Insurance Reimbursement for Special Foods and Phenylalanine Levels in Patients With PKU in China.

Importance: Recent changes in China's social medical insurance reimbursement policy have impacted the financial burden of patients with phenylketonuria (PKU) for special foods. However, whether this policy change is associated with their blood phenylalanine (PHE) concentration is unclear. Objective: To investigate the association between the reimbursement policy and blood PHE concentration in patients with PKU. Design, Setting, and Participants: This cohort study measured the blood PHE concentrations of 167 patients with PKU across 4 newborn screening centers in China from January 2018 to December 2021. The reimbursement policy for special foods for patients with PKU at 2 centers was canceled in 2019 and restored from 2020 onwards. In contrast, the other 2 centers consistently implemented the policy. Data were analyzed from September 10 to December 6, 2023. Exposures: The implementation and cancelation of the reimbursement policy for special foods of patients with PKU. Main Outcomes and Measures: The blood PHE concentration was regularly measured from 2018 to 2021. A 1-sided Z test was used to compare the mean of the blood PHE concentration between different years. Results: Among 167 patients with PKU (mean [SD] age, 84.4 [48.3] months; 87 males [52.1%]), a total of 4285 measurements of their blood PHE concentration were collected from 2018 to 2021. For patients at the center that canceled the reimbursement policy in 2019, the mean (SD) of the blood PHE concentrations in 2019 was 5.95 (5.73) mg/dL, significantly higher than 4.84 (4.11) mg/dL in 2018 (P < .001), 5.06 (5.21) mg/dL in 2020 (P = .006), and 4.77 (4.04) mg/dL in 2021 (P < .001). Similarly, for patients at the other center that canceled the policy in 2019, the mean (SD) of the blood PHE concentrations in 2019 was 5.95 (3.43) mg/dL, significantly higher than 5.34 (3.45) mg/dL in 2018 (P = .03), 5.13 (3.15) mg/dL in 2020 (P = .003), and 5.39 (3.46) mg/dL in 2021 (P = .03). On the contrary, no significant difference was observed between any of the years for patients at the 2 centers that consistently implemented the policy. Conclusions and Relevance: In this cohort study of patients with PKU from multiple centers, the implementation of the reimbursement policy for special foods was associated with controlling the blood PHE concentration. Special foods expenditure for patients with PKU should be included in the scope of long-term social medical insurance reimbursement.

Vitamin Status in Patients with Phenylketonuria: A Systematic Review and Meta-Analysis.

The published data on the vitamin status of patients with phenylketonuria (PKU) is contradictory; therefore, this systematic review and meta-analysis evaluated the vitamin status of PKU patients. A comprehensive search of multiple databases (PubMed, Web of Sciences, Cochrane, and Scopus) was finished in March 2024. The included studies compared vitamin levels between individuals diagnosed with early-treated PKU and healthy controls while excluding pregnant and lactating women, untreated PKU or hyperphenylalaninemia cases, control groups receiving vitamin supplementation, PKU patients receiving tetrahydrobiopterin or pegvaliase, and conference abstracts. The risk of bias in the included studies was assessed by the Newcastle-Ottawa scale. The effect sizes were expressed as standardised mean differences. The calculation of effect sizes with 95% CI using fixed-effects models and random-effects models was performed. A p-value < 0.05 was considered statistically significant. The study protocol was registered in the PROSPERO database (CRD42024519589). Out of the initially identified 11,086 articles, 24 met the criteria. The total number of participants comprised 770 individuals with PKU and 2387 healthy controls. The meta-analyses of cross-sectional and case-control studies were conducted for vitamin B12, D, A, E, B6 and folate levels. PKU patients demonstrated significantly higher folate levels (random-effects model, SMD: 1.378, 95% CI: 0.436, 2.320, p = 0.004) and 1,25-dihydroxyvitamin D concentrations (random-effects model, SMD: 2.059, 95% CI: 0.250, 3.868, p = 0.026) compared to the controls. There were no significant differences in vitamin A, E, B6, B12 or 25-dihydroxyvitamin D levels. The main limitations of the evidence include a limited number of studies and their heterogeneity and variability in patients' compliance. Our findings suggest that individuals with PKU under nutritional guidance can achieve a vitamin status comparable to that of healthy subjects. Our study provides valuable insights into the nutritional status of PKU patients, but further research is required to confirm these findings and explore additional factors influencing vitamin status in PKU.

Comprehensive analyses of phenylalanine hydroxylase variants and phenotypic characteristics of patients in the eastern region of Türkiye.

OBJECTIVES: Phenylalanine hydroxylase (PAH) is predominantly a hepatic enzyme that catalyzes phenylalanine (Phe) into tyrosine, which is the rate-limiting step in Phe catabolism. Biallelic variants in the PAH gene cause PAH enzyme deficiency. Phenylketonuria (PKU) is an autosomal recessive disorder that causes neurologic, behavioral, and dermatological findings. PKU could be divided clinically into three types based on the blood Phe levels: classic phenylketonuria (cPKU), mild-moderate phenylketonuria (mPKU), and mild hyperphenylalaninemia (MHP). This study aimed to determine the phenotypic and genotypic characteristics of Turkish PKU patients in the eastern region of Türkiye. METHODS: Demographic characteristics, serum Phe levels, treatments, and PAH variants of 163 patients with PKU and hyperphenylalaninemia (HPA) were retrospectively evaluated. Blood Phe levels of the patients were analyzed with the high-performance liquid chromatography method. For PAH gene analysis, next-generation sequencing was performed. RESULTS: Of the 163 patients included in the study, 38 (23.3 %) had cPKU, 16 (9.8 %) had mPKU, and 109 (66.9 %) had MHP. Homozygous variants in the PAH gene were detected in 66 (40.5 %) of the patients, while compound heterozygous variants were detected in 97 (59.5 %) patients. Two novel and 35 recurrent variants in the PAH gene were detected. Of the two novel variants, one was missense (p.Phe351Leu) and the other was frameshift (p.Met276Cysfs*65). The most frequently detected variants were p.Thr380Met (18 %), p.Arg261Gln (16.8 %), and p.Ala300Ser (12.8 %). All patients with the homozygous c.1066-11G>A variant exhibited cPKU phenotype. The c.898G>T (p.Ala300Ser), c.1139C>T (p.Thr380Met), and c.1208C>T (p.Ala403Val) variants were statistically related to mild phenotype. On the other hand, c.592_613del (p.Tyr198Serfs*136), c.1028A>G (p.Tyr343Cys), and c.782G>A (p.Arg261Gln) variants were more frequently detected in the cPKU group. CONCLUSIONS: Our study, conducted with patients from the eastern region of Türkiye, demonstrates the genetic heterogeneity in the Turkish population. Simultaneously, our research contributes to genotype-phenotype correlation and expands the genotypic spectrum by identifying novel variants.

Comparison of Cost Analysis in Patients with Tetrahydrobiopterin-Responsive and Non-Responsive Phenylketonuria in Turkey.

Phenylketonuria is an inherited metabolic disorder that leads to neurobehavioral dysfunction. The main treatment is a low-phenylalanine diet and/or the cofactor tetrahydrobiopterin. Regular outpatient follow-up care and measurement of the phenylalanine levels in the blood are required. We aimed to analyze the economic burden of phenylketonuria on families and the state. The patients with phenylketonuria were divided into three groups according to their treatment: a low-phenylalanine diet group (n = 50), a tetrahydrobiopterin group (n = 44), and a group taking tetrahydrobiopterin together with the diet (n = 25). A comparative cost analysis was carried out. The annual economic burden to the state was calculated to average EUR 18,801 ± 15,345 and was lowest in the diet group, then in the tetrahydrobiopterin group, and highest in the tetrahydrobiopterin + diet group (p < 0.001). Out-of-pocket costs amounted to EUR 1531 ± 1173 per year, and indirect losses averaged EUR 2125 ± 1930 per year for all families. The economic loss was significantly lower in the families taking tetrahydrobiopterin than in the other groups (p = 0.001). The combined use of medical nutrition and BH4 treatments has been shown to increase the economic burden on the state. Reimbursing low-protein products and increasing the number of patients eligible for financial allowances may reduce the economic burden on families.

Children and Adolescents with Early Treated Phenylketonuria: Cognitive Development and Fluctuations of Blood Phenylalanine Levels.

BACKGROUND: We assessed the relationship between the cognitive development of children and adolescents with phenylketonuria (PKU) and fluctuations in peripheral phenylalanine (Phe) levels. METHODS: We examined the neurocognitive performance of 33 children and adolescents with early treated PKU, of whom 18 were treated with sapropterin dihydrochloride, and 15 were on a classic diet. For 26 weeks, patients were assessed weekly for their blood phenylalanine (Phe) levels. Phe levels were analyzed for fluctuations indicated by the individual standard deviation. Fluctuations were compared to the standard deviation of 26 Phe level measurements before the study interval. We also assessed the concurrent IQ of the patients. This was repeated at one-, two-, and seven-year intervals. RESULTS: Full-scale IQ in patients treated with a classic diet did not change within the follow-up. In patients treated with Sapropterin dihydrochloride, however, there was a considerable gain in full-scale IQ. This was particularly true if blood Phe fluctuations increased in patients of this treatment group. CONCLUSIONS: Sapropterin dihydrochloride enhances Phe tolerance in patients with PKU. Increasing blood Phe fluctuations following enhanced Phe tolerance may indicate that the treatment not only allows patients to relax their Phe-restricted diet but also may support cognitive development in patients.

Satisfaction with home blood sampling methods and expectations for future point-of-care testing in phenylketonuria: Perspectives from patients and professionals.

INTRODUCTION: Phenylketonuria (PKU) requires regular phenylalanine monitoring to ensure optimal outcome. However, home sampling methods used for monitoring suffer high pre-analytical variability, inter-laboratory variability and turn-around-times, highlighting the need for alternative methods of home sampling or monitoring. METHODS: A survey was distributed through email and social media to (parents of) PKU patients and professionals working in inherited metabolic diseases in Denmark, The Netherlands, and United Kingdom regarding satisfaction with current home sampling methods and expectations for future point-of-care testing (POCT). RESULTS: 210 parents, 156 patients and 95 professionals completed the survey. Countries, and parents and patients were analysed together, in absence of significant group differences for most questions. Important results are: 1) Many patients take less home samples than advised. 2) The majority of (parents of) PKU patients are (somewhat) dissatisfied with their home sampling method, especially with turn-around-times (3-5 days). 3) 37% of professionals are dissatisfied with their home sampling method and 45% with the turn-around-times. 4) All responders are positive towards developments for POCT: 97% (n = 332) of (parents of) patients is willing to use a POC-device and 76% (n = 61) of professionals would recommend their patients to use a POC-device. 5) Concerns from all participants for future POC-devices are costs/reimbursements and accuracy, and to professionals specifically, accessibility to results, over-testing, patient anxiety, and patients adjusting their diet without consultation. CONCLUSION: The PKU community is (somewhat) dissatisfied with current home sampling methods, highlighting the need for alternatives of Phe monitoring. POCT might be such an alternative and the community is eager for its arrival.

PTC923 (sepiapterin) lowers elevated blood phenylalanine in subjects with phenylketonuria: a phase 2 randomized, multi-center, three-period crossover, open-label, active controlled, all-comers study.

BACKGROUND & AIM: PTC923 (formerly CNSA-001), an oral formulation of sepiapterin, a natural precursor of intracellular tetrahydrobiopterin (BH4), has been shown in humans to induce larger increases in circulating BH4 vs. sapropterin dihydrochloride. Sapropterin reduces blood phenylalanine (Phe) by ≥20-30% in a minority of subjects with PKU. This was a Phase 2 randomized, multicenter, three-period crossover, open-label, active controlled, all-comers [regardless of phenylalanine hydroxylase (PAH) variants] comparison of PTC923 60 mg/kg, PTC923 20 mg/kg and sapropterin 20 mg/kg in 24 adults with phenylketonuria (PKU) and hyperphenylalaninemia. METHODS: Eligible subjects were adult men or women (18-60 y) with PKU. Subjects enrolled received 7 days of once-daily oral treatment with PTC923 20 mg/kg/day, PTC923 60 mg/kg/day and sapropterin dihydrochloride 20 mg/kg/day each in a random order. Treatments were separated by a 7-day washout. Subjects maintained their usual pre-study diet, including consumption of amino acid mixtures. Blood Phe was measured on Day 1 (predose baseline), Day 3, Day 5, and Day 7 of each treatment period. RESULTS: Least squares mean changes (SE) from baseline in blood Phe were: -206.4 (41.8) µmol/L for PTC923 60 mg/kg (p < 0.0001); -146.9 (41.8) µmol/L for PTC923 20 mg/kg (p = 0.0010); and - 91.5 (41.7) µmol/L for sapropterin (p = 0.0339). Effects of PTC923 60 mg/kg on blood Phe vs. sapropterin were significantly larger (p = 0.0098) and faster in onset with a significantly larger mean reduction in blood Phe at day 3 of treatment, p = 0.0135 (20 mg/kg) and p = 0.0007 (60 mg/kg). Only PTC923 60 mg/kg reduced blood Phe in classical PKU subjects (n = 11, p = 0.0287). The mean blood Phe reduction (PTC923 60 mg/kg) in a cofactor responder analysis (n = 8; baseline Phe ≥300 µmol/L and blood Phe reduction ≥30%) was -463.3 µmol/L (SE 51.5) from baseline. Adverse events were mostly mild to moderate, transient, and similar across treatment groups with no serious adverse events or discontinuations. CONCLUSIONS: The substantially significantly better effect of PTC923 60 mg/kg on blood Phe reduction vs. sapropterin supports further clinical development of PTC923 for PKU; ANZCTR number, ACTRN12618001031257.

Beneficial Effects of Slow-Release Large Neutral Amino Acids after a Phenylalanine Oral Load in Patients with Phenylketonuria.

The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.

Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria.

Phenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.

Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse.

BACKGROUND: In phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. METHODS: In a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. RESULTS: Plasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. CONCLUSION: This study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. TAKE-HOME MESSAGE: Blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.

Metabolic Control of Patients with Phenylketonuria in a Portuguese Metabolic Centre Comparing Three Different Recommendations.

Blood phenylalanine (Phe) is used as the primary marker to evaluate metabolic control. Our study aimed to describe the metabolic control of patients with phenylketonuria (PKU) comparing three different treatment recommendations (European guidelines/US guidelines/Portuguese consensus). This was a retrospective, observational, single centre study in patients with PKU collecting data on blood Phe levels from 2017. Nutritional intake data and sapropterin (BH4) prescription were collected at the last appointment of 2017. The final sample studied included 87 patients (48% females) [13 hyperphenylalaninemia; 47 mild PKU; 27 classical PKU] with a median age of 18 y (range: 1-36 y). The median number of blood Phe measurements for patients was 21 (range: 6-89). In patients aged < 12 y, the median blood Phe level was 300 µmol/L (range 168-480) and 474 µmol/L (range 156-1194) for patients ≥ 12 y. Overall, a median of 83% of blood Phe levels were within the European PKU guidelines target range. In patients aged ≥ 12 years, there was a higher median % of blood Phe levels within the European PKU guidelines target range (≥12 y: 84% vs. <12 y: 56%). In children < 12 y with classical PKU (n = 2), only 34% of blood Phe levels were within target range for all 3 guidelines and 49% with mild PKU (n = 11). Girls had better control than boys (89% vs. 66% median Phe levels within European Guidelines). Although it is clear that 50% or more patients were unable to achieve acceptable metabolic control on current treatment options, a globally agreed upper Phe target associated with optimal outcomes for age groups is necessary. More studies need to examine how clinics with dissimilar resources, different therapeutic Phe targets and frequency of monitoring relate to metabolic control.

A Three-Year Longitudinal Study Comparing Bone Mass, Density, and Geometry Measured by DXA, pQCT, and Bone Turnover Markers in Children with PKU Taking L-Amino Acid or Glycomacropeptide Protein Substitutes.

In patients with phenylketonuria (PKU), treated by diet therapy only, evidence suggests that areal bone mineral density (BMDa) is within the normal clinical reference range but is below the population norm. AIMS: To study longitudinal bone density, mass, and geometry over 36 months in children with PKU taking either amino acid (L-AA) or casein glycomacropeptide substitutes (CGMP-AA) as their main protein source. METHODOLOGY: A total of 48 subjects completed the study, 19 subjects in the L-AA group (median age 11.1, range 5-16 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5-16 years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5-16 years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5-15 years) (n = 16), children taking a combination of CGMP-AA and L-AA. Dual X-ray absorptiometry (DXA) was measured at enrolment and 36 months, peripheral quantitative computer tomography (pQCT) at 36 months only, and serum blood and urine bone turnover markers (BTM) and blood bone biochemistry at enrolment, 6, 12, and 36 months. RESULTS: No statistically significant differences were found between the three groups for DXA outcome parameters, i.e., BMDa (L2-L4 BMDa g/cm2), bone mineral apparent density (L2-L4 BMAD g/cm3) and total body less head BMDa (TBLH g/cm2). All blood biochemistry markers were within the reference ranges, and BTM showed active bone turnover with a trend for BTM to decrease with increasing age. CONCLUSIONS: Bone density was clinically normal, although the median z scores were below the population mean. BTM showed active bone turnover and blood biochemistry was within the reference ranges. There appeared to be no advantage to bone density, mass, or geometry from taking a macropeptide-based protein substitute as compared with L-AAs.

Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study.

Phenylketonuria (PKU) is a rare disease caused by biallelic mutations in the PAH gene that result in an inability to convert phenylalanine (Phe) to tyrosine, elevated blood Phe levels and severe neurological complications if untreated. Most patients are unable to adhere to the protein-restricted diet, and thus do not achieve target blood Phe levels. We engineered a strain of E. coli Nissle 1917, designated SYNB1618, through insertion of the genes encoding phenylalanine ammonia lyase and L-amino acid deaminase into the genome, which allow for bacterial consumption of Phe within the gastrointestinal tract. SYNB1618 was studied in a phase 1/2a randomized, placebo-controlled, double-blind, multi-centre, in-patient study ( NCT03516487 ) in adult healthy volunteers (n = 56) and patients with PKU and blood Phe level ≥600 mmol l-1 (n = 14). Participants were randomized to receive a single dose of SYNB1618 or placebo (part 1) or up to three times per day for up to 7 days (part 2). The primary outcome of this study was safety and tolerability, and the secondary outcome was microbial kinetics. A D5-Phe tracer (15 mg kg-1) was used to study exploratory pharmacodynamic effects. SYNB1618 was safe and well tolerated with a maximum tolerated dose of 2 × 1011 colony-forming units. Adverse events were mostly gastrointestinal and of mild to moderate severity. All participants cleared the bacteria within 4 days of the last dose. Dose-responsive increases in strain-specific Phe metabolites in plasma (trans-cinnamic acid) and urine (hippuric acid) were observed, providing a proof of mechanism for the potential to use engineered bacteria in the treatment of rare metabolic disorders.

The Impact of the First 2020 COVID-19 Lockdown on the Metabolic Control of Patients with Phenylketonuria.

The present study assessed patients' metabolic control of phenylketonuria (PKU) during the first 2020 COVID-19 lockdown in Poland. Blood (phenylalanine) Phe results of the tests of 535 patients, performed in 2019 and in the first months of 2020, were analysed. The six-week lockdown period was compared to the preceding six-week period as well as to the two corresponding periods of 2019 (three non-lockdown periods). More patients failed to perform Phe tests in the lockdown period (32.7%) than in non-lockdown periods (15.6%, 15.1%, 17.2%; p < 0.001 for all). The median Phe levels for those patients who performed testing in all the four periods did not differ between periods. However, these patients tended to perform only one test during the lockdown (ORs: 1.43 to 1.60; 95% CI: from 1.01-2.04 to 1.11-2.30, p-value 0.02 to 0.005). Patients who did not take blood during the lockdown (46.7%) performed significantly fewer blood tests in the remaining periods (median : 1 <0-1> vs. 2 <1-4>; p < 0.001). In conclusion, direct assessment of patients' compliance based upon Phe levels during the pandemic lockdown was not possible. Pre-pandemic non-compliant patients frequently failed to perform the test during the lockdown, whereas the previously compliant ones were more likely to perform only one test. This strongly suggests that metabolic control might have worsened.

Long-term cognitive and psychosocial outcomes in adults with phenylketonuria.

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with phenylketonuria (PKU) may be explained by suboptimal adherence to dietary treatments, however, these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. One hundred and fifty-four participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. One hundred and forty-nine completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood.

Pharmacokinetic, pharmacodynamic, and immunogenic rationale for optimal dosing of pegvaliase, a PEGylated bacterial enzyme, in adult patients with phenylketonuria.

Phenylketonuria (PKU), a deficiency in the activity of the enzyme phenylalanine hydroxylase, leads to toxic levels of phenylalanine (Phe) in the blood and brain. Pegvaliase (recombinant Anabaena variabilis phenylalanine ammonia lyase conjugated with polyethylene glycol) is approved to manage PKU in patients aged greater than or equal to 18 years in the United States and in patients aged greater than or equal to 16 years in the European Union. Pharmacokinetic, pharmacodynamic, and immunogenicity results from five open-label pegvaliase trials were assessed. Studies with induction/titration/maintenance (I/T/M) dosing regimens demonstrated pharmacokinetic stabilization and sustained efficacy associated with maintenance doses (20, 40, or 60 mg/day). Immune-mediated pegvaliase clearance was high during induction/titration phases when the early immune response was peaking. The combination of low drug dosage and high drug clearance led to low drug exposure and minimal decreases in blood Phe levels during induction/titration. Higher drug exposure and substantial reductions in blood Phe levels were observed later in treatment as drug clearance was reduced due to the maturation of the immune response, which allowed for increased dosing to target levels. The incidence of hypersensitivity reactions was temporally associated with the peaking of the early antidrug immune response and decreased with time as immune response matured after the first 6 months of treatment. These results support an I/T/M dosing regimen and suggest a strategy for administration of other nonhuman biologics to achieve efficacy and improve tolerability.

Growth and Body Composition in PKU Children-A Three-Year Prospective Study Comparing the Effects of L-Amino Acid to Glycomacropeptide Protein Substitutes.

Protein quality and quantity are important factors in determining lean body (muscle) mass (LBM). In phenylketonuria (PKU), protein substitutes provide most of the nitrogen, either as amino acids (AA) or glycomacropeptide with supplementary amino acids (CGMP-AA). Body composition and growth are important indicators of long-term health. In a 3-year prospective study comparing the impact of AA and CGMP-AA on body composition and growth in PKU, 48 children were recruited. N = 19 (median age 11.1 years, range 5-15 years) took AA only, n = 16 (median age 7.3 years, range 5-15 years) took a combination of CGMP-AA and AA, (CGMP50) and 13 children (median age 9.2 years, range 5-16 years) took CGMP-AA only (CGMP100). A dual energy X-ray absorptiometry (DXA) scan at enrolment and 36 months measured LBM, % body fat (%BF) and fat mass (FM). Height was measured at enrolment, 12, 24 and 36 months. No correlation or statistically significant differences (after adjusting for age, gender, puberty and phenylalanine blood concentrations) were found between the three groups for LBM, %BF, FM and height. The change in height z scores, (AA 0, CGMP50 +0.4 and CGMP100 +0.7) showed a trend that children in the CGMP100 group were taller, had improved LBM with decreased FM and % BF but this was not statistically significant. There appeared to be no advantage of CGMP-AA compared to AA on body composition after 3-years of follow-up. Although statistically significant differences were not reached, a trend towards improved body composition was observed with CGMP-AA when it provided the entire protein substitute requirement.

Implementing a Transition Program from Paediatric to Adult Services in Phenylketonuria: Results After Two Years of Follow-Up with an Adult Team.

We aimed to report the implementation of a phenylketonuria (PKU) transition program and study the effects of follow-up with an adult team on metabolic control, adherence, and loss of follow-up. Fifty-five PKU patients were analysed in the study periods (SP): 2 years before (SP1) and after the beginning of adult care (SP2). Retrospective data on metabolic control and number of clinic appointments were collected for each SP, and protein intakes were analysed. In SP2, three patients (6%) were lost to follow-up. There was a small but statistically significant increase in median number of annual blood spots from SP1 to SP2: 11 (7-15) vs. 14 (7-20); p = 0.002. Mean ± SD of median blood Phe remained stable (525 ± 248 µmol/L vs. 552 ± 225 µmol/L; p = 0.100); median % of blood Phe < 480 µmol/L decreased (51 (4-96)% vs. 37 (5-85)%; p = 0.041) and median number of clinic appointments increased from SP1 to SP2: (5 (4-6) vs. 11 (8-13); p < 0.001). No significant differences were found regarding any parameter of protein intake. Our results suggest that the implementation of an adult service was successful as impact on metabolic control was limited and attendance remained high. Continuous dietetic care likely contributed to these results by keeping patients in follow-up and committed to treatment.

Factors that increase risk for poor adherence to phenylketonuria treatment in Brazilian patients.

Neurotoxic effects caused by high phenylalanine (Phe) in patients with phenylketonuria (PKU) can be avoided through dietary treatment. However, achieving the recommended Phe levels has been a challenge. This study aimed to investigate factors associated with adherence to PKU treatment among patients followed at a medical genetics public service in southern Brazil. Twenty-nine patients (early diagnosed, n = 20; late-diagnosed, n = 9) with classical (n = 16) or mild PKU (n = 13) aged 6-34 years (16.4 ± 7.5) and 16 caregivers were included. Blood Phe levels were recorded, and assessment tools measuring barriers to treatment, IQ, knowledge about disease, treatment, and perceived adherence were collected. Classical PKU patients showed higher current blood Phe levels than mild PKU patients (U = 37.000, p = 0.003). Lifetime and childhood Phe levels were associated with recent metabolic control (τ = 0.76, p = 0.000; τ = 0.70, p = 0.000, respectively). The perception of barriers to treatment was associated with a higher blood Phe level (τ = 0.39, p = 0.003). Tolerance to Phe, metabolic control throughout childhood, and perceived difficulty in living with demands of treatment are important factors of greater vulnerability to poor adherence in PKU patients.

Protein Substitutes in PKU; Their Historical Evolution.

Protein substitutes developed for phenylketonuria (PKU) are a synthetic source of protein commonly based on L-amino acids. They are essential in the treatment of phenylketonuria (PKU) and other amino acid disorders, allowing the antagonistic amino acid to be removed but with the safe provision of all other amino acids necessary for maintaining normal physiological function. They were first formulated by a chemist and used experimentally on a 2-year-old girl with PKU and their nutritional formulations and design have improved over time. Since 2008, a bioactive macropeptide has been used as a base for protein substitutes in PKU, with potential benefits of improved bone and gut health, nitrogen retention, and blood phenylalanine control. In 2018, animal studies showed that physiomimic technology coating the amino acids with a polymer allows a slow release of amino acids with an improved physiological profile. History has shown that in PKU, the protein substitute's efficacy is determined by its nutritional profile, amino acid composition, dose, timing, distribution, and an adequate energy intake. Protein substitutes are often given little importance, yet their pharmacological actions and clinical benefit are pivotal when managing PKU.