Tetrahydrobiopterin Therapy for Phenylketonuria in Infants and Young Children

Burton, Barbara K.; Adams, Darius; Grange, Dorothy K.; Malone, John I.; Jurecki, Elaina; Bausell, Heather; Marra, Kayt D.; Sprietsma, Laurie; Swan, Kathleen T.

doi:10.1016/j.jpeds.2010.08.016

Cited by 31 publications

(17 citation statements)

References 23 publications

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“…Late-responders can be missed with this protocol; longer term challenges should then be considered at a later age. Although the few publications regarding this subject have not mentioned any side-effects of BH4 in very young patients [50–52], there have been no standardized tests to measure safety in children under 4 years of age. For this reason, the European authorities do not recommend its use in this age group, and the centers that do so must do it under compassionate use.…”

Section: Tetrahydrobiopterin (Bh4)mentioning

confidence: 99%

Up to date knowledge on different treatment strategies for phenylketonuria

Bélanger-Quintana

Burlina

Harding

et al. 2011

Molecular Genetics and Metabolism

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Dietary management for phenylketonuria was established over half a century ago, and has rendered an immense success in the prevention of the severe mental retardation associated with the accumulation of phenylalanine. However, the strict low-phenylalanine diet has several shortcomings, not the least of which is the burden it imposes on the patients and their families consequently frequent dietary non-compliance. Imperfect neurological outcome of patients in comparison to non-PKU individuals and nutritional deficiencies associated to the PKU diet are other important reasons to seek alternative therapies. In the last decade there has been an impressive effort in the investigation of other ways to treat PKU that might improve the outcome and quality of life of these patients. These studies have lead to the commercialization of sapropterin dihydrochloride, but there are still many questions regarding which patients to challenge with sapropterin what is the best challenge protocol and what could be the implications of this treatment in the long-term. Current human trials of PEGylated phenylalanine ammonia lyase are underway, which might render an alternative to diet for those patients non-responsive to sapropterin dihydrochloride. Preclinical investigation of gene and cell therapies for PKU is ongoing. In this manuscript, we will review the current knowledge on novel pharmacologic approaches to the treatment of phenylketonuria.

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Section: Tetrahydrobiopterin (Bh4)mentioning

confidence: 99%

Up to date knowledge on different treatment strategies for phenylketonuria

Bélanger-Quintana

Burlina

Harding

et al. 2011

Molecular Genetics and Metabolism

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“…With a mean evolution time of 53 months (12-87 months), phe tolerance increases have persisted following the phase of maximum growth after six months since birth, which constitutes a "honeymoon period," and protein requirement, including Phe intake, is easily assimilated (Burlina and Blau 2009) without any secondary effects resulting from the medication. Medical literature includes few published studies that use sapropterin at those ages (Spaapen et al 2001;Shintaku et al 2004;Hennermann et al 2005;Burton et al 2011), like us, all of them found the drug to be safe and no significant side effects were observed. Classical dietary treatment of PKU may cause several micronutrient deficiencies (Acosta and Yannicelli 1999); children treated with BH4 since neonatal period had a good somatic growth development and an adequate nutritional status, including selenium which was deficient in many patients treated with dietary treatment.…”

Section: Discussionmentioning

confidence: 76%

“…Although this formulation has been used extensively in experimental studies, it has not been evaluated in formal clinical trials and was not recorded. A newer formulation of BH4 (sapropterin dihydrochloride, Kuvan ® ) for the treatment of PKU that is more stable at room temperature has been available in the USA and Europe (Burnett 2007) Burton et al 2011;Blau et al 2010;Vernon et al 2010;Trefz et al 2010). No serious adverse events with BH4 treatment were reported in medical literature (Belanger-Quintana et al 2005;Nielsen et al 2010); headache, upper respiratory tract infections, and rhinorrhea were the side effects observed in sapropterin-treated patients with PKU in clinical trials (Kuvan Trefz et al 2009a).…”

Section: Introductionmentioning

confidence: 99%

Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

Couce¹,

Bóveda²,

Valerio³

et al. 2011

JIMD Reports

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BH4 therapy is an advancement in the treatment of phenylketonuria, reducing blood phenylalanine (phe) levels and increasing tolerance to natural proteins of responding patients. We report the results of 16 patients undergoing long-term BH4 treatment. Responding patients to BH4 was usually based on 24-h loading tests; a !30% decrease in blood phe was considered a positive response. Weekly loading made it possible to identify an additional "slow responder." The 16 responders constitute 24.6% of patients who completed the trial (87.5% of responders in mild hyperphenylalaninemia, 38.1% in mild PKU, and 2.8% in classical PKU).Mean dose of BH4 used was 9.75 AE 0.9 mg/kg per day, during a mean of 62 months. Age at treatment start was below 4 years in seven patients; five of which begun treatment during their first month since birth. All but one patient showed good treatment compliance; six continue on BH4 monotherapy without dietary phe restriction; six showed an increase in phe tolerance of 24-55%; and in the five patients who received treatment since the neonatal period an increase in phe tolerance following the phase of maximum growth has persisted. None of the patients showed side effects except one whom vomiting at the beginning of the treatment.Testing at the time of diagnosis in the neonatal period is very appropriate, and if there is a positive response, the patient can be treated with BH4 from onset with the advantage of being able to continue breast-feeding.

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“…It is prescribed to patients 4 years of age and onwards 4 . The implementation of pharmacological intervention at a younger age has been recently indicated to be feasible and beneficial 37 . It is also noted that sapropterin could be considered as a treatment option in pregnant women with PKU who cannot achieve the recommended ranges of blood Phe level with dietary therapy alone 38 .…”

Section: Discussionmentioning

confidence: 99%

The Predictive Value of Genetic Analyses in the Diagnosis of Tetrahydrobiopterin (BH4)-Responsiveness in Chinese Phenylalanine Hydroxylase Deficiency Patients

Zhu

Han

et al. 2017

Sci Rep

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Molecular characterization of PAH deficiency has been proven essential in establishing treatment options. We examine the diagnostic accuracy of two genetic assays to predict BH4 responsiveness: to determine whether the AV sum test or mutation-status assessment test can obviate the need for BH4 loading in Chinese patients. The overall predicted response in 346 patients was 31.65% by the AV sum test and 25.43% by the other assay; both percentages were lower than 51.06% derived from loading results in 94 patients. Responders were compound heterozygotes with definite BH4 responsive mutations, while non-responders had null/null ones; some consistently with specific mutations and genotypes. The sensitivity and specificity of the assays were 81.1% and 92.5% for the AV sum, and 82.9%, 97.3% for the other. An AV sum cutoff >2 has a positive predictive value (PPV) of 90.9%, while the presence of at least one BH4 responsive mutation has a PPV of 97.1%. The two approaches showed good concordance. Our data confirmed that the mutation-status assessment has a higher diagnostic accuracy in predicting response for Chinese patients than the AV sum test. BH4-responsiveness may be predicted or excluded from patients’ molecular characteristics to some extent, thus some patients may avoid the initial loading.

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Tetrahydrobiopterin Therapy for Phenylketonuria in Infants and Young Children

Cited by 31 publications

References 23 publications

Up to date knowledge on different treatment strategies for phenylketonuria

Up to date knowledge on different treatment strategies for phenylketonuria

Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

The Predictive Value of Genetic Analyses in the Diagnosis of Tetrahydrobiopterin (BH4)-Responsiveness in Chinese Phenylalanine Hydroxylase Deficiency Patients

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