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


CONCLUSIONS
The comparison of simple Phe loading and combined Phe + BH(4) loading seems to be an optimal method to evaluate responsiveness to BH(4) in patients with good metabolic control.
Post-Graduation Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Tatiéle
T
Nalin
Ingrid Dalira Schweigert
ID
Perry
Angela
A
Sitta
Carmen Regla
CR
Vargas
Maria Luiza
ML
Saraiva-Pereira
Roberto
R
Giugliani
Nenad
N
Blau
Ida Vanessa Doederlein
IV
Schwartz
D000293:Adolescent; D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001938:Brazil; D002648:Child; D019937:Diagnostic Techniques and Procedures; D004032:Diet; D005247:Feeding Behavior; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D010649:Phenylalanine / Q000097:blood; D010661:Phenylketonurias / Q000097:blood / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D055815:Young Adult
D001708:Biopterins; D010649:Phenylalanine; C003402:sapropterin