Tetrahydrobiopterin responsiveness of patients with phenylalanine hydroxylase deficiency

Abstract

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 .

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

“…A clinically meaningful definition of BH 4 responsiveness is widely accepted as the observation of a 20%–30% reduction in blood Phe concentration (Blau, ; Levy, Burton, Cederbaum, & Scriver, ). Several protocols have been employed to demonstrate this reduction, as there is no consensus regarding the best BH 4 overload test (Giugliani et al., ). The sequential first clinical trials of sapropterin—Burton et al.…”

“…If the BIOPKU database were used for phenotype prediction of 45 genotypes from 66 patients in our sample, the discordance would decrease to 19.7%; and if both prediction systems, the BIOPKU database and the AV system, were accepted as valid, the genotype-phenotype discordance for 91 patients distributed among 67 genotypes would fall from 51.7% to 23.1%. The BIOPKU database uses the allelic phenotype value for predicting the metabolic phenotype of PAH variants and genotypes (Garbade et al, 2018). Nevertheless, the "predicted" phenotypes from the BIOPKU database of Table 2 were the reported phenotypes of the patients tabulated in that database.…”