Phe Levels Research Articles

Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial

BackgroundThe population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain.MethodsThe PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial.ParticipantsThirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life.Intervention: The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach.ObjectivesThe primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland.RandomizationCentral randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician.Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment.DiscussionUsing a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed.Trial registrationThe study is registered at clinicaltrials.gov (NCT03788343) on the 27th of December 2018, at kofam.ch (SNCTP000003117) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO.

Plasma adiponectin is a potential biomarker for organ involvement in male Fabry disease patients

Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial.A retrospective chart review was conducted at two U.S. clinics for individuals 10–40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017.152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites.Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.

A global disease patient registry for neuronopathic Gaucher

Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial.A retrospective chart review was conducted at two U.S. clinics for individuals 10–40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017.152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites.Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.

Metabolic and catecholamine response to sympathetic stimulation in early-treated adult male patients with phenylketonuria

PurposeDefective function of phenylalanine hydroxylase in phenylketonuria (PKU) results in the accumulation of phenylalanine (Phe) and the reduction of tyrosine (Tyr) in the blood, interfering in the normal development and function of organs and tissues in the body. Tyr is the precursor of catecholamines, secreted in response to stress by the adrenal medulla and paraganglia. The aim of this study was to evaluate plasma catecholamine and amino acid response to an escalating series of sympathetic stress tests in PKU patients.MethodsTwelve males with classical PKU (aged 18–41 years) and ten healthy male controls were included in this study. The subjects were exposed to three different sympathetic stress stimulations: cold pressor, isometric handgrip, and peak treadmill tests to exhaustion. Physiological, metabolic, and hormonal changes were determined.ResultsAerobic capacity (VO2max) was significantly lower in the PKU group (p = 0.018); however, relative VO2max was similar in the two groups during the spiroergometric test. No significant differences in norepinephrine or in epinephrine response were found between the two groups during the different stimulation tests. Blood Phe increased significantly in the PKU group compared with controls (p = 0.027) during the spiroergometric test, while Tyr levels remained stable in both groups.ConclusionPKU itself might not influence stress-induced catecholamine changes. Only strenuous exercise increased blood Phe levels in PKU subjects.

STAT1 upregulates glutaminase and modulates amino acids and glutathione metabolism

We previously reported the upregulation of cellular Glu and glutathione levels in human ABCB5- and murine Abcb5-transfected cells. Here, we demonstrate the upregulation of STAT1 and glutaminase (GLS) in ABCB5/Abcb5-transfected cells. Among a total of four ABCB5/Abcb5 high-expressing clones with docetaxel resistance, three of the clones expressed STAT1 and GLS highly and showed resistance to docetaxel and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. Neither STAT1 nor GLS upregulation was observed in the remaining ABCB5 high-expressing clone, as well as in another two ABCB5 low-expressing clones; these three clones did not show BSO resistance. The ABCB5/STAT1 high-expressing clones showed higher cellular levels of Ala, Glu, and Asp and lower cellular levels of Phe, Trp, Leu, Ile, Gly, Met, Tyr, Val, and His compared to the ABCB5/STAT1 low-expressing clones. The former clones also showed a higher resistance to Glu. The STAT1-transfected clones expressed high levels of GLS and the corresponding mRNA, suggesting the transactivation of GLS by STAT1. These clones showed resistance to Glu and BSO, similar to the ABCB5/STAT1 high-expressing clones. The cellular glutathione levels of the STAT1-transfected clones were significantly higher than that of the control. The STAT1-transfected clones also showed greater resistance to the effect of BSO on the cellular glutathione depletion compared to the control. These results demonstrate that STAT1 upregulates GLS and modulates amino acids and glutathione metabolism. Although we were unable to directly prove STAT1 upregulation by ABCB5, our results suggest that ABCB5 expression, directly or indirectly, leads to the overexpression of STAT1.

Monitoring of Phenylalanine Levels in Patients with Phenylketonuria Using Dried Blood Spots: a Comparison of Two Methods

Abstract Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), responsible for the conversion of phenylalanine (Phe) to tyrosine (Tyr). Monitoring of patients with PKU requires the measurement of Phe in plasma using high-performance liquid chromatography (HPLC) or in dried blood spots (DBS) using different techniques to adjust treatment strategy. The objective of this study was to evaluate Phe levels in DBS measured by two different methods and compare them with Phe levels measured in plasma by HPLC. We analyzed 89 blood samples from 47 PKU patients by two different methods: fluorometric method developed in-house (method A) and the commercially available PerkinElmer® Neonatal Phenylalanine Kit (method B) and in plasma by HPLC. The mean Phe levels by method A, method B, and HPLC were 430.4±39.9μmol/L, 439.3±35.4μmol/L, and 442.2±41.6μmol/L, respectively. The correlation values between HPLC and methods A and B were 0.990 and 0.974, respectively (p < 0.001 for both). Our data suggest that methods A and B are useful alternatives for monitoring Phe levels in patients with PKU, with method A being in closer agreement with the reference standard (HPLC).

Significance of tetrahydrobiopterin in management of hyperphenylalaninemia

Background: The Sapropterin dihydrochloride enzyme cofactor, a synthetic analog form of 6R-BH4, was offered as an oral treatment for hyperphenylalaninemia. The sapropterin dihydrochloride role in patients with phenylketonuria (PKU) is to activate the endogenous phenylalanine hydroxylase (PAH) and to restore partially the oxidative metabolism of phenylalanine (Phe), when patients have insufficiency or lack of tetrahydrobiopterin. The sapropterin dihydrochloride anticipated to restore PAH activity through providing an exogenous source of the lost or deficient cofactor. Aim of Study: This study aims to evaluate the effects and clinical significance of tetrahydrobiopterin supplementation in hyperphenylalaninemia. Patients and Methods: This study describes the use of tetrahydrobiopterin in 58 patients with hyperphenylalaninemia treated before the age of 15 years with the use of tetrahydrobiopterin loading test. More than 30% decrement in Phe consider positive. Results: Fifty-eight patient been enrolled in this prospective study as follows; seven patient non PKU hyperphenylalaninemia (Phe level

Does the 48-hour BH4 loading test miss responsive PKU patients?

BackgroundPhenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism. Besides dietary treatment, some patients are responsive to and treated with tetrahydrobiopterin (BH4). Our primary objective was to examine whether the 48-hour BH4 loading test misses BH4-responsive PKU patients. Secondary, we assessed if it would be beneficial to 1) use a cut-off value of 20% Phe reduction instead of commonly used 30%, and 2) extend the loading test to 7 days. Methods24 patients with a 20–30% decrease of blood Phe levels during their initial 48-hour BH4 loading test or at least one mutation associated with long-term BH4 responsiveness, were invited to participate. 22 of them underwent the 7-day BH4 loading test. During the BH4 loading test, BH4 was administered orally once daily for 7 days (20 mg/kg/day). Blood samples on filter paper were collected at 13 time points. Potential BH4 responders (≥20% decrease in blood Phe concentrations at ≥1 moment within the first 48 h or ≥30% at ≥1 moment during the entire test) underwent a treatment trial to assess true long-term responsiveness (≥30% decrease of Phe levels compared to baseline and/or ≥50% increase in natural protein tolerance in accordance with the Dutch guidelines before 2017). The duration of the treatment trial varied from 2 to 18 months. ResultsOf the 22 patients who completed the 7-day BH4 loading test, 2 were excluded, 8 had negative tests and 12 were considered to be potential BH4 responders. Of these 12 potential BH4-responsive PKU patients, 5 turned out to be false positive, 6 true-responder and 1 was withdrawn. ConclusionEven though the 48-hour BH4 loading test has proven its efficacy in the past, a full week may be necessary to detect all responders. So, if blood Phe concentrations during the 48-hour BH4 test shows a clear tendency, but not sufficient decrease, a full week (with only measurements each 24 h) could be offered. A threshold of ≥20% decrease within 48 h is not useful for predicting true BH4 responsiveness.

Psychosocial functioning in children with phenylketonuria: Relationships between quality of life and parenting indicators.

This study aimed to assess the impact of phenylketonuria (PKU) and its treatment on parent and child health-related quality of life (HRQoL) and to identify the parenting-related correlates of parent and child HRQoL, as well as metabolic control. Eighteen mothers of 2- to 12-year-old children with PKU participated and completed a series of self-report questionnaires including the PKU Impact and Treatment Quality of Life Questionnaire (PKU-QOL). Mothers reported that the most significant impact of PKU on HRQoL was in relation to the impact of their child's anxiety during blood tests on their own HRQoL and guilt related to poor adherence to dietary restrictions and supplementation regimens. Higher reported intensity of child emotional and behavioural difficulties and parenting stress were associated with higher scores for PKU symptoms on the PKU-QOL, higher scores for emotional, social, and overall impact of PKU, and higher scores for the impact of dietary restriction. Where mothers reported greater use of overreactivity as a parenting strategy, children tended to have better lifetime phenylalanine levels; however, the overall impact of PKU and the impact of supplement administration on mothers' HRQoL were worse for these families. These findings have implications for a holistic family-centred approach to the care of children with PKU and their families.

5-year retrospective analysis of patients with phenylketonuria (PKU) and hyperphenylalaninemia treated at two specialized clinics

BackgroundPhenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial. MethodsA retrospective chart review was conducted at two U.S. clinics for individuals 10–40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017. Results152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites. ConclusionDespite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.

Adult cognitive outcomes in phenylketonuria: explaining causes of variability beyond average Phe levels

ObjectiveThe objective was to deepen the understanding of the causes of individual variability in phenylketonuria (PKU) by investigating which metabolic variables are most important for predicting cognitive outcomes (Phe average vs Phe variation) and by assessing the risk of cognitive impairment associated with adopting a more relaxed approach to the diet than is currently recommended.MethodWe analysed associations between metabolic and cognitive measures in a mixed sample of English and Italian early-treated adults with PKU (N = 56). Metabolic measures were collected through childhood, adolescence and adulthood; cognitive measures were collected in adulthood. Metabolic measures included average Phe levels (average of median values for each year in a given period) and average Phe variations (average yearly standard deviations). Cognition was measured with IQ and a battery of cognitive tasks.ResultsPhe variation was as important, if not more important, than Phe average in predicting adult outcomes and contributed independently. Phe variation was particularly detrimental in childhood. Together, childhood Phe variation and adult Phe average predicted around 40% of the variation in cognitive scores. Poor cognitive scores (> 1 SD from controls) occurred almost exclusively in individuals with poor metabolic control and the risk of poor scores was about 30% higher in individuals with Phe values exceeding recommended thresholds.ConclusionsOur results provide support for current European guidelines (average Phe value = < 360 μmol/l in childhood; = < 600 μmo/l from 12 years onwards), but they suggest an additional recommendation to maintain stable levels (possibly Phe SD = < 180 μmol/l throughout life).Public significance statementsWe investigated the relationship between how well people with phenylketonuria control blood Phe throughout their life and their ability to carry out cognitive tasks in adulthood. We found that avoiding blood Phe peaks was as important if not more important that maintaining average low Phe levels. This was particularly essential in childhood. We also found that blood Phe levels above recommended European guidelines was associated with around 30% increase in the risk of poor cognitive outcomes.

Large Neutral Amino Acid Therapy Increases Tyrosine Levels in Adult Patients with Phenylketonuria: A Long-Term Study.

The standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitutes; however, adult patients often show poor adherence to therapy. Alternative treatment options include the use of large neutral amino acids (LNAA). The aim of this study was to determine the Phe, tyrosine (Tyr), and Phe/Tyr ratio in a cohort of sub-optimally controlled adult patients with classical PKU treated with a new LNAA formulation. Twelve patients received a Phe-restricted diet plus a slow-release LNAA product taken three times per day, at a dose of 1 g/kg body weight (mean 0.8 ± 0.24 g/kg/day), over a 12-month period. The product is in a microgranulated formulation, which incorporates all amino acids and uses sodium alginate as a hydrophilic carrier to prolong its release. This LNAA formulation provides up to 80% of the total protein requirement, with the rest of the protein supplied by natural food. Patients had fortnightly measurements of Phe and Tyr levels over a 12-month period after the introduction of LNAA. All patients completed the 12-month treatment period. Overall, adherence to the new LNAA tablets was very good compared with a previous amino acid mixture, for which taste was a major complaint by patients. Phe levels remained unchanged (p = 0.0522), and Tyr levels increased (p = 0.0195). Consequently, the Phe/Tyr ratio decreased significantly (p < 0.05) in the majority of patients treated. In conclusion, LNAA treatment increases Tyr levels in sub-optimally controlled adult PKU patients, while offering the potential to improve their adherence to treatment.

Tunable Coffee Ring Formation on Polycarbonate Nanofiber Film for Sensitive SERS Detection of Phenylalanine in Urine.

A new method based on the coffee ring effect was developed for improving the sensitivity, simplicity, and robustness of surface-enhanced Raman scattering (SERS) in determining trace levels of analytes. In this method, a polyvinylpyrrolidone (PVP)-stabilized silver colloidal (AgC) solution was first prepared and mixed with a sample solution. Following deposition of the mixture solution on a solid substrate with a rough surface, a coffee ring was formed once the solvent had evaporated. The formation of a coffee ring not only concentrated the analyte but also reduced the space between silver nanoparticles (AgNPs) to strengthen the hotspot effect, thereby considerably improving SERS sensitivity. To strengthen the coffee ring effect further, the surface roughness of the solid support and PVP content of the AgC solution were investigated. The results indicated that an increase in surface roughness reduced the size of the coffee rings, whereas the addition of PVP not only stabilized the AgNPs but also improved the compactness of the coffee rings. When applying the proposed method to determine the phenylalanine (Phe) level in urine for rapid screening of the phenylketonuria disorder, strong chemical interference from uric acid (UA), which is a major component in urine, was observed. To minimize the interference from UA, ZnO powder was applied to the urine sample to adsorb UA prior to SERS detection. After cleaning by using ZnO, the SERS signals of Phe were revealed for quantitative purposes. Under the optimized conditions, both the sensitivity and reproducibility of SERS measurement considerably improved. Quantitative analyses revealed that the developed method is highly feasible for the rapid determination of Phe in real samples.

Phenylketonuric patients represent their disease.

Background Phenylketonuria (PKU) is a metabolic disorder resulting in high phenylalanine (Phe) blood concentrations due to the deficiency of the hepatic enzyme Phe hydroxylase. High Phe levels are currently treated with diet, thus avoiding mental retardation, psychomotor delay, etc. The aim of this study was to find out the self-presentation of the disease by the patients. Methods A total number of 110 patients self-represented their disease: food allergy (Phe allergy) n = 34/110 (30.9%), health problems n = 31/110 (28.2%), severe health problems n = 26/110 (23.6%), very severe health problems n = 19/110 (17.3%). The Wechsler Intelligence Scale for Children (WISC III) psychometric test was utilized for the evaluation of IQ scores of each participant. A special questionnaire was used focusing on quality of life (QL), social discrimination (SD) and anxiety or depression (AD). Results IQ scores were found to be higher in food allergy self-represented patients than those of the other tested groups. The lowest IQ scores were observed in those who represented very severe disease. QL, SD and AD were not observed in the food allergy groups. On the contrary, those who self-presented as very severe diseased patients felt high a disturbance of QL, SD and AD. Conclusions The food allergy group seemed to be a very clever excuse for adhering to PKU treatment resulting in high IQ scores and absence of the mentioned upsets. In contrast, in the other groups of patients' IQ scores were found to be lower than that of food allergy group. Damage of QL, SD, AD were also apparent.

Therapy compliance in children with phenylketonuria younger than 5 years: A cohort study.

Phenylketonuria (PKU) is a metabolic disease. It is manifested by a complete or partial inability to convert phenylalanine (Phe) to tyrosine and leads to increased concentrations of Phe in the blood and in other tissues, including the brain, causing irreversible neurological damage if left untreated. Low-phenylalanine diet is a key component of classical PKU therapy. The objective of this study was to assess the effectiveness of classical phenylketonuria therapy and compliance with doctors' recommendations in the first 5 years of life. Data was collected from all diagnosed and treated patients (n = 57) born 1999-2010. Phenylalanine blood levels, the number of visits to a specialist outpatients' center, the number of blood tests, as well as socioeconomic status (SES) and parents' education level have been analyzed, and potential relationships have been assessed. In the 1st year of life patients visited their doctors (odds ratio (OR) = 6.8267; 95% confidence interval (95% CI) = 2.827-16.5163; p < 0.0001) and had their blood collected (OR = 2.7875; 95% CI = 1.0467-7.4234; p < 0.0402) significantly more frequently than in the 2nd year. This tendency persisted into subsequent years. Similarly, in infancy they had statistically significantly lower odds of exceeding more than 40% of their Phe levels over therapeutic range than 1 year later (OR = 3.6078; 95% CI = 1.4859-8.7599; p < 0.0046). No PKU child had more than 70% of Phe levels over the therapeutic range in the 1st year of life, whereas 4 years later there were 18 such children. Phe levels were correlated with the number of visits to a specialist (ρ = 0.39) and the number of Phe blood tests with index of dietary control (ρ = -0.33). The effectiveness of therapy and compliance with the doctor's recommendations seem to depend neither on the level of education of the patient's parents nor on their SES. Therapy effectiveness and patients' compliance in PKU is very good in infancy. However, both deteriorate in subsequent years. Moreover, they do not seem to depend on the family background.

A benefit-risk analysis of pegvaliase for the treatment of phenylketonuria: A study of patients' preferences

BackgroundPhenylketonuria (PKU) leads to an accumulation of phenylalanine (Phe) in the blood and subsequent neurologic, cognitive, psychiatric, and behavioral dysfunction. Many patients report social isolation and decreased quality of life. Pegvaliase is an enzyme substitution therapy that reduces blood Phe levels in patients with PKU and is associated with a risk of hypersensitivity reactions. ObjectiveTo define the minimum acceptable benefit (MAB) of pegvaliase, i.e., the minimum probability of achieving a blood Phe level <360 μmol/L, which patients require to tolerate the risks of hypersensitivity associated with pegvaliase. MethodsAdult, pegvaliase-naïve patients with blood Phe levels >600 μmol/L participated in a patient-preference web survey using two surveys: adapted swing-weighting and thresholding. Participants were asked to make ordinal choices between varying clinical benefit and severity levels for hypersensitivity. Disease effects and treatment satisfaction were also assessed. ResultsAmong 45 participants, the mean (standard deviation) self-reported blood Phe level was 976.9 (429.9) μmol/L; only 28.8% reported satisfaction with their current treatment. Most (84.4%) indicated difficulty in following a PKU diet; 60% reported that the PKU diet was burdensome, and 58% reported feeling socially isolated. Most (≥69%) reported their MAB to be less than the expected clinical benefit provided by pegvaliase; the mean MAB was 22.7% and 34.4% in the swing-weighting and thresholding surveys, respectively. ConclusionMost participants felt the burden of PKU on their daily lives, were dissatisfied with current treatments, and were willing to accept the risks of hypersensitivity reactions to achieve recommended blood Phe levels with pegvaliase treatment.

Of mice and men: Plasma phenylalanine reduction in PKU corrects neurotransmitter pathways in the brain

In phenylketonuria (PKU), mutations of the phenylalanine hydroxylase (PAH) gene decrease the ability of PAH to convert phenylalanine (Phe) to tyrosine (Tyr), resulting in Phe accumulation in the blood and brain and disruption of neurotransmitter (NT) biosynthesis and metabolism. The following translational study explored the relationship between pegvaliase-mediated Phe correction in plasma and the NT biosynthesis and metabolism pathway in mice and humans with PKU. Lower plasma Phe levels were associated with normalization of the NT biosynthesis pathway which correlated with an improvement in inattention symptoms in subjects with PKU.

Food Neophobia in Patients With Phenylketonuria

Background: In phenylketonuria (PKU), only a limited range of natural foods, such as fruits, vegetables, oils and sugars, can be consumed without restrictions. The present study aimed to study if food neophobia (i.e. an unwillingness to eat novel food) occurs in patients with PKU and to compare in non-PKU healthy controls and to identify any associated factors. Methods: This cross-sectional case-control study used a convenience sampling strategy to recruit patients diagnosed with PKU and healthy controls matched by gender and age. Patients and controls were invited to complete the food neophobia scale (FNS) questionnaire, and clinical and treatment data were collected through a review of medical records. Results: Twenty-five patients (mean age 19.3 ± 4.7 years, 13 women) with PKU and 25 controls (mean age 19.9 ± 4.9 years; P = 0.676, 13 women) were evaluated. The mean age of treatment onset in patients with PKU was 52.8 ± 29.7 days. The mean phenylalanine (Phe) level in the 12-month preceding neophobia study was 710.5 ± 346 µmol/L. The mean FNS score of patients with PKU was significantly higher (47.2 ± 9.7) than controls (29.4 ± 12.5, P < 0.001). Food neophobia was associated more with male gender (P = 0.039). Conclusions: Food neophobia is frequent in patients with PKU. It does not appear to be associated with female gender, with Phe levels and not just in children. J Endocrinol Metab. 2019;9(4):108-112 doi: https://doi.org/10.14740/jem581

Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency, resulting in high blood and brain Phenylalanine (Phe) concentrations that can lead to impaired brain development and function. Standard treatment involves a Phe-restricted diet alone or in conjunction with sapropterin dihydrochloride in responsive patients. The Food and Drug Administration approved pegvaliase enzyme substitution therapy for adults with blood Phe >600 μmol/L in the US. Recently, the European Commission also approved pegvaliase for treatment of PKU patients aged 16 years or older with blood Phe >600 μmol/L. The analyses presented below were conducted to provide comparative evidence on long-term treatment effectiveness of pegvaliase versus standard of care in adults with PKU.Adult patients (≥18 years) with baseline blood Phe >600 μmol/L who had enrolled in the pegvaliase phase 2 and phase 3 clinical trials were propensity score-matched to historical cohorts of patients treated with “sapropterin + diet” or with “diet alone”. These cohorts were derived from the PKU Demographics, Outcome and Safety (PKUDOS) registry and compared for clinical outcomes including blood Phe concentration and natural intact protein intake after 1 and 2 years. Propensity scores were estimated using logistic regression with probability of treatment as outcome (i.e. pegvaliase, “sapropterin + diet”, or “diet alone”) and patient demographic and disease severity covariates as predictors. An additional analysis in adult PKU patients with baseline blood Phe ≤600 μmol/L comparing non-matched patient groups “sapropterin + diet” to “diet alone” using PKUDOS registry data only was also conducted.The analyses in patients with baseline blood Phe >600 μmol comparing pegvaliase with “sapropterin + diet” (N = 64 matched pairs) showed lower mean blood Phe concentrations after 1 and 2 years with pegvaliase (505 and 427 μmol/L) versus “sapropterin + diet” (807 and 891 μmol/L); mean natural intact protein intake after 1 and 2 years was 49 and 57 g/day respectively with pegvaliase versus 23 and 28 g/day with “sapropterin + diet”. The analysis comparing pegvaliase with “diet alone” (N = 120 matched pairs) showed lower mean blood Phe at 1 and 2 years with pegvaliase (473 and 302 μmol/L) versus “diet alone” (1022 and 965 μmol/L); mean natural intact protein intake after 1 and 2 years was 47 and 57 g/day with pegvaliase and 27 and 22 g/day with “diet alone”. Considerably more patients achieved blood Phe ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe after 1 and 2 years of pegvaliase versus standard treatments. The analysis in patients with baseline blood Phe ≤600 μmol/L showed lower blood Phe after 1 and 2 years with “sapropterin + diet” (240 and 324 μmol/L) versus “diet alone” (580 and 549 μmol/L) and greater percentages of patients achieving blood Phe targets ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe.These results support pegvaliase as the more effective treatment option to lower Phe levels in adults with PKU who have difficulty keeping blood Phe ≤600 μmol/L with “diet alone”. For patients with blood Phe ≤600 μmol/L, adding sapropterin to dietary management is an appropriate treatment option, for those responsive to the treatment.

Phenylalanine and tyrosine measurements across gestation by tandem mass spectrometer on dried blood spot cards from normal pregnant women

PurposeMaternal phenylketonuria (MPKU) requires strict control of phenylalanine (Phe) and supplemental tyrosine (Tyr). Monitoring during pregnancy using dried blood spot (DBS) cards by tandem mass spectrometry (MS/MS) is now standard practice, however there are no Phe and Tyr reference ranges for DBS MS/MS method in healthy pregnant women. MethodsDBS cards (63–1364 days in storage) from healthy women with singleton pregnancies were analyzed by MS/MS. Three hundred ninety DBS cards from 170 pregnancies (5/1–39/6 weeks’ gestation), were tested. ResultsBoth Phe and Tyr levels declined from the first trimester (Phe: 36.2 +/− 10.6; Tyr 25.7 +/− 9.7 µmol/L) to the second trimester (Phe 33.4+/−9.3; Tyr 21.7+/− 6.7 µmol/L) and remained stable in the third trimester (Phe 32.3 +/− 8.7; Tyr 21.0 +/− 6.6 µmol/L). Phe and Tyr levels declined over time since collection (Phe: 0.004 µmol/L per day; Tyr 0.002 µmol/L). Nomograms by gestational age were created using raw data and data adjusted for time from sample collection. Reference ranges by trimester are provided. ConclusionsBoth Phe and Tyr decline quickly during the first trimester and remain relatively constant over the second and third trimesters. These nomograms will provide a valuable resource for care of MPKU.