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Objective: Management of patients with phenylketonuria mainly includes limiting the content of phenylalanine in the diet. Therefore, the purpose of this study was to investigate oral problems in children with phenylketonuria compared to the healthy population as a case-control study. Materials and Methods: The subjects of the case and control groups were selected according to the inclusion criteria. First, the oral cavity and tooth were examined by a specialist dentist to indicate the decayed, missing due to caries, and filled teeth index in both groups. To investigate the level of phenylalanine and evaluate other laboratory examinations, 2 mL of blood and saliva samples was taken from the subjects. Blood and saliva phenylalanine levels were measured by high-performance liquid chromatography. Phosphorus, calcium, and pH levels were investigated through calorimetric measurement. The data were analyzed using Statistical Package for Social Sciences software. Results: There was no significant difference between the case and control groups in terms of age and sex. The average level of calcium and phosphorus in the case group was higher than in the control group. Also, the average decayed, missing due to caries, and filled teeth index in the case group was not significantly different compared to the control group. None of the above-investigated indicators had a significant relationship with each other. On the other hand, it was found that there was a positive and significant relationship between phenylalanine in blood, saliva, and pH as well as between saliva phenylalanine with decayed, missing due to caries, and filled teeth. Conclusion: The results of this study indicate a significant effect of phenylketonuria disease on calcium, phosphorus, and oral pH levels in children. [ABSTRACT FROM AUTHOR]

Objective Phenylketonuria (PKU) is one of the most common inherited metabolic diseases, which is classified into classic and non-classic types. It is estimated that 2% of children with PKU develop a severe and progressive neurological disease, called non-classic (malignant) PKU. This study aimed to demonstrate the clinical features, laboratory findings, and diagnostic/therapeutic characteristics of non-classic PKU patients referred to a tertiary referral center for children in Tehran, Iran. Materials & Methods In this study, background information, such as gender and age, clinical manifestations, laboratory findings, and response rate to conventional treatment, was investigated in patients with non-classic PKU, who were referred to Mofid Children's Hospital in Tehran, Iran, through neonatal screening. Results Twenty patients with a diagnosis of non-classic PKU were included in this study. The mean age of the patients was 6.00±2.81 years (range: 2-12 years), and 45.0% were male. In patients with a late diagnosis, the most common presentations were motor developmental delay (15.0%), skin and cutaneous manifestations (15.0%), seizure (5.0%), and restlessness (5.0%). The overall response rate to treatment was 85.0%. Factors that predict good response to treatment included female gender, higher neopterin level, and lower age at diagnosis and management. Conclusion In conclusion, about half of patients with non-classic PKU remain asymptomatic, which is due to early diagnosis via neonatal screening. Also, higher age at diagnosis and treatment, besides low neopterin levels, may be useful as prognostic factors. [ABSTRACT FROM AUTHOR]

The article titled "Evaluation of Decayed, Missing Due to Caries, and Filled Teeth Index in Children with Phenylketonuria in Comparison to Normal Population" discusses a case-control study conducted by Ghasemi et al. The study examined dental caries in Iranian children with phenylketonuria (PKU) and found that there was no significant difference in the average decayed, missing, and filled teeth index between the case and control groups. The study also found a correlation between phenylalanine levels and dental caries. The article acknowledges some limitations of the study and emphasizes the importance of using appropriate dental caries assessment instruments. Overall, the study supports previous observations that PKU patients have a higher risk of developing dental caries. [Extracted from the article]

Objective: The aim of this study was to explore the relationship between age at the time of diagnosis of pediatric phenylketonuria (PKU) and clinical manifestations in a sample of Egyptian children. Patients and methods: This retrospective cohort included children diagnosed as PKU. The collected data included the time, age, and phenylalanine (Phe) level at diagnosis, sex, serial plasma Phe levels, neurological and behavioral problems, developmental quotient, and anthropometric measurements. Results: Sixty-six patients were included. Compared with early diagnosed patients, late cases had significantly lower median Phe levels (P<0.001) and higher rates of neurological complications (P<0.001) and behavioral problems (P<0.001). Compared with compliant patients, noncompliance was significantly associated with late diagnosis (P=0.001), neurological complications (P=0.001), and hyperactivity (P=0.017). Conclusions: Stature and head circumference were not significantly affected by time of diagnosis or compliance with treatment. Early diagnosis and compliance with dietary treatment have a potential impact on neurological and behavioral problems in pediatric PKU patients. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the cost-effectiveness of newborn screening and treatment for phenylketonuria (PKU) in the context of new data on adherence to recommended diet treatment and a newly available drug treatment (sapropterin dihydrochloride). A computer simulation model was developed to project outcomes for a hypothetical cohort of newborns with PKU. Four strategies were compared: (1) clinical identification (CI) with diet treatment; (2) newborn screening (NBS) with diet treatment; (3) CI with diet and medication (sapropterin dihydrochloride); and (4) NBS with diet and medication. Data sources included published literature, primary data, and expert opinion. From a societal perspective, newborn screening with diet treatment had an incremental cost-effectiveness ratio of $6400/QALY compared to clinical identification with diet treatment. Adding medication to NBS with diet treatment resulted in an incremental cost-effectiveness ratio of more than $16,000,000/QALY. Uncertainty analyses did not substantially alter the cost-effectiveness results. Newborn screening for PKU with diet treatment yields a cost-effectiveness ratio lower than many other recommended childhood prevention programs even if adherence is lower than previously assumed. Adding medication yields cost-effectiveness results unlikely to be considered favorable. Future research should consider conditions under which sapropterin dihydrochloride would be more economically attractive. [ABSTRACT FROM AUTHOR]

Importance: Sapropterin hydrochloride, a natural coenzyme (6R‐tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin‐responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. Guidelines are required on the proper use of sapropterin hydrochloride for tetrahydrobiopterin‐responsive hyperphenylalaninemia. Observations: It is recommended that tetrahydrobiopterin‐responsive hyperphenylalaninemia should be diagnosed in all cases of hyperphenylalaninemia, including phenylketonuria, by tetrahydrobiopterin administration tests rather than by phenotype or blood phenylalanine levels. Conclusions and Relevance: If tetrahydrobiopterin‐responsive hyperphenylalaninemia is diagnosed, all ages can be treated with sapropterin hydrochloride. Although there are reports that sapropterin hydrochloride is effective and safe for the prevention of maternal phenylketonuria, further investigation is required. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this article is to review literature for neurocognitive, neuropsychiatric, neurological complications associated with phenylalanine hydroxylase (PAH) deficiency. The goal is to familiarize nurse practitioners with treatment and monitoring guidelines for persons living with the disorder. Conclusions: Appropriate treatment can maximize neurocognitive and neuropsychiatric outcomes. Practice Implications: Nurse practitioners can help persons with PAH deficiency through education and providing appropriate referrals and by supporting disease‐specific treatment. [ABSTRACT FROM AUTHOR]

Background: According to studies of phenylketonuria (PKU), the Brazilian population's metabolic control shows unsatisfactory indexes from childhood. Research on patients' perceived difficulties or barriers to adherence to treatment can help us to comprehend how these outcomes are associated. The present study aimed to: (1) describe the development of an inventory for identifying the most frequent and relevant perceived barriers to PKU treatment from the perspective of patients, caregivers, and healthcare professionals; (2) evaluate certain psychometric characteristics of the new measure; and, (3) explore potential predictors (sociodemographic and medical characteristics) that may contribute to increasing the number of perceived barriers and examine whether the number of barriers is associated with the degree of adherence shown by the patient. Results: Participants in the study were 23 patients with PKU (M age = 18.0 years; SD = 7.3; range 6 to 34 years; 69% early-treated) in classical (n = 11) and mild (n = 12) form, and 11 caregivers. The inventory, developed to ascertain perceived barriers to treatment, was completed by patients (≥ 13 years) and caregivers of patients aged 6 to 17 years. Analyses were conducted to investigate whether barrier inventory scores were associated with adherence to treatment as measured by phenylalanine levels in patients' medical records. Scores on the inventory differed across the patient age groups: adolescents had lower scores (i.e. reported fewer barriers) compared with those of adults (U = 8.000, p = 0.008); patients with better recent metabolic control also reported fewer perceived barriers than did patients with poor adherence (U = 20.000, p = 0.009); and the number of perceived barriers was positively associated with recent blood phenylalanine concentration (Kendall's taub = 0.41; p = 0.001). Conclusions: These results suggest that the inventory has merit in assessing perceived barriers and support the need for further research on barriers perceived by PKU patients. [ABSTRACT FROM AUTHOR]

Objectives To assess the presence of symptoms consistent with Attention Deficit Disorder with Hyperactivity (ADHD) in all patients with early-treated phenylketonuria (PKU) in the State of Santa Catarina in southern Brazil. Materials & Methods All of the patients diagnosed with PKU by newborn-screening tests, with ages varying from 6 to 18 years and who started treatment before 60 days of life and presented phenylalanine levels consistently below 6 mg/dL throughout treatment, were included. The subjects were invited to complete a questionnaire that collected sociodemographic, gestational and clinical data. ADHD symptoms were assessed using the revision of the Swanson, Nolan and Pelham Questionnaire. Results A total of 34 patients were evaluated, who were 53% male and 94% white and had an average age of 12 years, and 15% were born premature. According to the Swanson, Nolan and Pelham Questionnaire, 13 patients (38%) met the diagnostic criteria for ADHD, with 2 patients having the inattentive type, 6 patients having the hyperactive or impulsive type and 1 patient having the oppositional defiant disorder type. Conclusion Although the patients with PKU were regularly treated from birth, there was a high prevalence of symptoms consistent with ADHD. A pathophysiological interface that involves the dopamine metabolic pathway may exist between the two conditions. [ABSTRACT FROM AUTHOR]

Limited published research has evaluated mental health in parents of children with phenylketonuria (PKU) and their coping strategies. We aimed to assess anxiety, depression and coping in parents of Tunisian children treated for PKU. We conducted a cross-sectional study in the reference center for the management of inherited metabolic diseases in Tunisia. We used the Hospital Anxiety and Depression (HAD) scale and the Brief-COPE. Dependent variables were anxiety, depression, HAD Depression (HADD) and Anxiety (HADA) scores, and coping scores. Linear regression and logistic binary regression were used for multivariate analysis. Sixty-five parents from 42 families participated. 62% and 57% of them had anxiety and depression, respectively. Parental female gender (p = 0.049), rural origin (p = 0.005) and agitation in children with PKU (p = 0.031) were associated with anxiety. Parental age under 35 years (p = 0.043), agitation in children with PKU (p = 0.012) and behavioral disengagement (p = 0.003) were associated with higher HADA scores. Parents used problem focused (5.64 ± 1.34) more often than emotion focused coping (4.55 ± 0.90). Female gender was associated with emotion-focused coping (p = 0.042) and religion (p = 0.018). Motor disability in children with PKU was associated with humor (p = 0.047) and negatively associated with religion (p = 0.037). Psychological follow-up was associated with venting (p = 0.039). A low education level was negatively associated with self-blame (p = 0.024). Our study provided preliminary data which could be used to develop a targeted psychological support strategy for parents at risk for anxiety and depression not only in Tunisia but also in comparable populations where newborn screening for PKU is not available. [ABSTRACT FROM AUTHOR]

Background: The standard, lifelong therapy of phenylketonuria (PKU) is a natural protein-restricted diet complemented with phenylalanine (Phe)-free L-amino acid mixtures that provide the daily necessary micronutrients. Objective: To assess thyroid function and structure and the iodine status of early-treated adult PKU (ETPKU) patients in Hungary. Methods: Sixty-nine PKU patients (aged 18–41 years) and 50 healthy controls were enrolled in the study. Thyroid hormones, serum thyroglobulin, thyroid antibodies, urinary iodine, and selenium concentrations were measured, and thyroid ultrasound was performed. Results: The incidence of thyroid dysfunction was infrequent (n = 2). Blood Phe was negatively correlated with thyroid-stimulating hormone (TSH), and PKU patients had higher free thyroxine and lower TSH levels than healthy controls. Although optimal iodine status was found in the entire PKU population, by dividing the patients according to their therapy compliance, we observed that lower therapy adherence was associated with mild iodine deficiency and lower urinary selenium levels. Conclusions: The results of this study suggest that iodine status is strongly influenced by the adherence to therapy in ETPKU patients. No or not enough medical food consumption combined with a low-Phe diet can lead to subclinical iodine deficiency. [ABSTRACT FROM AUTHOR]

Low-phenylalanine diet, the mainstay of treatment for phenylketonuria (PKU), has been shown to increase glycemic index and glycemic load, affecting the availability of substrates for microbial fermentation. Indeed, changes in the PKU gut microbiota compared with healthy controls have been previously reported. In this study we compared the gut microbial communities of children with PKU and with mild hyperphenylalaninemia (MHP, unrestricted diet). For each group, we enrolled 21 children (4–18 years old), for a total dataset of 42 subjects. We assessed dietary intake and performed gut microbiota analysis by sequencing the V3–V4 hypervariable regions of the 16S rRNA gene. Short chain fatty acids (SCFAs) were quantified by gas chromatographic analysis. While alpha-diversity analysis showed no significant differences between PKU and MHP groups, microbial community analysis highlighted a significant separation of the gut microbiota according to both unweighted (p = 0.008) and weighted Unifrac distances (p = 0.033). Major differences were seen within the Firmicutes phylum. Indeed, PKU children were depleted in Faecalibacterium spp. and enriched in Blautia spp. and Clostridium spp (family Lachnospiraceae). We found a divergent response of members of the Firmicutes phylum with respect to daily glycemic index, higher in PKU children. Faecalibacterium prausnitzii , unclassified Ruminococcaceae and, to a lesser extent Roseburia spp. negatively correlated with glycemic index, whereas unclassified Lachnospiraceae were positively associated. Indicator species analysis suggested F. prausnitzii be related to MHP status and Ruminococcus bromii to be associated with PKU. Despite PKU children having a higher vegetable and fiber intake, resembling a vegan diet, their gut microbial profile is different from the microbiota reported in the literature for individuals consuming a high-fiber/low-protein diet. Indeed, beneficial microorganisms, such as F. prausnitzii , considered a biomarker for a healthy status and one of the main butyrate producers, are depleted in PKU gut microbiota. We suggest that both the quality and quantity of carbohydrates ingested participate in determining the observed Firmicutes shifts on the PKU population. [ABSTRACT FROM AUTHOR]

Phenylalanine hydroxylase (PAH) deficiency is an inborn error of metabolism that results in elevated phenylalanine levels in blood. The classical form of the disease with phenylalanine level > 1200 µmol/L in blood is called phenylketonuria (PKU) and is associated with severe intellectual disability when untreated. In addition, phenylalanine levels above the therapeutic range in pregnant female patients lead to adverse fetal effects. Lowering the plasma phenylalanine level prevents intellectual disability, maintaining the level in the therapeutic range of 120–360 µmol/L is associated with good outcome for patients as well as their pregnancies. Patient phenotypes are on a continuous spectrum from mild hyperphenylalaninemia to mild PKU, moderate PKU, and severe classic PKU. There is a good correlation between the biochemical phenotype and the patient's genotype. For over four decades the only available treatment was a very restrictive low phenylalanine diet. This changed in 2007 with the approval of cofactor therapy which is effective in up to 55% of patients depending on the population. Cofactor therapy typically is more effective in patients with milder forms of the disease and less effective in classical PKU. A new therapy has just been approved that can be effective in all patients with PAH deficiency regardless of their degree of enzyme deficiency or the severity of their phenotype. This article reviews the mainstay therapy, adjunct enzyme cofactor therapy, and the newly available enzyme substitution therapy for hyperphenylalaninemia. It also provides an outlook on emerging approaches for hyperphenylalaninemia treatment such as recruiting the microbiome into the therapeutic endeavor as well as therapies under development such as gene therapy. [ABSTRACT FROM AUTHOR]

Tetrahydrobiopterin (BH 4) is the natural cofactor of aromatic amino acid hydroxylases and essential for degradation of phenylalanine and synthesis of catecholamines and serotonin. It can be synthesized either de novo from GTP or through the salvage pathway from sepiapterin. Sepiapterin, a natural precursor of BH 4 , is a more stable molecule and is transported more efficiently across cellular membranes, thus having potentially significant advantage over BH 4 as a pharmacological agent for diseases associated with BH 4 -deficient conditions. We report the results of a first-in-humans, randomized, double-blind, placebo-controlled, dose-ranging, Phase I clinical trial in 83 healthy volunteers of CNSA-001, a novel formulation of sepiapterin. Single oral doses of 2.5–80 mg/kg CNSA-001 caused dose-related increases in plasma sepiapterin (mean C max 0.58–2.92 ng/mL) and BH 4 (mean C max 57–312 ng/mL). Maximum plasma concentrations were achieved in about 1–2 h (sepiapterin) or about 4 h (BH 4) after CNSA-001 oral intake. Increases in plasma BH 4 were substantially larger in absolute terms and on a dose-for-dose basis following treatment with CNSA-001 vs. sapropterin dihydrochloride, a synthetic form of BH 4. The pharmacokinetics of plasma sepiapterin and BH 4 were similar before and after seven days of repeat daily dosing with CNSA-001 at 5, 20 or 60 mg/kg indicating little or no drug accumulation. Oral administration of CNSA-001 resulted in higher concentrations of sepiapterin in fasted vs. fed subjects, but overall BH 4 plasma exposure following CNSA-001 intake increased by 1.7–1.8-fold in fed subjects. CNSA-001 was well tolerated, with no clear dose-relationship for adverse events (AE), no serious AE and no study discontinuations for AE. These data indicate that CNSA-001 is rapidly and efficiently converted to BH 4 in humans supporting further clinical evaluation of CNSA-001 for the management of PKU, primary BH 4 deficiencies and other diseases associated with deficient BH 4 metabolism. [ABSTRACT FROM AUTHOR]

Abstract Phenylketonuria remains one of the most common inborn errors of metabolism. In the UK it is detected on the newborn heel-prick screening sample allowing early treatment with a strict low phenylalanine diet supplemented with artificial amino acids and appropriate vitamin and minerals. Although the long-term prognosis is good, there is an increasing body of evidence highlighting subtle problems in neuropsychological function with slower reaction times and poorer executive function than peers. White matter changes clearly seen on brain magnetic resonance imaging may have some relationship to these neuropsychological difficulties but their significance is not clearly understood. The diet, although successful, is difficult to follow lifelong and with its attendant risks of nutritional deficiencies needs careful specialist management. In view of these challenges new treatments such as sapropterin (a tetrahydrobiopterin analogue) and large neutral amino acids are currently being used in phenylketonuria and clinical trials are underway using ammonia lyase as enzyme replacement therapy. Maternal phenylketonuria syndrome remains a risk for those who conceive whilst blood phenylalanine is elevated and females must be counselled early in childhood to avoid this risk. [ABSTRACT FROM AUTHOR]

Key content: Phenylketonuria (PKU) is a rare, autosomal recessive metabolic disorder characterised by the body's inability to utilise the essential amino acid phenylalanine. There are three different subgroups of this disorder.Untreated or poorly controlled phenylalanine levels are associated with intrauterine growth restriction and other fetal abnormalities.Fetuses born to mothers with PKU exhibit clinical similarities to those born with fetal alcohol syndrome.Management of pregnant women with PKU is best performed under a multidisciplinary team with close monitoring of phenylalanine blood levels. Learning objectives: To understand the importance of pre‐conception counselling in women born with PKU.To understand the implications of hyperphenylalaninaemia on pregnancy and fetal outcomes.To understand the importance of involving a multidisciplinary team in the management of patients with PKU. Ethical issues: Women with poor compliance to PKU management in the prepregnancy period are at significant risk of fetal abnormalities. Should we recommend alternative reproductive options? [ABSTRACT FROM AUTHOR]

BioMarin Pharmaceutical is developing pegvaliase (PALYNZIQ™) as a treatment for phenylketonuria, a genetic disorder caused by deficiency of phenylalanine hydroxylase which leads to neurotoxic accumulation of phenylalanine. Data from the phase III PRISM clinical trial program indicate treatment with pegvaliase is associated with sustained reductions in blood phenylalanine levels and sustained improvements in neurological sequelae in patients with phenylketonuria. Based on these positive results pegvaliase was recently approved in the US for adults with phenylketonuria who have uncontrolled blood phenylalanine concentrations on current treatment. This article summarizes the milestones in the development of pegvaliase leading to this first approval. [ABSTRACT FROM AUTHOR]

Abstract Phenylketonuria (PKU) is a genetic inborn error in metabolism that impacts many people globally, with profound individual and societal consequences when left untreated. The journey of phenylalanine ammonia lyase (PAL) from plant enzyme to enzyme substitution therapy for PKU is a fascinating story that illustrates the importance of collaboration between basic scientists and industry in the drug development process. The story begins with the curiosity of plant physiologists about the origin of lignin, a polymer involved in maintaining the rigidity of plants. They learned that the critical element in this synthesis was an intermediary enzyme that deaminates phenylalanine to cinnamic acid and ammonia (later called phenylalanine ammonia lyase or PAL). Recognition of this ability to metabolize phenylalanine led to subsequent consideration of PAL as a treatment for PKU. This was initially attempted as enteral therapy with extracted enzyme, but that showed only minimal efficacy. Crucially, further development of PAL as a therapy for PKU required quantities of enzyme that could only be obtained after successfully cloning the gene, expressing the enzyme in vitro and modifying the protein via PEGylation to enable parenteral administration of this non-mammalian enzyme. Ultimately, PEGylated PAL was developed as an enzyme substitution therapy for PKU now approved under the name “Palynziq.” The multidisciplinary academic-industrial partnership engaged throughout this process has been key to the successful pursuit of this therapeutic possibility and serves as a model for the development of future innovative therapies. [ABSTRACT FROM AUTHOR]

Abstract Objective The objective of this study was to assess the long-term effects of BH 4 treatment on anthropomorphic measurements and nutritional biomarkers in phenylketonuria patients. Study design A retrospective cohort study was conducted using data from 21 BH 4 -treated (mean age ± SD: 13.12 ± 9.18 years) and 21 birth date- and gender-matched phenylketonuria patients. Study parameters were age- and gender-adjusted SD scores of anthropomorphic measurements, various nutritional biomarkers, and prescribed vitamin/mineral supplements from baseline and after 5 years of BH 4 treatment. Parametric and non-parametric statistical analyses were performed for continuous data, and McNemar's and Chi-squared tests were used for dichotomous outcomes. Results Prescribed natural protein intake increased following BH 4 treatment (p < 0.001), while amino acid supplement intake decreased (p < 0.001). Weight SDS had increased significantly after 5 years of BH 4 treatment. Serum concentration of cholesterol, hemoglobin, phosphate, and MMA had changed significantly after 5 years of BH 4 treatment as well. These changes in nutritional biomarkers are however probably age-related, as no differences compared to the control group were seen. A tendency to an increase in calcium supplementation was observed in BH 4 -treated patients (p = 0.063). Conclusions The dietary changes following BH 4 treatment had little effect on anthropomorphic measurements and nutritional biomarkers when compared to a control group, although dietary follow-up of BH 4 -treated patients is still warranted. [ABSTRACT FROM AUTHOR]

Introduction Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. Methods PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20 mg/day or 40 mg/day) or switch to matching placebo. Results The pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9 μM (504.6) in the group assigned to the 20 mg/day placebo group ( n  = 14), 508.2 μM (363.7) in those assigned to the 40 mg/day placebo group (n = 14), and 503.9 μM (520.3) in those assigned to continue pegvaliase treatment ( n  = 58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8 μM (760.4 to 1139.1) for the 20 mg/day placebo group and 664.8 μM (465.5 to 864.1) for the 40 mg/day placebo group in comparison to 26.5 μM (−68.3 to 121.3) for the pooled (20 mg/day and 40 mg/day) pegvaliase group ( P  < 0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). Conclusion Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants. [ABSTRACT FROM AUTHOR]

Untreated phenylketonuria (PKU) results in severe neurodevelopmental disorders, which can be partially prevented by an early and rigorous limitation of phenylalanine (Phe) intake. Enzyme substitution therapy with recombinant Anabaena variabilis Phe Ammonia Lyase (r Av PAL) proved to be effective in reducing blood Phe levels in preclinical and clinical studies of adults with PKU. Aims of present study were: a) to gather proofs of clinical efficacy of r Av PAL treatment in preventing neurological impairment in an early treated murine model of PKU; b) to test the advantages of an alternative delivering system for r Av PAL such as autologous erythrocytes. BTBR-Pah enu2−/− mice were treated from 15 to 64 post-natal days with weekly infusions of erythrocytes loaded with r Av PAL. Behavioral, neurochemical, and brain histological markers denoting untreated PKU were examined in early treated adult mice in comparison with untreated and wild type animals. r Av PAL therapy normalized blood and brain Phe; prevented cognitive developmental failure, brain depletion of serotonin, dendritic spine abnormalities, and myelin basic protein reduction. No adverse events or inactivating immune reaction were observed. In conclusion present study testifies the clinical efficacy of r Av PAL treatment in a preclinical model of PKU and the advantages of erythrocytes as carrier of the enzyme in term of frequency of the administrations and prevention of immunological reactions. [ABSTRACT FROM AUTHOR]

Background Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. Methods Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 μmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. Results Of 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 μmol/L, 60.7% of participants achieved blood Phe ≤360 μmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 μmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. Conclusion Results from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment. [ABSTRACT FROM AUTHOR]

Phenylketonuria treatment mainly consists of a phenylalanine-restricted diet but still results in suboptimal neuropsychological outcome, which is at least partly based on cerebral monoamine deficiencies, while, after childhood, treatment compliance decreases. Supplementation of large neutral amino acids (LNAAs) was previously demonstrated in young phenylketonuria mice to target all three biochemical disturbances underlying brain dysfunction in phenylketonuria. However, both its potential in adult phenylketonuria and the comparison with the phenylalanine-restricted diet remain to be established. To this purpose, several LNAA supplements were compared with a severe phenylalanine-restricted diet with respect to brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice. Adult phenylketonuria mice received a phenylalanine-restricted diet, unrestricted diet supplemented with several combinations of LNAAs or AIN-93M control diet for 6 weeks. In addition, adult wild-type mice on AIN-93M diet served as controls. The severe phenylalanine-restricted diet in adult phenylketonuria mice significantly reduced plasma and brain phenylalanine and restored brain monoamine concentrations, while brain concentrations of most nonphenylalanine LNAAs remained subnormal. Supplementation of eight LNAAs was similarly effective as the severe phenylalanine-restricted diet to restore brain monoamines, while brain and plasma phenylalanine concentrations remained markedly elevated. These results provide biochemical support for the effectiveness of the severe phenylalanine-restricted diet and showed the possibilities of LNAA supplementation being equally effective to restore brain monoamines in adult phenylketonuria mice. Therefore, LNAA supplementation is a promising alternative treatment to phenylalanine restriction in adult phenylketonuria patients to further optimize neuropsychological functioning. [ABSTRACT FROM AUTHOR]

Detrimental effects of hyperaccumulation of the aromatic amino acid phenylalanine (Phe) in animals, known as phenylketonuria, are mitigated by excretion of Phe derivatives; however, how plants endure Phe accumulating conditions in the absence of an excretion system is currently unknown. To achieve Phe hyperaccumulation in a plant system, we simultaneously decreased in petunia flowers expression of all three Phe ammonia lyase ( PAL) isoforms that catalyze the non-oxidative deamination of Phe to trans-cinnamic acid, the committed step for the major pathway of Phe metabolism. A total decrease in PAL activity by 81-94% led to an 18-fold expansion of the internal Phe pool. Phe accumulation had multifaceted intercompartmental effects on aromatic amino acid metabolism. It resulted in a decrease in the overall flux through the shikimate pathway, and a redirection of carbon flux toward the shikimate-derived aromatic amino acids tyrosine and tryptophan. Accumulation of Phe did not lead to an increase in flux toward phenylacetaldehyde, for which Phe is a direct precursor. Metabolic flux analysis revealed this to be due to the presence of a distinct metabolically inactive pool of Phe, likely localized in the vacuole. We have identified a vacuolar cationic amino acid transporter ( Ph CAT2) that contributes to sequestering excess of Phe in the vacuole. In vitro assays confirmed Ph CAT2 can transport Phe, and decreased Ph CAT2 expression in PAL- RNAi transgenic plants resulted in 1.6-fold increase in phenylacetaldehyde emission. These results demonstrate mechanisms by which plants maintain intercompartmental aromatic amino acid homeostasis, and provide critical insight for future phenylpropanoid metabolic engineering strategies. [ABSTRACT FROM AUTHOR]

PKU patients react to therapy with a low phenylalanine diet, but adherence to this diet is troublesome, subsequently the expansion of alternative ways is demand. Phenylalanine ammonia lyase (PAL) is one of this ways, which converts phenylalanine to harmless metabolites; trans-cinnamic acid and ammonia. In the current study, the extraction of PAL enzyme was used to investigate the efficiency for production of functional PKU egg white and mushroom flour with good quality by evaluation of colour characteristics, determination of phenylalanine concentrations and genetic materials expression of PKU related genes and DNA damage. Results indicated that the PAL enzyme treated of egg white and mushroom flour was stable colour and the calculated reduction per cent in phenylalanine concentration from female mice fed on untreated and PAL–treated samples was 22.77% in egg white and 31.37% in mushroom flour. Also, the results revealed that female mice fed on diet contained treated egg white exhibited low expression levels of PKU exons (3, 6, 7, 11, and 12) and low DNA damage which were similar to those in control mice. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is one of the most common human inborn errors of metabolism, caused by phenylalanine hydroxylase deficiency, leading to high phenylalanine and low tyrosine levels in blood and brain causing profound cognitive disability, if untreated. Since 1960, population is screened for hyperphenylalaninemia shortly after birth and submitted to early treatment in order to prevent the major manifestations of the disease. However, the dietetic regimen (phenylalanine free diet) is difficult to maintain, and despite the recommendation to a strict and lifelong compliance, up to 60% of adolescents partially or totally abandons the treatment. The development and the study of new treatments continue to be sought, taking advantage of preclinical models, the most used of which is the PAHenu2 (BTBR ENU2), the genetic murine model of PKU. To date, adult behavioral and neurochemical alterations have been mainly investigated in ENU2 mice, whereas there are no clear indications about the onset of these deficiencies. Here we investigated and report, for the first time, a comprehensive behavioral and neurochemical assay of the developing ENU2 mice. Overall, our findings demonstrate that ENU2 mice are significantly smaller than WT until pnd 24, present a significant delay in the acquisition of tested developmental reflexes, impaired communicative, motor and social skills, and have early reduced biogenic amine levels in several brain areas. Our results extend the understanding of behavioral and cerebral abnormalities in PKU mice, providing instruments to an early preclinical evaluation of the effects of new treatments. [ABSTRACT FROM AUTHOR]

Background In phenylketonuria ( PKU), there are no data available for children with respect to evaluating casein glycomacropeptide ( CGMP) as an alternative to phenylalanine-free protein substitutes [Phe-free L-amino acid ( AA)]. CGMP contains a residual amount of phenylalanine, which may alter blood phenylalanine control. Methods In a prospective 6-month pilot study, we investigated the effect on blood phenylalanine control of CGMP-amino acid ( CGMP- AA) protein substitute in 22 PKU subjects (13 boys, nine girls), median age (range) 11 years (6-16 years). Twelve received CGMP- AA and nine received Phe-free L- AA, (1 CGMP- AA withdrawal). Subjects partially or wholly replaced Phe-free L- AA with CGMP- AA. If blood phenylalanine exceeded the target range, the CGMP- AA dose was reduced and replaced with Phe-free L-amino acids. The control group remained on Phe-free L- AAs. Phenylalanine, tyrosine and Phe : Tyr ratio concentrations were compared with the results for the previous year. Results In the CGMP- AA group, there was a significant increase in blood phenylalanine concentrations (pre-study, 275 μmol L−1; CGMP- AA, 317 μmol L−1; P = 0.02), a decrease in tyrosine concentrations (pre-study, 50 μmol L−1; CGMP- AA, 40 μmol L−1; P = 0.03) and an increase in Phe : Tyr ratios (pre-study, Phe : Tyr 4.9:1; CGMP- AA, Phe : Tyr 8:1; P = 0.02). In the control group there was a non-significant fall in phenylalanine concentrations (pre-study 325μmol/L: study 280μmol/L [p = 0.9], and no significant changes for tyrosine or phe/tyr ratios [p = 0.9]. Children taking the CGMP-AA found it more acceptable to L-AA. Conclusions Blood phenylalanine control declined with CGMP- AA but, by titrating the dose of CGMP- AA, blood phenylalanine control remained within target range. The additional intake of phenylalanine may have contributed to the change in blood phenylalanine concentration. CGMP- AA use requires careful monitoring in children. [ABSTRACT FROM AUTHOR]

Background: Newborn Screening Connect (NBS Connect) is a web-based self-reported patient registry and resource for individuals and families affected by disorders included in the newborn screening panel. NBS Connect was launched in 2012 by Emory University after years of planning and grassroots work by professionals, consumers, and industry. Individuals with phenylketonuria (PKU), maple syrup urine disease (MSUD) or tyrosinemia (TYR) have been recruited through distribution of outreach materials, presentations at parent organization meetings and direct recruitment at clinic appointments. Participants complete online profiles generating data on diagnosis, treatment, symptoms, outcomes, barriers to care, and quality of life. Resources such as education materials, information on the latest research and clinical trials, recipes, interactive health tracking systems, and professional support tools are described. In addition, to examine the ability of NBS Connect to generate data that guides hypothesis-driven research, data pertaining to age at diagnosis, bone health, and skin conditions in individuals with PKU were assessed. The objective of this paper is to describe the development of NBS Connect and highlight its data, resources and research contributions.Results: In September 2016, NBS Connect had 442 registered participants: 314 (71%) individuals with PKU, 68 (15%) with MSUD, 20 (5%) with TYR, and 40 (9%) with other disorders on the NBS panel. Age at diagnosis was less than 4 weeks in 285 (89%) of 319 respondents to this question and between 1 month and 14 years in 29 (9%) individuals. Of 216 respondents with PKU, 33 (15%) had a DXA scan in the past year. Of 217 respondents with PKU, 99 (46%) reported at least one skin condition.Conclusions: NBS Connect was built and refined with feedback from all stakeholders, including individuals with inherited metabolic disorders. Based on patient-reported data, future studies can be initiated to test hypotheses such as the relationship between PKU and skin conditions. Patient registries like NBS Connect can inform hypothesis-driven research, contributing to knowledge generation and following the current trend in moving from traditional medicine towards evidence-based practice. NBS Connect will help clinicians understand long-term outcomes of rare disorders, contributing to better patient care and quality of life. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAHenu2 (PKU model) mice. Initial trials of two PAHenu2 homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pahenu2 (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is a genetic metabolic disease in which the decrease or loss of phenylalanine hydroxylase (PAH) activity results in elevated, neurotoxic levels of phenylalanine (Phe). Due to many obstacles, PAH enzyme replacement therapy is not currently an option. Treatment of PKU with an alternative enzyme, phenylalanine ammonia lyase (PAL), was first proposed in the 1970s. However, issues regarding immunogenicity, enzyme production and mode of delivery needed to be overcome. Through the evaluation of PAL enzymes from multiple species, three potential PAL enzymes from yeast and cyanobacteria were chosen for evaluation of their therapeutic potential. The addition of polyethylene glycol (PEG, MW = 20,000), at a particular ratio to modify the protein surface, attenuated immunogenicity in an animal model of PKU. All three PEGylated PAL candidates showed efficacy in a mouse model of PKU (BTBR Pahenu2) upon subcutaneous injection. However, only PEGylated Anabaena variabilis (Av) PAL-treated mice demonstrated sustained low Phe levels with weekly injection and was the only PAL evaluated that maintained full enzymatic activity upon PEGylation. A PEGylated recombinant double mutant version of AvPAL (Cys503Ser/Cys565Ser), rAvPAL-PEG, was selected for drug development based on its positive pharmacodynamic profile and favorable expression titers. PEGylation was shown to be critical for rAvPAL-PEG efficacy as under PEGylated rAvPAL had a lower pharmacodynamic effect. rAvPAL and rAvPAL-PEG had poor stability at 4°C. L-Phe and trans-cinnamate were identified as activity stabilizing excipients. rAvPAL-PEG is currently in Phase 3 clinical trials to assess efficacy in PKU patients. [ABSTRACT FROM AUTHOR]

Context:Phenylketonuria(PKU) is the most common hereditary defect of phenylalanine hydroxylase (PAH) enzyme achieving the hydroxylation of phenylalanine (Phe). Phenylalanine ammonia lyase (PAL) converts Phe to a harmless metabolite, trans-cinnamic acid (TCA) in plants and PAL enzyme activity is fairly high in plants rich in flavonoids. Objective:The study aimed the biochemical analysis of PAL formCentaurea depressaBIEB. (Asteraceae) a flavonoid rich plant. This study may form the main frame of future research efforts for the development of a plant preparation aimed for oral intake in PKU patients in an attempt to enrich their diet by allowing them to ingest some food stuff containing Phe without being exposed to complications. Materials and methods:PAL was partially purified from the leaves ofC. depressa. Enzyme activity was determined in comparison with that of other herbs that reportedly have a high PAL activity. Enzyme optimization was achieved and the PAL protein was detected by western blotting. Results:C. depressaPAL demonstrated high activity (34.9 ± 0.6 U/mg protein). The enzyme was purified by 1.92-fold, which resulted in an activity of 53.30 ± 0.2 U/mg protein. The high-performance liquid chromatography analyzes of the PAL activity both before and after purification were in agreement. Western blot of PAL exhibited a 70 kDa protein band. The optimum pH and temperature are pH 8.8 and 37 °C. The optimum activities under gastric and intestinal digestion conditions were observed at pH 4.0 and pH 8.0, respectively. Discussion and conclusion:PAL activity ofC. depressais high, and does not disappear under different environmental conditions. This enzyme could be used for the development of dietary foods and biotechnological products for patients with PKU. [ABSTRACT FROM AUTHOR]

Background: Phenylketonuria treatment consists mainly of a Pherestricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. Objective: In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. Design: Pah-enu2 (PKU) mice received 1 of 5 different LNAAsupplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Results: Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. Conclusion: The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus provides essential information for the development of optimal LNAA supplementation as an alternative dietary treatment strategy to optimize neurocognitive outcome in patients with phenylketonuria. [ABSTRACT FROM AUTHOR]

Background: The mainstay of treating patients with phenylketonuria (PKU) is based on a Phe-restricted diet, restrictive in natural protein combined with Phe-free L-amino acid supplements and low protein foods. This PKU diet seems to reduce atherogenesis and confer protection against cardiovascular diseases but the results from the few published studies have been inconclusive. The aim of our study was to evaluate the relationship between the lipid profile and several treatment-related risk factors in patients with hyperphenylalaninaemia (HPA) in order to optimize their monitoring.Methods: We conducted a cross-sectional multicentre study. A total of 141 patients with HPA were classified according to age, phenotype, type of treatment and dietary adherence. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, blood pressure (BP) and biochemical parameters [(triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), apolipoprotein A (ApoA), apolipoprotein B (ApoB), vitamin B12, total homocysteine (tHcy), Methionine (Met), high sensitivity C-Reactive Protein (hsCRP)] were collected for each patient.Results: Plasma TC levels were lower in patients with PKU than in the mild-HPA group (150 ± 31 vs. 164 ± 22 mg/dL), and there was a weak inverse correlation between plasma TC and Phe levels. HDL-C, LDL-C, ApoA and ApoB levels were lower in the PKU group than in mild-HPA. Patients with PKU had higher systolic BP than the mild-HPA group and there was found a quadratic correlation between median Phe levels and systolic BP (p = 6.42e(-5)) and a linear correlation between median Phe levels and diastolic BP (p = 5.65e(-4)). In overweight or obese PKU patients (24.11 %), biochemical parameters such as TC, triglycerides, LDL-C, tHcy, hsCRP and BP were higher. By contrast, HDL-C was lower in these patients.Conclusion: Our data show a direct correlation between lipid profile parameters and good adherence to the diet in PKU patients. However, lipid profile in overweight or obese patients displayed an atherogenic profile, in addition to higher hsCRP concentrations and BP. Our study contributes to a better understanding of the relationship between phenotype and treatment in patients with HPA, which could be useful in improving follow-up strategies and clinical outcome.Trial Registration: Research Ethics Committee of Santiago-Lugo 2015/393. Registered 22 September 2015, retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: Phenylketonuria (PKU) is due to a defective hepatic enzyme, phenylalanine (Phe) hydroxylase. Transport of the precursor amino acids from blood into the brain for serotonin and dopamine synthesis is reported to be inhibited by high blood Phe concentrations. Deficiencies of serotonin and dopamine are involved in neurocognitive dysfunction in PKU. Objective: (1) To evaluate the effects of sapropterin (BH4) and concurrent use of large neutral amino acids (LNAA) on the peripheral biomarkers, melatonin and dopamine with the hypothesis they reflect brain serotonin and dopamine metabolism. (2) To evaluate synergistic effects with BH4 and LNAA. (3) To determine the effects of blood Phe concentrations on the peripheral biomarkers concentrations. Methods: Nine adults with PKU completed our study consisting of four 4-week phases: (1) LNAA supplementation, (2) Washout, (3) BH4 therapy, and (4) LNAA with BH4 therapy. An overnight protocol measured plasma amino acids, serum melatonin, and 6-sulfatoxymelatonin and dopamine in first void urine after each phase. Results: (1) Three out of nine subjects responded to BH4. A significant increase of serum melatonin levels was observed in BH4 responders with decreased blood Phe concentration. No significant change in melatonin, dopamine or Phe levels was observed with BH4 in the subjects as a whole. (2) Synergistic effects with BH4 and LNAA were observed in serum melatonin in BH4 responders. (3) The relationship between serum melatonin and Phe showed a significant negative slope (p = 0.0005) with a trend toward differing slopes among individual subjects (p = 0.066). There was also a negative association overall between blood Phe and urine 6-sulfatoxymelatonin and dopamine (P = 0.040 and 0.047). Conclusion: Blood Phe concentrations affected peripheral monoamine neurotransmitter biomarker concentrations differently in each individual with PKU. Melatonin levels increased with BH4 therapy only when blood Phe decreased. Monitoring peripheral neurotransmitter metabolites may assist in optimizing individualized treatment in PKU. [ABSTRACT FROM AUTHOR]

Background In 2014, recommendations for the nutrition management of phenylalanine hydroxylase deficiency were published as a companion to the concurrently published American College of Medical Genetics and Genomics guideline for the medical treatment of phenylketonuria (PKU). These were developed primarily from a summary of findings from the PKU scientific review conference sponsored by the National Institutes of Health and Agency for Healthcare Research & Quality along with additional systematic literature review. Since that time, the Genetic Metabolic Dietitians International and the Southeast Regional Newborn Screening and Genetics Collaborative have partnered to create a web-based technology platform for the update and development of nutrition management guidelines for inherited metabolic disorders. Objective The purpose of this PKU guideline is to establish harmonization in treatment and monitoring, to guide the integration of nutrition therapy in the medical management of PKU, and to improve outcomes (nutritional, cognitive, and developmental) for individuals with PKU in all life stages while reducing associated medical, educational, and social costs. Methods Six research questions critical to PKU nutrition management were formulated to support guideline development: Review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature, along with expert Delphi survey feedback, nominal group process, and external review from metabolic physicians and dietitians were utilized for development of recommendations relevant to each question. Recommendations address nutrient intake, including updated protein requirements, optimal blood phenylalanine concentrations, nutrition interventions, monitoring parameters specific to life stages, adjunct therapies, and pregnancy and lactation. Recommendations were graded using a rigorous system derived from the Academy of Nutrition and Dietetics. Results and Conclusion These guidelines, updated utilizing a thorough and systematic approach to literature analysis and national consensus process, are now easily accessible to the global community via the newly developed digital platform. For additional details on specific topics, readers are encouraged to review materials on the online portal: https://GMDI.org /. [ABSTRACT FROM AUTHOR]

Dietary therapy is the most common therapy applied in treatment of Phenylketonuria (PKU) with restriction of intake of most natural proteins that are rich in Phenylalanine (Phe). Recently, it has been claimed that caseinoglycomacropeptide (GMP), derived of whey, may be used to replace the amino acid formulae (AAF). The Aim of Work. To study the feasibility of use of GMP for partial replacement of artificial formula in treatment of children with PKU. Methods. Ten patients with PKU were included in the study. They received the recommended daily allowances of protein in the form of AAF or a combination of AAF and GMP. The percent of intake of GMP in phases 1 and 2 was 50% and zero%, respectively. Results. The median and interquartiles of phenyl alanine Phe levels phase were not significantly different in phases I and II, 376 (167–551) μmol/L versus 490 (289–597) μmol/L, respectively. Phenylalanine/tyrosine ratio, amino acids, and other laboratory data showed no significant difference between the two phases. Conclusion. GMP may be used to replace 50% of the protein intake to improve the nutritive value and palatability of diet and to provide a more satisfactory diet. No toxicity or side effects were reported in patients on that regimen. [ABSTRACT FROM AUTHOR]

The most widely-reported neurologic finding in individuals with early-treated phenylketonuria (PKU) is abnormality in the white matter of the brain. In contrast, much less is known regarding the impact of PKU on cortical gray matter (GM) structures. Presently, we applied advanced morphometric methods to the analysis of high-resolution structural MRI images from a sample of 19 individuals with early-treated PKU and an age- and gender-matched comparison group of 22 healthy individuals without PKU. Data analysis revealed decreased GM volume in parietal cortex for the PKU group compared with the non-PKU group. A similar trend was observed for occipital GM volume. There was no evidence of group-related differences in frontal or temporal GM volume. Within the PKU group, we also found a significant relationship between blood phenylalanine levels and GM volume for select posterior cortical sub-regions. Taken together with previous research on white matter and gray matter abnormalities in PKU, the present findings point to the posterior cortices as the primary site of neurostructural changes related to early-treated PKU. [ABSTRACT FROM AUTHOR]

Abstract: Despite a century of progress in medical knowledge, many diagnostic odysseys end in disappointment, especially when the child has a developmental disorder. In cases of autism and intellectual disability, relatively few children receive a specific diagnosis, and virtually none of those diagnoses lead to a specific medical treatment. Whole‐genome or ‐exome sequencing offers a quantum leap in the diagnostic odyssey, in that we will always learn something from sequencing—sometimes much more than families bargained for, as discussed elsewhere in this special report. The trick is whether the knowledge gained will help the child and family. A family‐centered approach gives families permission to choose but does not lay all of the responsibility on them. The goal is to pursue the degree of medical diagnostic evaluation that matches the family's values. [ABSTRACT FROM AUTHOR]

Unlabelled: To avoid potentially severe outcomes, phenylketonuria (PKU) must be detected as soon as possible after birth and managed with life-long treatment. A questionnaire-based survey was performed to document diagnosis and management practices for PKU in a region of Southern and Eastern Europe. Prevalence and management data were obtained from 37/59 (63 %) centres within 19/22 (86%) contacted countries (N = 8600 patients). The main results' analysis was based on completed questionnaires obtained from 31 centres (53%) within 15 countries (68%). A median of 10 % of patients per centre had been diagnosed after the newborn period. Metabolic dieticians and specialised adult PKU clinics were lacking in 36 and 84% of centres, respectively. In 26% of centres, treatment initiation was delayed until >15 days of life. Blood phenylalanine (Phe) thresholds to start treatment and upper Phe targets were inconsistent across centres. Ten percent of centres reported monitoring Phe every 2 weeks for pregnant women with PKU, which is insufficient to minimise risk of neonatal sequalae. Sapropterin dihydrochloride treatment was available in 48% of centres, with 24-h responsiveness tests most common (36%). Only one centre among the five countries lacking newborn screening provided a completed questionnaire.Conclusion: Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches for PKU in Southern and Eastern Europe.What Is Known: PKU must be detected early and optimally managed throughout life to avoid poor outcomes, yet newborn screening is not universal and diagnostic and management practices for PKU are known to vary widely between different centres and countries. Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches.What Is New: PKU management practices are documented in 19 South and Eastern European countries indicating a heterogeneous situation across the region. Key areas for improvement identified in surveyed centres include a need for comprehensive screening in all countries, increased number of metabolic dietitians and specialised adult PKU clinics, delayed time to treatment initiation, appropriate Phe thresholds, Phe targets and monitoring frequencies, and universal access to currently available treatment options. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) deficiencies of the monoamine neurotransmitters, dopamine and serotonin, have been implicated in the pathophysiology of neuropsychiatric dysfunction in phenylketonuria (PKU). Increased brain phenylalanine concentration likely competitively inhibits the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), the rate limiting steps in dopamine and serotonin synthesis respectively. Tetrahydrobiopterin (BH 4 ) is a required cofactor for TH and TPH activity. Our hypothesis was that treatment of hyperphenylalaninemic Pah enu2 / enu2 mice, a model of human PKU, with sapropterin dihydrochloride, a synthetic form of BH 4 , would stimulate TH and TPH activities leading to improved dopamine and serotonin synthesis despite persistently elevated brain phenylalanine. Sapropterin (20, 40, or 100 mg/kg body weight in 1% ascorbic acid) was administered daily for 4 days by oral gavage to Pah enu2 / enu2 mice followed by measurement of brain biopterin, phenylalanine, tyrosine, tryptophan and monoamine neurotransmitter content. A significant increase in brain biopterin content was detected only in mice that had received the highest sapropterin dose, 100 mg/kg. Blood and brain phenylalanine concentrations were unchanged by sapropterin therapy. Sapropterin therapy also did not alter the absolute amounts of dopamine and serotonin in brain but was associated with increased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), dopamine and serotonin metabolites respectively, in both wild type and Pah enu2 / enu2 mice. Oral sapropterin therapy likely does not directly affect central nervous system monoamine synthesis in either wild type or hyperphenylalaninemic mice but may stimulate synaptic neurotransmitter release and subsequent metabolism. [ABSTRACT FROM AUTHOR]

The recent advances in the molecular engineering of aromatic ammonia lyases (ALs) and aminomutases (AMs) attracted increased interest towards their applications in the treatment of phenylketonuria and/or the synthesis of non-natural amino acids. Herein we describe the cloning, isolation and purification of recombinant L-phenylalanine ammonia-lyase from Rhodosporidium toruloides for future biocatalytic and therapeutic applications. [ABSTRACT FROM AUTHOR]

Introduction The few published case reports of co-existent disease with phenylketonuria (PKU) are mainly genetic and familial conditions from consanguineous marriages. The clinical and demographic features of 30 subjects with PKU and co-existent conditions were described in this multi-centre, retrospective cohort study. Methods Diagnostic age of PKU and co-existent condition, treatment regimen, and impact of co-existent condition on blood phenylalanine (Phe) control and PKU management were reported. Results 30 patients (11 males and 19 females), with PKU and a co-existent condition, current median age of 14 years (range 0.4 to 40 years) from 13 treatment centres from Europe and Turkey were described. There were 21 co-existent conditions with PKU; 9 were autoimmune; 6 gastrointestinal, 3 chromosomal abnormalities, and 3 inherited conditions. There were only 5 cases of parental consanguinity. Some patients required conflicting diet therapy (n = 5), nutritional support (n = 7) and 5 children had feeding problems. There was delayed diagnosis of co-existent conditions (n = 3); delayed treatment of PKU (n = 1) and amenorrhea associated with Grave's disease that masked a PKU pregnancy for 12 weeks. Co-existent conditions adversely affected blood Phe control in 47% (n = 14) of patients. Some co-existent conditions increased the complexity of disease management and increased management burden for patients and caregivers. Conclusions Occurrence of co-existent disease is not uncommon in patients with PKU and so investigation for co-existent disorders when the clinical history is not completely consistent with PKU is essential. Integrating care of a second condition with PKU management is challenging. [ABSTRACT FROM AUTHOR]

Background: Hyperphenylalaninemia (HPA) and Phenylkeonuria (PKU) are metabolic errors caused by deficiency of phenylalanine hydroxylase enzyme, which results in increased level of phenylalanine. This increase is toxic to the growing brain. Objectives: The purpose of this study was to compare the intellectual and developmental status in HPA and PKU children with normal population in national screening program. Patients and Methods: In a historical cohort study, 41 PKU patients who had the inclusion criteria and 41 healthy children were evaluated. Wechsler preschool and primary scale of intelligence-3rd edition (WPPI-3) was used in order to assess the intellectual status of children 4 years and older and Ages and stages questionnaire (ASQ) was used to assess the developmental status of children 5 years and younger. Results: In intellectual test comparison, the two groups showed significant difference in Wechsler’s performance intelligence score and some performance subscales (P-value < 0.01). In comparison of developmental status, no significant difference was observed between the two groups (P-value > 0.05). Conclusions: Even with early diagnosis and treatment of PKU patients, these children show some deficiencies intellectually compared to normal children. This study emphasizes on necessity for screening intellectual and developmental status of PKU patients so that effective medical or educational measures can taken in case of deficiencies. [ABSTRACT FROM AUTHOR]

Background: The strict and demanding dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life (HRQoL) of patients and their families. Our aim was to describe the HRQoL of patients with PKU from a large international study, using generic HRQoL measures and an innovative PKU-specific HRQoL questionnaire (PKU-QOL). Analyses were exploratory, performed post-hoc on data collected primarily to validate the PKU-QOL. Methods: A multicentre, prospective, non-interventional, observational study conducted in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Patients diagnosed with PKU aged =9 years old and treated with a Phe-restricted diet and/or Phe-free amino acid protein supplements and/or pharmacological therapy were included in the study; parents of at least one patient with PKU aged <18 years were also included. HRQoL was assessed by generic measures (Pediatric Quality-of-Life Inventory; Medical Outcome Survey 36 item Short Form; Child Health Questionnaire 28 item Parent Form) and the newly developed PKU-QOL. Mean generic domain scores were interpreted using published reference values from the general population. PKU-QOL domain scores were described overall and in different subgroups of patients defined according to severity of PKU, overall assessment of patient's health status by the investigator and treatment with tetrahydrobiopterin (BH4). Results: Data from 559 subjects were analysed: 306 patients (92 children, 110 adolescents, 104 adults) and 253 parents. Mean domain scores of generic measures in the study were comparable to the general population. The highest PKU-QOL impact scores (indicating greater impact) were for emotional impact of PKU, anxiety about blood Phe levels, guilt regarding poor adherence to dietary restrictions or Phe-free amino acid supplement intake and anxiety regarding blood Phe levels during pregnancy. Patients with mild/moderate PKU and those receiving BH4 reported lower practical and emotional impacts of the diet and Phe-free amino acid supplement intake. Conclusion: Patients with PKU showed good HRQoL in the study, both with the generic and PKU-specific measures. Negative impacts of PKU on a patient's life, including the emotional impact of PKU and its management, was delineated by the PKU-QOLs across all age groups. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) results in an accumulation of phenylalanine (phe) in the blood which can lead to multiple health consequences in affected individuals. Treatment for PKU is available; however adherence to medical management recommendations can be difficult. When recommendations are not followed and the health of a child is at risk, one intervention that may be necessary is a referral for medical neglect to the local child protective services (CPS) agency. This study summarizes the cases that were referred from our metabolic clinic at the Children's Hospital of Michigan to CPS, and the outcomes of that intervention. CPS referrals helped to improve adherence to medical management recommendations in the majority of cases, including a lower blood phe level for the child; however, at times that improvement did not occur until after a second referral and/or the child's temporary removal from the home. [ABSTRACT FROM AUTHOR]

Natural sources of protein and some vitamins and minerals are limited in phenylketonuria (PKU) treated patients, who should receive optimal supplementation although this is not yet fully established. We conducted a cross-sectional observational multicenter study including 156 patients with hyperphenylalaninemia. Patients were stratified by age, phenotype, disease detection and type of treatment. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, and biochemical parameters (total protein, prealbumin, electrolytes, selenium, zinc, B 12 , folic acid, ferritin, 25-OH vitamin D) were collected in all patients. 81.4% of patients had biochemical markers out of recommended range but no clinical symptoms. Total protein, calcium, phosphorus, B 12 , ferritin, and zinc levels were normal in most patients. Prealbumin was reduced in 34.6% of patients (74% with PKU phenotype and 94% below 18 years old), showing almost all (96.3%) an adequate adherence to diet. Selenium was diminished in 25% of patients (95% with PKU phenotype) and also 25-OHD in 14%. Surprisingly, folic acid levels were increased in 39% of patients, 66% with classic PKU. Phosphorus and B 12 levels were found diminished in patients with low adherence to diet. Patients under BH4 therapy only showed significant lower levels of B 12 . This study shows a high percentage of prealbumin and selenium deficiencies as well as an increased level of folic acid in PKU treated patients, which should lead us to assess an adjustment for standards supplements formulated milks. [ABSTRACT FROM AUTHOR]

Background Previous qualitative research among adults and parents of children with phenylketonuria (PKU) has identified inattention as an important psychiatric aspect of this condition. The parent-reported ADHD Rating Scale-IV (ADHD RS-IV) and the Adult ADHD Self-Report Scale (ASRS) have been validated for measuring inattention symptoms in persons with attention-deficit/hyperactivity disorder (ADHD); however, their psychometric attributes for measuring PKU-related inattention have not been established. Objective The primary objective of this investigation was to demonstrate the reliability, validity, and responsiveness of the ADHD RS-IV and ASRS inattention symptoms subscales in a randomized controlled trial of patients with PKU aged 8 years or older. Methods A post hoc analysis investigated the psychometric properties (Rasch model fit, reliability, construct validity, and responsiveness) of the ADHD RS-IV and ASRS inattention subscales using data from a phase 3b, double-blind, placebo-controlled clinical trial in those with PKU aged 8 years or older. Results The Rasch results revealed good model fit, and reliability analyses revealed strong internal consistency reliability ( α ≥ 0.87) and reproducibility (intraclass correlation coefficient ≥ 0.87) for both measures. Both inattention measures demonstrated the ability to discriminate between known groups ( P < 0.001) created by the Clinical Global Impression-Severity scale. Correlations between the ADHD RS-IV and the ASRS with the Clinical Global Impression-Severity scale and the age-appropriate Behavior Rating Inventory of Executive Function Working Memory subscale were consistently moderate to strong ( r ≥ 0.56). Similarly, results of the change score correlations were of moderate magnitude ( r ≥ 0.43) fo r both measures when compared with changes over time in Behavior Rating Inventory of Executive Function Working Memory subscales. Conclusions These findings of reliability, validity, and responsiveness of both the ADHD RS-IV and the ASRS inattention scales, in addition to content validation results, support their use for the assessment of inattention symptoms among persons with PKU aged 8 years or older in both clinical and research settings. [ABSTRACT FROM AUTHOR]

The aim of the study was to explore the outcome of neurocognitive deficits and neuroimaging correlates in young adult early treated phenylketonuric (PKU) patients. We conducted a longitudinal study of 14 PKU patients that were assessed for IQ and neuropsychological functioning including executive functions (EF) over 14 years of follow-up (age range at 1st and 2nd assessments were 7.8–13.5 and 22.2–27.7 years, respectively). The IQ of all 14 PKU patients was within the normal range. With respect to the 1st assessment, mean IQ at follow-up did not decrease significantly. Compared to control subjects (n = 14), mean IQ of patients was significantly lower (p = .0005). Throughout adolescence and early adulthood there was an improvement of neuropsychological functioning of PKU patients in spite of the relaxation of diet, however some deficits were still detectable when compared to controls. All patients that underwent a second MRI scan showed white matter alterations ranging from mild to severe which was correlated neither with IQ nor with EF scoring. Cognitive, neuropsychological and neuroimaging outcome was influenced from life-long and/or second decade of life metabolic control. Nevertheless patients' developmental trajectories were in some cases independent from metabolic control. Our results support the hypothesis of an individual vulnerability to phenylalanine. However, as long as individual factors that account for the vulnerability to Phe are not recognized, strict dietary control is recommended for all the patients also in the second decade of life. [ABSTRACT FROM AUTHOR]