Tetrahydrobiopterin responsiveness in patients with phenylketonuria

Pérez‐Dueñas, Belén; Vilaseca, M. A.; Mas, Anna; Lambruschini, Nilo; Artuch, Rafael; Sánchez, Lydia; Pineda, Julia; Gutiérrez, Amparo Del Pino; Mila, Montse; Campistol, Jaume

doi:10.1016/j.clinbiochem.2004.09.005

Cited by 34 publications

(28 citation statements)

References 26 publications

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“…The protocol to evaluate responsiveness in this study is innovative for two reasons: (1) it included the use of a simple Phe and a combined Phe + BH 4 loading test for 18 patients with PKU and good metabolic control; (2) it defined BH 4 responsiveness parameters based on the comparison of results of these two tests. According to the strategy adopted in this study, 33.3% (6/18) of the patients were classified as responsive, which is in agreement with data in the literature [17][18][19]23,30,34]. Of the responsive patients, two had the classical PKU (n= 2/8; 25.5%) and four, the mild PKU (n= 4/10; 40%), which confirmed that responsiveness is greater among individuals with milder forms of PKU.…”

Section: Discussionsupporting

confidence: 90%

“…The collection point 3 h after Phe loading was used because it has been described in the literature as the point at which Phe plasma levels peak predominantly [24]. However, in 9 patients in this study, the highest Phe plasma concentration values occurred at least, in one of the Tests, 11 h after Phe loading, which has also been reported by other studies [19,20].…”

Section: Comments On Dietary Ingestion and Phe Levels During The Testssupporting

confidence: 62%

“…The increase of Phe levels is often achieved by increasing the ingestion of dietary Phe [8,9,20,22,[28][29][30], which may raise ethical and psychological issues. A single Phe dose using L-Phe may also be administered, with the advantage that the patient's diet does not have to be changed [19,[31][32][33]; however, Phe levels after this type of loading tend to spontaneously decrease in 24 h even when BH 4 is not been administered [20,32]. Therefore, BH 4 responsiveness would have to be confirmed by comparing Phe plasma levels after the Phe + BH 4 loading test and after the simple Phe loading test.…”

Section: Discussionmentioning

confidence: 99%

“…Studies, however, have used different protocols to evaluate responsiveness: BH 4 doses are different and may range from 10 to 20 mg/kg/day in a single dose or distributed along the day; test evaluation times range from some hours to weeks or even months; the cut-off point of Phe variation defined to determine responsiveness also varies, and the criterion most frequently adopted is a decrease of 30% in Phe levels 24 h after BH 4 administration. In addition, different diets are used during tests: normal diets, Phe-restricted diet, or even a Phe-loading diet using, for example, powder milk or L-Phe [7,[9][10][11][12][13][14][15][16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency

Nalin

Perry

Sitta

et al. 2011

Molecular Genetics and Metabolism

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INTRODUCTION:Recent studies showed that phenylalanine (Phe) plasma concentrations may decrease in some patients with hyperphenylalaninemia (HPA) due to phenylalanine hydroxylase (PAH) deficiency, after the administration of tetrahydrobiopterin (BH(4)). OBJECTIVE: To determine responsiveness to a single dose of BH(4) administered according to an innovative protocol using a combined Phe and BH(4) loading test in Brazilian phenylketonuria (PKU) patients. METHODS: Patient age should be 4 years, and median Phe plasma concentration 600 mol/L when following dietary restrictions. Participants received a simple Phe loading test using 100mg/kg L-Phe (Test 1) and a combined Phe+BH(4) loading test using 100mg/kg L-Phe and 20mg/kg/BH(4) (Test 2). Blood samples were collected at baseline and 3, 11 and 27 h after Phe ingestion (T0, T1, T2 and T3). Responsiveness was defined as: criterion A: plasma Phe reduction of 30% at T1 and T2 for Tests 1 and 2; criterion B: plasma Phe reduction of 30% at T1 and T3 for Tests 1 and 2; and criterion C: at least 30% difference of the areas under the Phe curve for Tests 1 and 2. RESULTS: Eighteen patients (median age 12 yrs; 8 classical PKU; 10 mild PKU) participated in the study. Six patients (2 classical PKU; 4 mild PKU) were classified as responsive according to at least one of the criteria. Responsiveness was concordant when criteria A + B we compared with criterion C (kappa = 0.557; p = 0.017). Of the patients whose genotype was available (n = 16), six had data about BH(4)-responsiveness genotypes described in the literature, which were in agreement with our findings. CONCLUSION: The comparison of simple Phe loading and combined Phe + BH(4) loading seems to be an optimal method to evaluate responsiveness to BH (4) Introduction: Recent studies showed that phenylalanine (Phe) plasma concentrations may decrease in some patients with hyperphenylalaninemia (HPA) due to phenylalanine hydroxylase (PAH) deficiency, after the administration of tetrahydrobiopterin (BH 4 ). Objective: To determine responsiveness to a single dose of BH 4 administered according to an innovative protocol using a combined Phe and BH 4 loading test in Brazilian phenylketonuria (PKU) patients. Methods: Patient age should be ≥4 years, and median Phe plasma concentration ≤600 μmol/L when following dietary restrictions. Participants received a simple Phe loading test using 100 mg/kg L-Phe (Test 1) and a combined Phe + BH 4 loading test using 100 mg/kg L-Phe and 20 mg/kg/BH 4 (Test 2). Blood samples were collected at baseline and 3, 11 and 27 h after Phe ingestion (T0, T1, T2 and T3). Responsiveness was defined as: criterion A: plasma Phe reduction of ≥30% at T1 and T2 for Tests 1 and 2; criterion B: plasma Phe reduction of ≥30% at T1 and T3 for Tests 1 and 2; and criterion C: at least 30% difference of the areas under the Phe curve for Tests 1 and 2. Results: Eighteen patients (median age 12 yrs; 8 classical PKU; 10 mild PKU) participated in the study. Six patients (2 classical PKU; 4 mild PKU) were classified a...

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Section: Discussionsupporting

confidence: 90%

Section: Comments On Dietary Ingestion and Phe Levels During The Testssupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency

Nalin

Perry

Sitta

et al. 2011

Molecular Genetics and Metabolism

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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

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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Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

et al. 2008

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Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia has been recently described as a variant of PAH deficiency caused by specific mutations in the PAH gene. It has been suggested that BH(4)-responsiveness may be predicted from the corresponding genotypes. Data from BH(4) loading tests indicated an incidence of BH(4)-responsiveness of >40% in the general PKU population and >80% in mild PKU patients. The current project entailed genotype analysis of 315 BH(4)-responsive patients tabulated in the BIOPKUdb database and comparison with the data from the PAHdb locus-specific knowledgebase, as well as with previously published PAH mutations for several European countries, Northern China, and South Korea. We identified 57 mutations, presenting with a substantial residual PAH activity (average approximately 47%), presumed to be associated with BH(4)-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in >5% of BH(4)-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH(4)-responsiveness in European populations was calculated to be 55% (range 17-79%, lowest in Baltic countries and Poland and highest in Spain), 57% in Northern China, and 55% for South Korea. The genotype-predicted prevalence of BH(4)-responsiveness was higher than prevalence data obtained from BH(4) loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH(4)-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient's genotype.

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Tetrahydrobiopterin responsiveness in patients with phenylketonuria

Cited by 34 publications

References 26 publications

Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency

Optimized loading test to evaluate responsiveness to tetrahydrobiopterin (BH4) in Brazilian patients with phenylalanine hydroxylase deficiency

Tetrahydrobiopterin responsiveness of patients with phenylalanine hydroxylase deficiency

Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

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