The effect of blood phenylalanine concentration on Kuvan™ response in phenylketonuria

Elsas, Louis J.; Greto, Josephine; Wierenga, Andrea

doi:10.1016/j.ymgme.2010.12.003

Cited by 18 publications

(18 citation statements)

References 36 publications

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“…Two of our BH 4 -sensitive patients only showed significantly lower phe concentrations in dried blood after 96 h. Previously it was often difficult to decide whether a patient was BH 4 -sensitive or not (Elsas et al 2011). This might be one of the reasons why different authors have come to different results when trying to define patients as BH 4 -sensitive or BH 4 -resistant based on their specific mutation in the PAH gene (Lindner et al 2001;Hennermann et al 2005;Fiori et al 2005;Elsas et al 2011). We also found some patients showed a reduction in phe concentration in dried blood of between 15 and 30%.…”

Section: Discussionmentioning

confidence: 91%

Tetrahydrobiopterin (BH₄) in PKU: effect on dietary treatment, metabolic control, and quality of life

Ziesch¹,

Weigel²,

Thiele

et al. 2012

J of Inher Metab Disea

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Section: Discussionmentioning

confidence: 91%

Tetrahydrobiopterin (BH₄) in PKU: effect on dietary treatment, metabolic control, and quality of life

Ziesch¹,

Weigel²,

Thiele

et al. 2012

J of Inher Metab Disea

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“…Accordingly, discovery of a subset of PKU/HPA patients (Kure et al 1999), who respond to daily pharmacological oral doses of tetrahydrobiopterin (BH 4 ), the catalytic cofactor for the PAH enzyme, has attracted interest (Bernegger and Blau 2002;Panel NIoHCD 2001;Phenylketonuria MRCWPo 1993). For such patients, treatment with oral BH 4 in pharmacological doses improves enzyme activity, enhances Phe oxidation, and leads to reduction in blood Phe levels (Burton et al 2010;Elsas et al 2011;Levy et al 2007;Muntau et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?

et al. 2011

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Prospectively enrolled phenylketonuria patients (n ¼ 485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN ® ). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5-20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.

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“…In untreated PKU patients, Phe concentrations in blood and tissues are high, while tyrosine concentrations are low‐to‐normal (Elsas et al . ; Demirkol et al . ).…”

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confidence: 99%

“…In untreated PKU patients, Phe concentrations in blood and tissues are high, while tyrosine concentrations are lowto-normal (Elsas et al 2011;Demirkol et al 2011). Accumulation of phenylalanine and its metabolites results in a variety of symptoms, including hypopigmentation of skin and hair, growth failure, and behavioral abnormalities (Pietz 1998;Gonz alez et al 2011).…”

mentioning

confidence: 99%

Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model

Imperlini

Orrú

Corbo

et al. 2014

Journal of Neurochemistry

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Phenylketonuria (PKU), if not detected and treated in newborns, causes severe neurological dysfunction and cognitive and behavioral deficiencies. Despite the biochemical characterization of PKU, the molecular mechanisms underlying PKU-associated brain dysfunction remain poorly understood. The aim of this study was to gain insights into the pathogenesis of this neurological damage by analyzing protein expression profiles in brain tissue of Black and Tan BRachyury-PahEnu2 mice (a mouse model of PKU). We compared the cerebral protein expression of homozygous PKU mice with that of their heterozygous counterparts using two-dimensional difference gel electrophoresis analysis, and identified 21 differentially expressed proteins, four of which were over-expressed and 17 under-expressed. An in silico bioinformatic approach indicated that protein under-expression was related to neuronal differentiation and dendritic growth, and to such neurological disorders as progressive motor neuropathy and movement disorders. Moreover, functional annotation analyses showed that some identified proteins were involved in oxidative metabolism. To further investigate the proteins involved in the neurological damage, we validated two of the proteins that were most strikingly under-expressed, namely, Syn2 and Dpysl2, which are involved in synaptic function and neurotransmission. We found that Glu2/3 and NR1 receptor subunits were over-expressed in PKU mouse brain. Our results indicate that differential expression of these proteins may be associated with the processes underlying PKU brain dysfunction, namely, decreased synaptic plasticity and impaired neurotransmission.

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The effect of blood phenylalanine concentration on Kuvan™ response in phenylketonuria

Cited by 18 publications

References 36 publications

Tetrahydrobiopterin (BH₄) in PKU: effect on dietary treatment, metabolic control, and quality of life

Tetrahydrobiopterin (BH₄) in PKU: effect on dietary treatment, metabolic control, and quality of life

Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?

Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model

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The effect of blood phenylalanine concentration on Kuvan™ response in phenylketonuria

Cited by 18 publications

References 36 publications

Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life

Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life

Chaperone-Like Therapy with Tetrahydrobiopterin in Clinical Trials for Phenylketonuria: Is Genotype a Predictor of Response?

Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model

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Resources

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Tetrahydrobiopterin (BH₄) in PKU: effect on dietary treatment, metabolic control, and quality of life

Tetrahydrobiopterin (BH₄) in PKU: effect on dietary treatment, metabolic control, and quality of life