The tetrahydrobiopterin loading test in 36 patients with hyperphenylalaninaemia: Evaluation of response and subsequent treatment

Bóveda, M. Dolores; Couce, María L.; Castiñeiras, Daisy; Cocho, José A.; Pérez, Belén López; Ugarte, Magdalena; Fraga, José M.

doi:10.1007/s10545-007-0567-1

Cited by 30 publications

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“…13 It has been previously shown that, depending on the country, ∼20% to 50% of all PKU patients (predominantly mild to moderate PKU) respond to oral administration of BH4, which lowers their blood Phe concentrations significantly. [14][15][16][17][18] Sapropterin dihydrochloride (Kuvan; Merck Serono SA, Geneva, Switzerland) has been approved by the Food and Drug Administration in the United States and by the European Medicines Agency in Europe for the treatment of PKU patients in combination with diet. 1 In short-and long-term prospective and retrospective clinical studies, it has resulted in significant and sustained reductions in blood Phe concentrations in patients with PKU, even if administrated as monotherapy.…”

Section: Discussionmentioning

confidence: 99%

Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study

et al. 2013

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WHAT'S KNOWN ON THIS SUBJECT: Pharmacologic treatment with sapropterin dihydrochloride (6R-tetrahydrobiopterin; BH4) has been an effective option for some phenylketonuria patients since its approval by the US Food and Drug Administration in 2007 and the European Medicines Agency in 2008. WHAT THIS STUDY ADDS:This retrospective multicenter study revealed the long-term effects of sapropterin on metabolic control, dietary tolerance, and the outcome of BH4-responsive phenylketonuria patients harboring specific phenotypes and genotypes. It also confirmed that the minor adverse events disappeared by lowering the dose. abstract OBJECTIVE: Sapropterin dihydrochloride, the synthetic form of 6R-tetrahydrobiopterin (BH4), is an approved drug for the treatment of patients with BH4-responsive phenylketonuria (PKU). The purpose of this study was to assess genotypes and data on the long-term effects of BH4/sapropterin on metabolic control and patient-related outcomes in 6 large European countries. METHODS:A questionnaire was developed to assess phenotype, genotype, blood phenylalanine (Phe) levels, Phe tolerance, quality of life, mood changes, and adherence to diet in PKU patients from 16 medical centers. RESULTS:One hundred forty-seven patients, of whom 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU, were followed up over #12 years. A total of 85 different genotypes were reported. With the exception of two splice variants, all of the most common mutations were reported to be associated with substantial residual Phe hydroxylase activity. Median Phe tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet was reported in 47% of patients, and improvement in adherence to treatment was reported in 63.3% of patients. No severe adverse events were reported. CONCLUSIONS: Our data document a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving the metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life. Patient genotypes help in predicting BH4 responsiveness.

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Section: Discussionmentioning

confidence: 99%

Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study

et al. 2013

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“…A mediana (intervalo interquartil) de idade dos pacientes foi de 14 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) anos. Consanguinidade parental não foi relatada.…”

Section: Resultsunclassified

“…A redução significativa nos níveis de Phe em resposta à administração oral de BH 4 é normalmente observada em cerca de 50% em pacientes com PKU leve 8,19 , e a redução dos níveis de Phe é maior em pacientes com fenótipos mais leves de PKU em comparação a pacientes com fenótipos mais graves, uma vez que a atividade residual da PAH é maior nas formas mais amenas da doença 20,21 . Nossos resultados demonstraram que pacientes com PKU clássica também podem ser responsivos ao teste de BH 4 .…”

Section: Responsividadeunclassified

Tetrahydrobiopterin responsiveness of patients with phenylalanine hydroxylase deficiency

et al. 2011

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Objective: To identify patients responsive to tetrahydrobiopterin (BH 4 ) in a sample of Brazilians with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency (HPA-PAH). Methods:Interventional study, convenience sampling. The inclusion criteria were: diagnosis of HPA-PAH; age ≥ 7 years; phenylalaninerestricted diet and phenylalanine (Phe) levels ≥ 6 mg/dL in all blood tests 1 year before inclusion. Blood samples were obtained the day before (day 1) and at 0, 4, 8 (day 2) and 24 h (day 3) after BH 4 intake. Phe levels were measured using tandem mass spectrometry. The criteria used to define responsiveness to BH 4 were: criterion 1-Phe reduction ≥ 30% 8 h after BH 4 administration; criterion 2 -Phe reduction ≥ 30% 24 h after BH 4 administration.Results: Eighteen patients were enrolled (median age, 14 years; 12 boys). Five patients were responsive to BH 4 , 3 according to both criteria (one classical PKU, two mild PKU); and two according to criterion 2 (one classical PKU; one indefinite PKU type). There were no differences between Phe serum levels on day 1 and at the other time points (p = 0.523). However, Phe levels on days 1 and 2 were significantly different (p = 0.006). The analysis of the phenotype-genotype association confirmed its multifactorial character. Conclusion ResumoObjetivo: Identificar indivíduos responsivos à tetrahibrobiopterina (BH 4 ) em uma amostra de pacientes brasileiros com hiperfenilalaninemia por deficiência de fenilalanina-hidroxilase (HPA-PAH).Métodos: Estudo intervencional, amostragem por conveniência. Para serem incluídos no estudo, os pacientes deveriam: possuir diagnóstico bioquímico de HPA-PAH; ter idade ≥ 7 anos; estar em tratamento dietético; e apresentar níveis de fenilalanina (Phe) ≥ 6 mg/dL em todas as medidas realizadas no ano anterior à inclusão no estudo. Os níveis de Phe foram determinados por meio de espectrometria de massas in tandem no dia anterior (dia 1) e nos pontos de hora 0, 4 e 8 h (dia 2) e 24 h (dia 3) após ingestão de BH 4 . Os critérios utilizados para definir responsividade ao BH 4 foram: critério 1-redução ≥ 30% de Phe após 8 h da administração de BH 4 ; e critério 2-redução ≥ 30% de Phe após 24 h da administração.Resultados: Dezoito pacientes foram incluídos no estudo (mediana de idade = 14 anos, sexo masculino = 12). Cinco pacientes foram responsivos ao BH 4 , sendo três (forma clássica: um; forma leve: dois) de acordo com ambos os critérios, e dois (forma clássica: um; forma não definida: um) de acordo com o critério 2. Os níveis de Phe plasmáticos do dia 1 não demonstraram variação nos pontos de hora (p = 0,523). Entretanto, quando comparamos os níveis de Phe nos pontos de hora dos dias 1 e 2, encontramos uma variação significativa (p = 0,006). A análise da associação genótipo-fenótipo confirmou o caráter multifatorial da responsividade ao BH 4. Conclusão:Os nossos achados estão de acordo com a literatura e indicam que um número relevante de pacientes brasileiros com HPA-PAH é responsivo à BH 4 .

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“…Patient no. 14, who at 2 years and 5 months underwent combined Phe/BH4 loading test (Bóveda et al 2007) with a 28% decrease of Phe level after 24 h, continued dietary treatment and at 8 years 6 months underwent a weekly BH4 loading test, with a 34% decrease in phe levels, since then, pharmacological treatment was added to dietary treatment. Table 2 shows the evolution of the group of patients with PKU treated with sapropterin; the table shows, tolerance and mean Phe levels before and after treatment with sapropterin, cofactor dose in each case, and time to treatment evolution.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous work (Bóveda et al 2007), we reported a study of response to oral BH4 loading in a group of 36 patients with PKU, and subsequent treatment and follow-up of patients who responded positively in this test. Here, we describe the evolution of patients in the PKU group, with different phenotypes, who responded to BH4 and are currently being treated with sapropterin (Kuvan ® ) in the Metabolic Disorders Unit of the University Clinical Hospital of Santiago de Compostela (Galicia, Spain).…”

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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The tetrahydrobiopterin loading test in 36 patients with hyperphenylalaninaemia: Evaluation of response and subsequent treatment

Cited by 30 publications

References 0 publications

Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study

Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study

Tetrahydrobiopterin responsiveness of patients with phenylalanine hydroxylase deficiency

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

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