Tetrahydrobiopterin-responsive phenylketonuria: The New South Wales experience

Mitchell, John; Wilcken, Bridget; Alexander, Ian E.; Ellaway, Carolyn; O’Grady, Helen; Wiley, Veronica; Earl, John; Christodoulou, John

doi:10.1016/j.ymgme.2005.06.008

Cited by 31 publications

(20 citation statements)

References 15 publications

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“…Following the assumption (Muntau et al 2002) that patients with at least one BH 4 -responsive mutation would be responsive to BH 4 , as many as 47 % of patients in our cohort may benefit from this treatment. A number of the patients in the NSW cohort have been previously tested for BH 4 responsiveness (Mitchell et al 2005). The correlation between genotypes and BH 4 responses in these patients is uncertain (Table 3), supporting previous findings that genotype is not an absolute predictor of BH 4 responsiveness (Lindner et al 2001;Karačić et al 2009).…”

Section: Discussionsupporting

confidence: 60%

“…A number of patients in this cohort have been previously tested for response to a BH 4 -load (Mitchell et al 2005). These patients were given BH 4 over a period of 7 days, and blood Phe levels were measured at 8 h, 32 h and the 7th day.…”

Section: Resultsmentioning

confidence: 99%

“…These patients were given BH 4 over a period of 7 days, and blood Phe levels were measured at 8 h, 32 h and the 7th day. A decrease of Phe of 30 %, compared to pre-BH 4 level, was deemed to be clinically significant (Mitchell et al 2005). Patients are classed as 'positive' if they reached a decrease of 30% after 8 h, 'intermediate' if a decrease of 30 % was observed at 32 h or at the 7th day and 'negative' if no decrease of 30% or greater was observed at any point (Leuzzi et al 2006), but one of our patient's homozygous for this mutation was not responsive (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…There are various reasons proposed for the difficulty of correlating BH 4 responsiveness with genotype. First, the methods of ascertaining BH 4 responsiveness have changed with time, and there may also be differences in the interpretation of responsiveness between the centers at which the tests were carried out (Mitchell et al 2005;Fiege and Blau 2007;Anjema et al 2011). Individuals may differ in their rate of BH 4 -absorption, protein catabolic rate and Phe intake during the test.…”

Section: Discussionmentioning

confidence: 99%

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The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutation screening was carried out in a large cohort of PKU patients from New South Wales, Australia. Pathogenic mutations were identified in 99% of the alleles screened, with the two most common mutations (p.R408W and IVS12+1G>A) accounting for 30.7% of alleles. Most individuals were compound heterozygotes for previously reported mutations, but four novel mutations (c. 163+1G>T, c.164-2A>G, c.461A>T [p.Y154F], and c.510-1G>A) and a novel polymorphism (c.60+62C>T) were also identified.A number of patients have been previously tested for their response to dietary supplementation of tetrahydrobiopterin (BH 4 ), the cofactor of PAH. Correlation between genotype and the responses revealed that although genotype is a major determinant of BH 4 responsiveness, patients with the same genotype may also show disparate responses to this treatment. A clinical and biochemical evaluation should be undertaken to determine the effectiveness of PKU treatment by supplementation of BH 4 .

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Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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“…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%

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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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-responsive phenylketonuria: The New South Wales experience

Cited by 31 publications

References 15 publications

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

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

Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

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