-92
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Tatiéle Nalin, Ingrid Dalira Schweigert Perry, Angela Sitta, Carmen Regla Vargas, Maria Luiza Saraiva-Pereira, Roberto Giugliani, Nenad Blau, Ida Vanessa Doederlein Schwartz. (2011) Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency. Molecular Genetics and Metabolism
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Miroslaw Bik-Multanowski, Jacek J. Pietrzyk. (2011) Blood phenylalanine clearance and BH4-responsiveness in classic phenylketonuria. Molecular Genetics and Metabolism 103:4, 399-400
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John J. Mitchell, Yannis J. Trakadis, Charles R. Scriver. (2011) Phenylalanine hydroxylase deficiency. Genetics in Medicine 13:8, 697-707
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Barbara K. Burton, Maria Nowacka, Julia B. Hennermann, Mark Lipson, Dorothy K. Grange, Anupam Chakrapani, Friedrich Trefz, Alex Dorenbaum, Michael Imperiale, Sun Sook Kim, Paul M. Fernhoff. (2011) Safety of extended treatment with sapropterin dihydrochloride in patients with phenylketonuria: Results of a phase 3b study. Molecular Genetics and Metabolism 103:4, 315-322
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Amaya Bélanger-Quintana, Alberto Burlina, Cary O. Harding, Ania C. Muntau. (2011) Up to date knowledge on different treatment strategies for phenylketonuria. Molecular Genetics and Metabolism
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Nenad Blau, Julia B. Hennermann, Ulrich Langenbeck, Uta Lichter-Konecki. (2011) Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Molecular Genetics and Metabolism
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Anita MacDonald, Kirsten Ahring, Katharina Dokoupil, Hulya Gokmen-Ozel, Anna Maria Lammardo, Kristina Motzfeldt, Martine Robert, Júlio César Rocha, Margreet van Rijn, Amaya Bélanger-Quintana. (2011) Adjusting diet with sapropterin in phenylketonuria: what factors should be considered?. British Journal of Nutrition 106:02, 175-182
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M. Staudigl, S. W. Gersting, M. K. Danecka, D. D. Messing, M. Woidy, D. Pinkas, K. F. Kemter, N. Blau, A. C. Muntau. (2011) The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response. Human Molecular Genetics 20:13, 2628-2641
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João Leandro, Jaakko Saraste, Paula Leandro, Torgeir Flatmark. (2011) The G46S-hPAH mutant protein: A model to study the rescue of aggregation-prone PKU mutations by chaperones. Molecular Genetics and Metabolism
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David C. Swinney, Jason Anthony. (2011) How were new medicines discovered?. Nature Reviews Drug Discovery 10:7, 507-519
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Johannis B. C. de Klerk, Arnold P. Oranje. 2011. Inherited Metabolic Disorders and the Skin. , 169.1-169.15.
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Yoshiyuki Okano, Satoshi Kudo, Yasuaki Nishi, Tomoko Sakaguchi, Kazuyoshi Aso. (2011) Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan. Journal of Human Genetics 56:4, 306-312
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Steven F. Dobrowolski, Caroline Heintz, Trent Miller, Clinton Ellingson, Clifford Ellingson, Işıl Özer, Gulden Gökçay, Tolunay Baykal, Beat Thöny, Mübeccel Demirkol, Nenad Blau. (2011) Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. Molecular Genetics and Metabolism 102:2, 116-121
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Ivan M. Robbins, Anna R. Hemnes, J. Simon Gibbs, Brian W. Christman, Luke Howard, Sharon Meehan, Ines Cabrita, Rochelle Gonzalez, Tracy Oyler, Lan Zhao, Rui-Hong Du, Lisa A. Mendes, Martin R. Wilkins. (2011) Safety of sapropterin dihydrochloride (6r–bh4) in patients with pulmonary hypertension. Experimental Lung Research 37:1, 26-34
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Ania C. Muntau, Søren W. Gersting. (2010) Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism. Journal of Inherited Metabolic Disease 33:6, 649-658
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Florian B. Lagler, Søren W. Gersting, Clemens Zsifkovits, Alice Steinbacher, Anna Eichinger, Marta K. Danecka, Michael Staudigl, Ralph Fingerhut, Hartmut Glossmann, Ania C. Muntau. (2010) New insights into tetrahydrobiopterin pharmacodynamics from Pahenu1/2, a mouse model for compound heterozygous tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Biochemical Pharmacology 80:10, 1563-1571
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Francjan J. van Spronsen. (2010) Phenylketonuria: a 21st century perspective. Nature Reviews Endocrinology 6:9, 509-514
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Nenad Blau. (2010) Sapropterin dihydrochloride for phenylketonuria and tetrahydrobiopterin deficiency. Expert Review of Endocrinology & Metabolism 5:4, 483-494
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Usha Rani Somaraju, Marcus Merrin, Usha Rani Somaraju. 2010. Sapropterin dihydrochloride for phenylketonuria. .
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S. W. Gersting, F. B. Lagler, A. Eichinger, K. F. Kemter, M. K. Danecka, D. D. Messing, M. Staudigl, K. A. Domdey, C. Zsifkovits, R. Fingerhut, H. Glossmann, A. A. Roscher, A. C. Muntau. (2010) Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. Human Molecular Genetics 19:10, 2039-2049
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Hong Ding, Chris R. Triggle. (2010) Endothelial dysfunction in diabetes: multiple targets for treatment. Pflügers Archiv - European Journal of Physiology 459:6, 977-994
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Alberto Ponzone, Francesco Porta, Alessandro Mussa, Alessandra Alluto, Silvio Ferraris, Marco Spada. (2010) Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency. Metabolism 59:5, 645-652
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Donald G. Musson, William G. Kramer, Erik D. Foehr, Frederick A. Bieberdorf, Carl S. Hornfeldt, Sun Sook Kim, Alex Dorenbaum. (2010) Relative bioavailability of sapropterin from intact and dissolved sapropterin dihydrochloride tablets and the effects of food: A randomized, open-label, crossover study in healthy adults. Clinical Therapeutics 32:2, 338-346
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Jytte Bieber Nielsen, Karin E. Nielsen, Flemming Güttler. (2010) Tetrahydrobiopterin responsiveness after extended loading test of 12 Danish PKU patients with the Y414C mutation. Journal of Inherited Metabolic Disease 33:1, 9-16
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Usha Rani Somaraju, Marcus Merrin, Usha Rani Somaraju. 2009. Sapropterin dihydrochloride for phenylketonuria. .
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Sonja Pavlović, Maja Stojiljković. (2009) Molecular Diagnosis of Phenylketonuria: From Defective Protein to Disease-Causing Gene Mutation. Journal of Medical Biochemistry 28:4, 262-267
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M. Lindner, G. Gramer, S. F. Garbade, P. Burgard. (2009) Blood phenylalanine concentrations in patients with PAH-deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control. Journal of Inherited Metabolic Disease 32:4, 514-522
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Steven F Dobrowolski, K Borski, C C Ellingson, R Koch, H L Levy, E W Naylor. (2009) A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin. Journal of Human Genetics 54:6, 335-339
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Friedrich K. Trefz, Barbara K. Burton, Nicola Longo, Mercedes Martinez-Pardo Casanova, Daniel J. Gruskin, Alex Dorenbaum, Emil D. Kakkis, Eric A. Crombez, Dorothy K. Grange, Paul Harmatz, Mark H. Lipson, Andrzej Milanowski, Linda Marie Randolph, Jerry Vockley, Chester B. Whitley, Jon A. Wolff, Judith Bebchuk, Heidi Christ-Schmidt, Julia B. Hennermann. (2009) Efficacy of Sapropterin Dihydrochloride in Increasing Phenylalanine Tolerance in Children with Phenylketonuria: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study. The Journal of Pediatrics 154:5, 700-707.e1
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Nenad Blau, Amaya Bélanger-Quintana, Mübeccel Demirkol, François Feillet, Marcello Giovannini, Anita MacDonald, Friedrich K. Trefz, Francjan J. van Spronsen. (2009) Optimizing the use of sapropterin (BH4) in the management of phenylketonuria. Molecular Genetics and Metabolism 96:4, 158-163
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Aurora Daniele, Iris Scala, Giuseppe Cardillo, Cinzia Pennino, Carla Ungaro, Michelina Sibilio, Giancarlo Parenti, Luciana Esposito, Adriana Zagari, Generoso Andria, Francesco Salvatore. (2009) Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy. FEBS Journal 276:7, 2048-2059
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Ralph Fingerhut, Bernhard Olgemöller. (2009) Newborn screening for inborn errors of metabolism and endocrinopathies: an update. Analytical and Bioanalytical Chemistry 393:5, 1481-1497
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A. Burlina, N. Blau. (2009) Effect of BH4 supplementation on phenylalanine tolerance. Journal of Inherited Metabolic Disease 32:1, 40-45
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F. K. Trefz, D. Scheible, H. Götz, G. Frauendienst-Egger. (2009) Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria. Journal of Inherited Metabolic Disease 32:1, 22-26
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C. N. Sarkissian, A. Gámez, C. R. Scriver. (2009) What we know that could influence future treatment of phenylketonuria. Journal of Inherited Metabolic Disease 32:1, 3-9
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E. M. Maier, S. W. Gersting, K. F. Kemter, J. M. Jank, M. Reindl, D. D. Messing, M. S. Truger, C. P. Sommerhoff, A. C. Muntau. (2009) Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Human Molecular Genetics 18:9, 1612-1623
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Mark Sanford, Gillian M. Keating. (2009) Sapropterin. Drugs 69:4, 461-476
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Phillip Lee, Eileen P. Treacy, Eric Crombez, Melissa Wasserstein, Lewis Waber, Jon Wolff, Udo Wendel, Alex Dorenbaum, Judith Bebchuk, Heidi Christ-Schmidt, Margretta Seashore, Marcello Giovannini, Barbara K. Burton, Andrew A. Morris, . (2008) Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. American Journal of Medical Genetics Part A 146A:22, 2851-2859
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François Feillet, Céline Chery, Fares Namour, Antoine Kimmoun, Elisabeth Favre, Elisabeth Lorentz, Shyue-Fang Battaglia-Hsu, Jean-Louis Guéant. (2008) Evaluation of neonatal BH4 loading test in neonates screened for hyperphenylalaninemia. Early Human Development 84:9, 561-567
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Angel L. Pey, Ming Ying, Nunilo Cremades, Adrian Velazquez-Campoy, Tanja Scherer, Beat Thöny, Javier Sancho, Aurora Martinez. (2008) Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. Journal of Clinical Investigation 118:8, 2858-2867
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Søren W. Gersting, Kristina F. Kemter, Michael Staudigl, Dunja D. Messing, Marta K. Danecka, Florian B. Lagler, Christian P. Sommerhoff, Adelbert A. Roscher, Ania C. Muntau. (2008) Loss of Function in Phenylketonuria Is Caused by Impaired Molecular Motions and Conformational Instability. The American Journal of Human Genetics 83:1, 5-17
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Ilka Haase, Markus Fischer, Adelbert Bacher, Wolfgang Eisenreich, Felix Rohdich. 2008. Cofactor Biosynthesis. .
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S. Kölker, S. W. Sauer, G. F. Hoffmann, I. Müller, M. A. Morath, J. G. Okun. (2008) Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. Journal of Inherited Metabolic Disease 31:2, 194-204
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Barbara K. Burton, Santwana Kar, Peter Kirkpatrick. (2008) Sapropterin. Nature Reviews Drug Discovery 7:3, 199-200
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Kimberlee Michals-Matalon. (2008) Sapropterin dihydrochloride, 6- R -L-erythro-5,6,7,8-tetrahydrobiopterin, in the treatment of phenylketonuria. Expert Opinion on Investigational Drugs 17:2, 245-251
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U. Langenbeck. (2008) Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias. Journal of Inherited Metabolic Disease 31:1, 67-72
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Sheila A Doggrell. (2008) Is sapropterin treatment suitable for all subjects with phenylketonuria?. Expert Opinion on Pharmacotherapy 9:1, 145-147
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Marcel R. Zurflüh, Johannes Zschocke, Martin Lindner, François Feillet, Céline Chery, Alberto Burlina, Raymond C. Stevens, Beat Thöny, Nenad Blau. (2008) Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Human Mutation 29:1, 167-175
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Harvey Levy, Barbara Burton, Stephen Cederbaum, Charles Scriver. (2007) Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment. Molecular Genetics and Metabolism 92:4, 287-291
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Yoshiyuki Okano, Kazuhiko Takatori, Satoshi Kudo, Tomoko Sakaguchi, Minoru Asada, Masahiro Kajiwara, Tsunekazu Yamano. (2007) Effects of tetrahydrobiopterin and phenylalanine on in vivo human phenylalanine hydroxylase by phenylalanine breath test. Molecular Genetics and Metabolism 92:4, 308-314
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W B Hanley. (2007) Phenylketonuria: questioning the gospel. Expert Review of Endocrinology & Metabolism 2:6, 809-816
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B. K. Burton, D. K. Grange, A. Milanowski, G. Vockley, F. Feillet, E. A. Crombez, V. Abadie, C. O. Harding, S. Cederbaum, D. Dobbelaere, A. Smith, A. Dorenbaum. (2007) The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. Journal of Inherited Metabolic Disease 30:5, 700-707
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Charles R. Scriver. (2007) ThePAH gene, phenylketonuria, and a paradigm shift. Human Mutation 28:9, 831-845
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Susan E. Waisbren, Kay Noel, Kyle Fahrbach, Catherine Cella, Diana Frame, Alex Dorenbaum, Harvey Levy. (2007) Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta-analysis. Molecular Genetics and Metabolism 92:1-2, 63-70
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G. Gramer, P. Burgard, S. F. Garbade, M. Lindner. (2007) Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia. Journal of Inherited Metabolic Disease 30:4, 556-562
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Harvey L Levy, Andrzej Milanowski, Anupam Chakrapani, Maureen Cleary, Philip Lee, Friedrich K Trefz, Chester B Whitley, François Feillet, Annette S Feigenbaum, Judith D Bebchuk, Heidi Christ-Schmidt, Alex Dorenbaum. (2007) Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. The Lancet 370:9586, 504-510
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Betina Fiege, Nenad Blau. (2007) Assessment of Tetrahydrobiopterin (BH4) Responsiveness in Phenylketonuria. The Journal of Pediatrics 150:6, 627-630
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R. Matalon, K. Michals-Matalon, G. Bhatia, A. B. Burlina, A. P. Burlina, C. Braga, L. Fiori, M. Giovannini, E. Grechanina, P. Novikov, J. Grady, S. K. Tyring, F. Guttler. (2007) Double blind placebo control trial of large neutral amino acids in treatment of PKU: Effect on blood phenylalanine. Journal of Inherited Metabolic Disease 30:2, 153-158
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M. Giovannini, E. Verduci, E. Salvatici, L. Fiori, E. Riva. (2007) Phenylketonuria: Dietary and therapeutic challenges. Journal of Inherited Metabolic Disease 30:2, 145-152
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M. R. Zurflüh, L. Fiori, B. Fiege, I. Ozen, M. Demirkol, K. H. Gärtner, B. Thöny, M. Giovannini, N. Blau. (2006) Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency. Journal of Inherited Metabolic Disease 29:6, 725-731
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R. Matalon, K. Michals-Matalon, G. Bhatia, E. Grechanina, P. Novikov, J. D. McDonald, J. Grady, S. K. Tyring, F. Guttler. (2006) Large neutral amino acids in the treatment of phenylketonuria (PKU). Journal of Inherited Metabolic Disease 29:6, 732-738
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Avihu Boneh, Dorothy EM Francis, Maureen Humphrey, Helen J Upton, Heidi L Peters. (2006) Three-year audit of the hyperphenylalaninaemia/phenylketonuria spectrum in Victoria. Journal of Paediatrics and Child Health 42:9, 496-498
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Zoltan Lukacs, René Santer. (2006) Evaluation of electrospray-tandem mass spectrometry for the detection of phenylketonuria and other rare disorders. Molecular Nutrition & Food Research 50:4-5, 443-450
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Sang-Wun Kim, Jongsun Jung, Hyun-Jeong Oh, Jihong Kim, Kwang-Soo Lee, Dong-Hwan Lee, Chan Park, Kuchan Kimm, Soo Kyung Koo, Sung-Chul Jung. (2006) Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene. Clinica Chimica Acta 365:1-2, 279-287
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Tatiana Kuznetsova, Jan A Staessen, Eva Brand, Marcin Cwynar, Katarzyna Stolarz, Lutgarde Thijs, Valérie Tikhonoff, Wiktoria Wojciechowska, Speranta Babeanu, Stefan-Martin Brand-Herrmann, Edoardo Casiglia, Jan Filipovský, Tomasz Grodzicki, Yuri Nikitin, Jan Peleška, Harry Struijker-Boudier, Giuseppe Bianchi, Kalina Kawecka-Jaszcz. (2006) Sodium excretion as a modulator of genetic associations with cardiovascular phenotypes in the European Project on Genes in Hypertension. Journal of Hypertension 24:2, 235-242
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V. Leuzzi, C. Carducci, C. Carducci, F. Chiarotti, C. Artiola, T. Giovanniello, I. Antonozzi. (2006) The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency. Journal of Inherited Metabolic Disease 29:1, 38-46
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Betina Fiege, Luisa Bonafé, Diana Ballhausen, Matthias Baumgartner, Beat Thöny, David Meili, Laura Fiori, Marcello Giovannini, Nenad Blau. (2005) Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: A pilot study. Molecular Genetics and Metabolism 86, 91-95
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Friedrich K. Trefz, Dagmar Scheible, Georg Frauendienst-Egger, Herbert Korall, Nenad Blau. (2005) Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. Molecular Genetics and Metabolism 86, 75-80
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Nilo Lambruschini, Belén Pérez-Dueñas, Maria Antonia Vilaseca, Anna Mas, Rafael Artuch, Rosa Gassió, Lilian Gómez, Alejandra Gutiérrez, Jaume Campistol. (2005) Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Molecular Genetics and Metabolism 86, 54-60
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Amaya Bélanger-Quintana, María José García, Margarita Castro, Lourdes R. Desviat, Belén Pérez, Blanca Mejía, Magdalena Ugarte, Mercedes Martínez-Pardo. (2005) Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: Evolution of seven patients on long-term treatment with tetrahydrobiopterin. Molecular Genetics and Metabolism 86, 61-66
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Reuben Matalon, Kimberlee Michals-Matalon, Richard Koch, James Grady, Stephen Tyring, Raymond C. Stevens. (2005) Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Molecular Genetics and Metabolism 86, 17-21
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Laura Fiori, Betina Fiege, Enrica Riva, Marcello Giovannini. (2005) Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. Molecular Genetics and Metabolism 86, 67-74
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A. Ormazabal, M. A. Vilaseca, B. Pérez-Dueñas, N. Lambruschini, L. Gómez, J. Campistol, R. Artuch. (2005) Platelet serotonin concentrations in PKU patients under dietary control and tetrahydrobiopterin treatment. Journal of Inherited Metabolic Disease 28:6, 863-870
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Christineh N. Sarkissian, Alejandra Gámez. (2005) Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now?. Molecular Genetics and Metabolism 86, 22-26
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Julia B. Hennermann, Christoph Bührer, Nenad Blau, Barbara Vetter, Eberhard Mönch. (2005) Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Molecular Genetics and Metabolism 86, 86-90
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Rossana Scavelli, Zhaobing Ding, Nenad Blau, Jan Haavik, Aurora Martínez, Beat Thöny. (2005) Stimulation of hepatic phenylalanine hydroxylase activity but not Pah-mRNA expression upon oral loading of tetrahydrobiopterin in normal mice. Molecular Genetics and Metabolism 86, 153-155
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John J. Mitchell, Bridget Wilcken, Ian Alexander, Carolyn Ellaway, Helen O’Grady, Veronica Wiley, John Earl, John Christodoulou. (2005) Tetrahydrobiopterin-responsive phenylketonuria: The New South Wales experience. Molecular Genetics and Metabolism 86, 81-85
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Angel L. Pey, Aurora Martinez. (2005) The activity of wild-type and mutant phenylalanine hydroxylase and its regulation by phenylalanine and tetrahydrobiopterin at physiological and pathological concentrations: An isothermal titration calorimetry study. Molecular Genetics and Metabolism 86, 43-53
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Reuben Matalon, Kimberlee Michals Matalon. 2005. Genetic Diseases and Errors of Metabolism. .
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Thomas Opladen, Marcel Zurflüh, Ilse Kern, Lucja Kierat, Beat Thöny, Nenad Blau. (2005) Severe mucitis after sublingual administration of tetrahydrobiopterin in a patient with tetrahydrobiopterin-responsive phenylketonuria. European Journal of Pediatrics 164:6, 395-396
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Belén Pérez-Dueñas, Maria Antonia Vilaseca, Anna Mas, Nilo Lambruschini, Rafael Artuch, Lilian Gómez, Julia Pineda, Alejandra Gutiérrez, Montse Mila, Jaume Campistol. (2004) Tetrahydrobiopterin responsiveness in patients with phenylketonuria. Clinical Biochemistry 37:12, 1083-1090
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Lourdes R. Desviat, Belén Pérez, Amaya Bèlanger-Quintana, Margarita Castro, Cristina Aguado, Ascensión Sánchez, Maria José García, Mercedes Martínez-Pardo, Magdalena Ugarte. (2004) Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype. Molecular Genetics and Metabolism 83:1-2, 157-162
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Shigeo Kure, Kenichi Sato, Kunihiro Fujii, Yoko Aoki, Yoichi Suzuki, Seiichi Kato, Yoichi Matsubara. (2004) Wild-type phenylalanine hydroxylase activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Molecular Genetics and Metabolism 83:1-2, 150-156
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HARUO SHINTAKU, SHIGEO KURE, TOSHIHIRO OHURA, YOSHIYUKI OKANO, MISAO OHWADA, NARUJI SUGIYAMA, NOBUO SAKURA, ICHIRO YOSHIDA, MAKOTO YOSHINO, YOICHI MATSUBARA, KEN SUZUKI, KIKUMARO AOKI, TERUO KITAGAWA. (2004) Long-Term Treatment and Diagnosis of Tetrahydrobiopterin-Responsive Hyperphenylalaninemia with a Mutant Phenylalanine Hydroxylase Gene. Pediatric Research 55:3, 425-430
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Reuben Matalon, Richard Koch, Kimberlee Michals-Matalon, Kathryn Moseley, Sankar Surendran, Stephen Tyring, Heidi Erlandsen, Alejandra Gamez, Raymond C. Stevens, Anne Romstad, Lisbeth B. Møller, Flemming Guttler. (2004) Biopterin responsive phenylalanine hydroxylase deficiency. Genetics in Medicine 6:1, 27-32
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(2003) Tetrahydrobiopterin and Mild Phenylketonuria. New England Journal of Medicine 348:17, 1722-1724
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