Dietary Phe Tolerance Research Articles

Maximal dietary responsiveness after tetrahydrobiopterin (BH4) in 19 phenylalanine hydroxylase deficiency patients: What super-responders can expect

BackgroundInherited phenylalanine hydroxylase deficiency, also known as phenylketonuria (PKU), causes poor growth and neurologic deficits in the untreated state. After ascertainment through newborn screen and dietary phenylalanine (Phe) restriction to achieve plasma Phe in the range of 120–360 μmol/L, these disease manifestations can be prevented. Poor compliance with protein restricted diets supported by medical food is typical in later years, beginning in the late toddler and teenage years. Pharmacologic doses of oral tetrahydrobiopterin (BH4; sapropterin dihydrochloride) is effective in reducing plasma Phe in about 40–50% of PKU patients but effectiveness is highly variable. ObjectiveTo assess the maximal responsiveness to 20 mg/kg/day oral BH4 as it affects plasma Phe and dietary Phe allowance in PKU patients. Materials and methodsThis was a single-center, retrospective observational study, combining case reports of individual patients. We reported an outcome of 85 patients with PKU who were trialed on BH4. Phe levels and dietary records of 19 BH4 “super-responders” were analyzed. ResultsOverall, 63.5% of the patients (54/85) were considered BH4 responders. However, we quantitated the dietary liberalization of 19 of our responsive patients (35%), those with at least a 2-fold increase in dietary Phe and maintenance of plasma Phe in treatment range. In these “super-responders”, the mean plasma Phe at baseline was 371 ± 237 μmol/L and decreased to 284 ± 273 μmol/L after 1 year on BH4. Mean dietary Phe tolerance increased significantly from 595 ± 256 to 2260 ± 1414 mg/day (p ≤0.0001), while maintaining mean plasma Phe levels within treatment range. Four patients no longer required dietary Phe restriction and could discontinue medical food. The majority of patients had at least one BH4-responsive genotype. ConclusionThis cohort demonstrates the maximally achievable dietary liberalization which some PKU patients may expect with BH4 therapy. Health benefits are considered to accrue in patients with increased intact protein.

Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at

BackgroundDuring the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin.ResultsAll 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘sapropterin extension’ group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘sapropterin continuous’ group (95% CI 28.9, 48.6; p < 0.0001). In the ‘sapropterin extension’ group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI − 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters.ConclusionsLong-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment.Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908.

Neonatal phenylalanine wash-out in phenylketonuria.

Phenylketonuria (PKU) is the most common inborn error of amino acids metabolism. PKU management aims to keep as soon as possible blood phenylalanine (Phe), a non-acutely neurotoxic metabolite, within safe ranges through a dietary Phe restriction tailored to individual dietary Phe tolerance. Information on initial neonatal management of PKU, when Phe tolerance is still unknown, is scanty.We reviewed the metabolic data from 304 patients with PAH deficiency detected at newborn screening within the last 37years. In keeping with the general neonatal management of intoxication-type inborn errors of metabolism, initial management consisted in a Phe wash-out through the exclusive administration of normocaloric Phe-free formulas until normalization of blood Phe.Based on genotype and Phe tolerance assessed at follow-up, 55 patients had classic PKU (18%), 50 mild PKU (17%), and 199 non-PKU hyperphenylalaninemia (HPA) (65%). The duration of Phe wash-out amounted to 7 ± 2days in classic PKU, 4 ± 2days in mild PKU, and < 24h in non-PKU HPA (p < 0.001). After the wash-out, dietary Phe re-introduction and its upwardly titration allowed the assessment of individual metabolic phenotype. During the first 6years of life, Phe tolerance was stable in classic PKU (~ 200mg/day) but increased in milder forms, allowing unrestricted diet in non-PKU HPA.Neonatal Phe wash-out in PKU ensures the earliest correction of HPA. This metabolic reset also facilitates the prompt definition of individual Phe tolerance, allowing anticipation of dietary personalization and optimization of longitudinal metabolic control.

Phenylalanine hydroxylase genotype-phenotype associations in the United States: A single center study

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase gene (PAH). The correlation between genotype and phenotype can be complex and sometimes variable but often very useful for categorizing and predicting dietary tolerance and potential outcome. We reviewed medical records for 367 patients diagnosed with PKU or persistent mild hyperphenylalaninemia (MHP) between 1950 and 2015 who had PAH genotyping. In 351 we had the full PAH genotype as well as phenotypic characteristics such as phenylalanine (Phe) concentrations (at newborn screening, confirmation, and highest known), and dietary Phe tolerance. On 716 mutant chromosomes, including 14 in genotypes with only one identified variant, we identified 114 different pathogenic variants. The most frequent, p.R408W, was present in 15.4% of the alleles; other frequent variants were c.1315 + 1G > A (6.1%), p.I65T (5.7%), and p.R261Q (5.7%). Three variants, c.142 T > G (p.L48 V), c.615G > C (p.E205D), and c.1342_1345delCTCC, were novel. We used the phenotypic parameters of variants paired with null alleles (functional hemizygotes) to assign the variants as classic PKU, moderate PKU, mild PKU, MHP-gray zone, or MHP. We also included the phenotype association(s) for all of the full genotypes. In 103 patients, we also could assign sapropterin dihydrochloride responsiveness, which is a synthetic form of the tetrahydrobiopterin (BH4) PAH cofactor. This compilation from a single metabolic center provides further information on PAH variants in the United States and the correlations between genotype and phenotype.

Efficacy and safety of sapropterin dihydrochloride in patients with phenylketonuria: A meta-analysis of randomized controlled trials.

AimsThe aim of the present meta‐analysis was to evaluate the efficacy and safety of sapropterin dihydrochloride in phenylketonuria (PKU) patients.MethodsThe following databases were searched for randomized controlled trials (RCT) regarding PKU patients treated with sapropterin dihydrochloride: PubMed, Embase, Cochrane Library and clinicaltrials. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta‐analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration.ResultsFour studies met the inclusion criteria. In PKU patients with low blood phenylalanine (Phe) concentration, no significant difference was indicated for the decrease of Phe level (weighted mean difference (WMD) = −7.75 μmol L−1; 95% confidence intervals (CI): −82.63 to 67.13, P = 0.84, I 2 = 0%), however, the dietary Phe tolerance was significantly improved in the sapropterin group (WMD = 19.89 mg kg−1 d−1; 95% CI: 10.26 to 29.52, P < 0.0001, I 2 = 0%). In PKU patients with high blood Phe level, sapropterin showed a significant lowering in blood Phe concentration (WMD = −225.31 μmol L−1; 95% CI: −312.28 to −138.34, P < 0.00001, I 2 = 0%). There was no significant difference for adverse events.ConclusionsSapropterin could bring benefit for PKU patients with high or low Phe level, due to Phe reduction in a short time or dietary Phe tolerance improvement respectively. Sapropterin has an acceptable safety profile.

Long-term safety and efficacy of sapropterin: the PKUDOS registry experience.

The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N = 504 who were continuously exposed to sapropterin from date of registry enrollment, N = 211 who had intermittent exposure to the drug, and N = 474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe)--from 591 ± 382 μmol/L at baseline to 392 ± 239 μmol/L (p = 0.0009) after 5 years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000 ± 959 mg/day (pre-sapropterin baseline) to 1539 ± 840 mg/day after 6 years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤ 1% of subjects. Similar safety and efficacy data were observed for children<4 years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance.

Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride.

We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake.

Longitudinal quality of life analysis in a phenylketonuria cohort provided sapropterin dihydrochloride

BackgroundSapropterin dihydrochloride effectively lowers plasma phenylalanine (Phe) for at least a third of phenylketonuria (PKU) patients, with potential for increased dietary Phe tolerance and decreased medical food requirement.ObjectiveTo investigate long-term quality of life (QOL) in patients with phenylketonuria (PKU) who took sapropterin (BH4, Kuvan®) for up to one year.Methods37 PKU patients, ages 10–49 years, were asked to complete a PKU-specific self-report QOL questionnaire (QOLQ) at baseline, 1, 4, 8, and 12 months. Questions were scored on a 5-point Likert scale under 5 sub-sections measuring Impact, Worries, Satisfaction, Support, and General wellbeing in relation to PKU. Responders with a plasma Phe decrease ≥ 15% after 1 month on sapropterin remained on the drug; Nonresponders ceased sapropterin after the trial month. Responders able to relax medical diet and maintain plasma Phe control were classified as Definitive; Responders unable to relax medical diet were classified as Provisional. All patients were routinely monitored by a registered dietitian. Data was analyzed in SPSS 19.0 using regression techniques.ResultsOf 17 Responders, 11 could maintain adequate Phe control on a less restrictive diet. One year mean Impact sub-score trends improved significantly for all sapropterin response groups, with greatest improvement among Definitive Responders (p < 0.0001). Satisfaction sub-scores also improved for Definitive Responders (p = 0.001). Trends for Total QOL score improved significantly over time for both Definitive (p = 0.001) and Provisional Responders (p = 0.028). Improvements in Definitive Responder scores were associated with increased Phe tolerance (Impact: p < 0.0001, Satisfaction: p = 0.022, Total QOL: p = 0.005) and MF adjustment (Satisfaction: p = 0.014, Total QOL: p = 0.026). Other sub-section scores remained steady, unaffected by sapropterin response or diet modification.ConclusionIncreased Phe tolerance and reduced MF requirement in sapropterin Definitive Responders improves QOL perception across one year, specifically for life impact and satisfaction.

Application of tetrahydrobiopterin in treatment of phenylketonuria

Until recently, the common treatment for phenylketonuria(PKU)was a phenylalanine(Phe)-restric-ted diet.Increasing evidence of suboptimal outcomes was observed in diet-treated individuals.The observation of clinically significant reductions in blood Phe levels in a subset of patients with PKU following oral administration of tetrahydrobiopterin(BH4), a cofactor of phenylalanine hydroxylase.Clinical studies suggest that treatment with BH4 provides better Phe control and increases dietary Phe tolerance, allowing significant relaxation or even discontinuation of dietary Phe restriction.The current knowledge on this novel pharmacologic approach to the treatment of PKU will be discussed. Key words: Tetrahydrobiopterin; Phenylalanine hydroxylase; Phenylketonuria

A Pilot Study of Fluorodeoxyglucose Positron Emission Tomography Findings in Patients with Phenylketonuria before and during Sapropterin Supplementation

Background and PurposePET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate. Phenylalanine (Phe) and its metabolites appear to impair several aspects of brain energy metabolism. 1) To evaluate brain glucose metabolism with FDG-PET imaging in phenylketonuria (PKU) patients before and 4 months after sapropterin therapy; 2) to evaluate neurodevelopmental changes, blood Phe levels and dietary Phe tolerance before and after sapropterin therapy; 3) to generate pilot data to assess the feasibility of evaluating brain glucose metabolism with FDG-PET imaging and to explore potential trends resulting from the administration of sapropterin therapy.MethodsWe enrolled 5 subjects, ranged in age from 22 years to 51 years, with PKU. Subjects underwent FDG-PET brain imaging, blood tests for Phe and tyrosine levels, and neurocognitive evaluations before and 4 months after sapropterin therapy (20 mg/kg/day). All subjects' Phe and tyrosine levels were monitored once a week during the study. Subjects kept 3 day diet records that allow calculation of Phe intake.ResultsNone of the subjects responded to sapropterin therapy based on 30% decrease in blood Phe level. The data show that glucose metabolism appeared depressed in the cerebellum and left parietal cortex while it was increased in the frontal and anterior cingulate cortices in all five subjects. In response to sapropterin therapy, relative glucose metabolism showed significant increases in left Broca's and right superior lateral temporal cortices. Interestingly, there was corresponding enhanced performance in a phonemic fluency test performed during pre- and postneurocognitive evaluation.ConclusionsFurther studies with a larger sample size are needed to confirm the above changes in both sapropterin non-responsive and responsive PKU patients.

Recommendations for the use of sapropterin in phenylketonuria

Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. Until recently, the only treatment for PKU was a Phe-restricted diet. Increasing evidence of suboptimal outcomes in diet-treated individuals, inconsistent PKU management practices, and the recent availability of tetrahydrobiopterin (BH4) therapy have fueled the need for new management and treatment recommendations for this metabolic disorder. BH4, now available as sapropterin dihydrochloride (sapropterin), may offer the potential for improved metabolic control as well as enhanced dietary Phe tolerance in some PKU patients. A group of metabolic dietitians from North America convened in June 2011 to draft recommendations for the use of sapropterin therapy in PKU. Physicians with extensive experience in PKU management were invited at a later date to contribute to the development of these recommendations. Based on extensive clinical experience and current evidence, the present recommendations provide guidance from patient selection and determination of sapropterin response to the long-term management of patients on sapropterin therapy. Target Phe levels, nutritional adequacy, neurocognitive screening and adherence to treatment are addressed to optimize patient outcomes.

Tetrahydrobiopterin Therapy for Phenylketonuria in Infants and Young Children

To describe patient selection, treatment administration, response evaluation, and side effect management associated with sapropterin therapy in infants and children aged <4 years. Six case reports are presented from 4 US metabolic clinics treating phenylketonuria with sapropterin in patients aged 7 months to 4 years. Outcomes included blood phenylalanine (Phe) levels before and during treatment. For 3 of 6 cases, diet records were used to monitor changes in dietary Phe. Severity of phenylketonuria ranged from mild to severe (classic). Treatment with sapropterin was safe and generally well tolerated. Blood Phe levels were reduced, or maximum dietary Phe tolerance was increased in patients with blood Phe that was well controlled by diet. Given the increasing evidence that maintaining blood Phe levels below 360 μmol/L is important for the normal development of neurocognitive and behavioral function, sapropterin can be combined with a Phe-restricted diet to control blood Phe levels in young patients responsive to sapropterin therapy.

Sapropterin dihydrochloride for phenylketonuria and tetrahydrobiopterin deficiency

Sapropterin dihydrochloride is the first registered synthetic form of the naturally occurring cofactor and cosubstrate, tetrahydrobiopterin (BH4). It is essential for the conversion of phenylalanine (Phe) by phenylalanine-4-hydroxylase (PAH) to tyrosine. BH4 is also the co-factor of rate-limiting enzymes involved in the synthesis of monoamine neurotransmitters. Phenylketonuria (PKU) is an inherited disorder of PAH, characterized by elevated Phe concentrations (hyperphenylalaninemia) in the blood and brain, with toxic neurological consequences. Sapropterin dihydrochloride is approved for treating patients (of all ages in the USA and >4 years old in Europe) with PKU who are BH4 responsive, and those with BH4 deficiency (Europe). It decreases blood Phe concentration and increases dietary Phe tolerance in some patients with PKU on a low-Phe diet, allowing dietary adjustment or even discontinuation of a low-Phe diet. This article reviews sapropterin dihydrochloride for the management of PKU – aimed at improving clinical outcomes and quality of life – and it considers the potential for incorporating such information into international consensus guidelines.

Influence of knowledge of the disease on metabolic control in phenylketonuria.

In patients with phenylketonuria (PKU) knowledge of the disease and its treatment is not a major independent predictor for dietary compliance. PKU is an inborn error of amino-acid metabolism caused by a deficiency of phenylalanine hydroxylase (PAH), resulting in high plasma phenylalanine (Phe) concentrations and consequently severe mental retardation. Treatment comprises a life-long diet and PKU patients maintaining good metabolic control develop normally [3]. Poor dietary compliance is a regularly encountered problem. Increasing knowledge of the disease and its treatment may be a possibility to improve dietary compliance. Until now few studies have investigated this issue in PKU and the results are not conclusive [2, 4, 5, 6]. We therefore conducted a study to assess knowledge of the disease and its treatment in a large population of PKU patients and their parents and to determine the association between knowledge and the plasma Phe concentration as an indicator of dietary compliance in PKU. Parents of 161 PKU patients (aged 1 to 22 years) and 62 PKU patients (aged 12 to 22 years) completed a questionnaire to assess knowledge. The mean plasma Phe concentration during a 3-year period (1994 to 1996) was taken as an indicator of metabolic control. Table 1 shows the questions and the number of parents and patients correctly answering each separate question. We had expected that the greater part of the patients and their parents would correctly answer the questions. However, only 52% of the parents and 29% of the patients answered more than 11 of the 14 questions adequately. Linear regression showed that higher knowledge was associated with lower Phe concentrations, but this association was statistically significant only in the parent group (parents: b=)28, 95% CI)39/)17; patients: b=)20, 95% CI)42/2). After adjustment for confounders (pre-treatment Phe concentrations and dietary Phe tolerance, both as indicators for the severity of the enzyme deficiency, patient’s age, parental educational level and ethnicity) this association disappeared (parents: b=)0.4, 95% CI)8/ 7; patients: b=)1.5, 95% CI)10/7) and pre-treatment Phe concentrations, Phe tolerance and ethnicity were the strongest predictors for Phe concentration.

Pretreatment Serum Phenylalanine Levels As a Predictor of the Severity of the Mutation in the Phenylalanine Hydroxylase Gene and Phenylalanine Tolerance in Patients with Phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of hepatic phenylalanine hydroxylase (PAH). This study was designed to determine the correlation between pretreatment serum Phe levels and dietary Phe tolerance in patients with PKU, >2 years of age. Pretreatment serum Phe levels during the neonatal period were obtained 2-3 hours postprandially and analyzed by ion exchange chromatography in thirty seven patients with classic PKU after a positive newborn screening Guthrie test. PAH mutations were classified as severe, intermediate, or mild on the basis of expression analysis of the mutant alleles in eukaryotic cells. Phe tolerance was calculated as the amount of dietary Phe intake in mg/kg body weight per day given as natural protein,while maintaining serum Phe levels within the range of 2-6mg/dL. Phe tolerance by patients within the three groups was <12mg/kg/day in the severe group, 12-18mg/kg/day in the intermediate group and >18mg/kg/day in the mild group. A strong correlation between pretreatment serum Phe levels and Phe tolerance was observed (p<0.003) . The mean of pretreatment serum Phe levels (mmol/L) in mild, intermediate,and severe groups was 841±500 (n=7) , 1513 ±657(n=10) and 1970±781(n=20), respectively. We conclude that the pretreatment serum Phe can be used as one of the predictive parameters by clinicians to estimate future Phe tolerance and severity of disease.