Sapropterin dihydrochloride for phenylketonuria

Somaraju, Usha Rani; Merrin, M. P.

doi:10.1002/14651858.cd008005.pub4

Cited by 27 publications

(7 citation statements)

References 43 publications

(39 reference statements)

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“…A subset of patients with PKU benefit from adjunctive treatment with pharmacological doses of tetrahydropterin (BH4) or sapropterin hydrochloride (178). Robust evidence from two systematic reviews demonstrates that BH4 is effective in reducing blood Phe concentrations and in increasing the Phe “tolerance” in BH4-responsive PKU patients (179, 180). Long-term treatment with sapropterin of such responsive patients with PKU also appears to improve Phe tolerance and may allow patients to discontinue highly restrictive diets (181).…”

Section: Case Vignettesmentioning

confidence: 99%

Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments

et al. 2019

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Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations in the gene for phenylalanine hydroxylase (PAH). Reduced PAH activity results in significant hyperphenylalaninemia, which leads to alterations in cerebral myelin and protein synthesis, as well as reduced levels of serotonin, dopamine, and noradrenaline in the brain. When untreated, brain development is grossly disrupted and significant intellectual impairment and behavioral disturbance occur. The advent of neonatal heel prick screening has allowed for diagnosis at birth, and the institution of a phenylalanine restricted diet. Dietary treatment, particularly when maintained across neurodevelopment and well into adulthood, has resulted in markedly improved outcomes at a cognitive and psychiatric level for individuals with PKU. However, few individuals can maintain full dietary control lifelong, and even with good control, an elevated risk remains of—in particular—mood, anxiety, and attentional disorders across the lifespan. Increasingly, dietary recommendations focus on maintaining continuous dietary treatment lifelong to optimize psychiatric and cognitive outcomes, although the effect of long-term protein restricted diets on brain function remains unknown. While psychiatric illness is very common in adult PKU populations, very little data exist to guide clinicians on optimal treatment. The advent of new treatments that do not require restrictive dietary management, such as the enzyme therapy Pegvaliase, holds the promise of allowing patients a relatively normal diet alongside optimized mental health and cognitive functioning.

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Section: Case Vignettesmentioning

confidence: 99%

Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments

et al. 2019

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“…A smallscale study from Brazil, encompassing 18 patients, found six (33.3%) BH 4 -responders . As the prevalence of BH 4 responsiveness has been variable in different studies (Somaraju & Merrin, 2015), we cannot make any assertion concerning the probability of the figures from our PAH genotyping study and Nalin et al (2011) combined Phe and BH 4 loading test study to be confirmed in future BH 4 loading tests of our PKU population.…”

Section: Discussionmentioning

confidence: 71%

Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Neto

Laranjeira

Quelhas

et al. 2019

Molec Gen & Gen Med

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Background Genetic heterogeneity and compound heterozygosis give rise to a continuous spectrum of phenylalanine hydroxylase deficiency and metabolic phenotypes in phenylketonuria (PKU). The most used parameters for evaluating phenotype in PKU are pretreatment phenylalanine (Phe) levels, tolerance for dietary Phe, and Phe overloading test. Phenotype can vary from a “classic” (severe) form to mild hyperphenylalaninemia, which does not require dietary treatment. A subset of patients is responsive to treatment by the cofactor tetrahydrobiopterin (BH 4 ). Genotypes of PKU patients from Rio de Janeiro, Brazil, were compared to predicted and observed phenotypes. Genotype‐based estimations of responsiveness to BH 4 were also conducted. Methods Phenotype was defined by pretreatment Phe levels. A standard prediction system based on arbitrary assigned values was employed to measure genotype‐phenotype concordance. Patients were also estimated as BH 4 ‐responders according to the responsiveness previously reported for their mutations and genotypes. Results A 48.3% concordance rate between genotype‐predicted and observed phenotypes was found. When the predicted phenotypes included those reported at the BIOPKU database, the concordance rate reached 77%. A total of 18 genotypes from 30 patients (29.4%) were estimated as of potential or probable BH 4 responsiveness. Inconsistencies were observed in genotypic combinations including the common “moderate” mutations p.R261Q, p.V388M, and p.I65T and the mild mutations p.L48S, p.R68S, and p.L249F. Conclusion The high discordance rate between genotype‐predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so‐called “moderate” common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although our results of BH 4 estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype‐phenotype association studies are important in selecting patients to be offered a BH 4 overload test, especially in low‐resource settings like Brazil.

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“…This is the first time that changes in protein equivalent intake from protein substitute with BH4 treatment have been assessed systematically, although other systematic reviews or meta-analyses have investigated the effects of BH4 treatment on blood Phe control and dietary Phe tolerance [ 56 , 57 , 58 ]. We have demonstrated that PKU patients with long-term BH4 responsiveness had a significant increase in dietary Phe and natural protein intake when on BH4 treatment.…”

Section: Discussionmentioning

confidence: 99%

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis

Ilgaz

Marsaux

Pinto³

et al. 2021

Nutrients

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The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.

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Sapropterin dihydrochloride for phenylketonuria

Abstract: al. Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: evolution of seven patients on long-term treatment with tetrahydrobiopterin.

Cited by 27 publications

References 43 publications

Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments

Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments

Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis

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Sapropterin dihydrochloride for phenylketonuria

Abstract: al. Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: evolution of seven patients on long-term treatment with tetrahydrobiopterin.

Cited by 27 publications

References 43 publications

Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments

Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments

Genotype‐phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis

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Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil