Phe Levels Research Articles

Increased serum phenylalanine/tyrosine ratio associated with the psychiatric symptom of anti-NMDAR encephalitis.

Encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) results in a distinctive neuro-psychiatric syndrome. It has been reported that the serum phenylalanine-tyrosine (Phe/Tyr) ratio increases during infection. However, the connection between phenylalanine-tyrosine metabolism and psychiatric symptoms remains unclear. We enrolled 24 individuals with anti-NMDAR encephalitis and 18 individuals with non-inflammatory neurological diseases (OND). Chromatography was used to measure serum levels of phenylalanine and tyrosine. Serum and cerebrospinal fluid (CSF) TNF-α levels were obtained from the clinical database. The modified Rankin Scale (mRS) score and Glasgow Coma Scale (GCS) score were recorded during the acute phase. The area under the curve (AUC) of the receiver operating characteristic curve was used to assess prediction efficacy. In NMDAR patients, levels of serum Phe and the ratio of serum Phe/Tyr were higher compared to OND patients. The serum Phe/Tyr ratio was also elevated in NMDAR patients with psychiatric syndrome. Furthermore, serum Phe and Tyr levels were correlated with inflammatory indexes. The serum Phe/Tyr ratio is elevated in NMDAR patients with psychiatric syndrome and is associated with severity. Therefore, the serum Phe/Tyr ratio may serve as a potential prognostic biomarker.

A-348 Portable aptamer-based home monitoring system for blood phenylalanine measurement

Abstract Background Aptatek BioSciences, Inc. has developed a home monitoring tool for blood phenylalanine (phe) levels. The Aptatek system integrates a proprietary aptamer assay approach with a user-friendly handheld, smartphone-enabled test platform. PKU (phenylketonuria), is an inborn error of phenylalanine (Phe) metabolism If undiagnosed or untreated, phe accumulates in all body tissues, including the blood and brain, where it is especially neurotoxic and when untreated it can cause significant cognitive impairment and neurological defects. PKU management targets maintaining blood Phe concentration within the therapeutic range (120-360uM) to avoid severe neurological sequelae, mainly through nutritional therapy. Methods PheCheck™ includes a portable hand-held reader, software accessible as a mobile phone application, and a disposable single-use lateral flow cassette, blood collection, cap, and buffer chamber. PheCheck™ detects phe by binding of the phe in a small blood sample using small molecule-specific DNA aptamers. A patient (or caregiver) collects 5μl of capillary blood using a lancet to lance the fingertip and use the collection cap to collect the specimen. Once collected, the specimen is placed into the buffer chamber where the blood is diluted and processed in preparation for a lateral flow assay. The buffer chamber is placed on top of a lateral flow cassette to release the solution into the cassette. The lateral flow cassette is inserted into a small electronic reader after specimen incubation. The reader will detect a fluorescent signal from the strip and report the quantitative Phe concentration present in the specimen to the integrated mobile phone application. The reader has a simple design with a single operating push button, USB data connection port, and replaceable battery compartment. The reader reads the output of the lateral flow cassette and reports the result to a Smartphone app. The app is designed to either display the quantitative results or store the results without displaying the quantitative value. Results Twelve patients were trained on the PheCheck system and observed using the system for self-testing. Patients also prepared dried blood spot cards for comparative testing using LC-mass spectrometry. Patients were asked to return to the clinic within two weeks to retest. The blood phenylalanine levels measured by the PheCheck system were within targeted standard deviation of the dried blood spots demonstrating the feasibility of portable home-based testing for routine monitoring of blood phenylalanine levels in phenylketonuria patients. Such a portable system would enable real time monitoring and adjustment of diet or therapy for chronic diseases such as PKU. Conclusions Aptatek has developed a DNA aptamer based portable monitor for measuring blood phenylalanine levels. The system quantitatively measures phenylalanine from a 5-microliter finger stick blood sampler. Aptamer-based detection of phenylalanine provides reliable quantitation across a wide clinical concentration range and encouraging performance relative to gold standard testing of venous blood draw or dried blood spots. Analysis of samples from patients on Palynziq indicate that the PheCheck system could provide more reliable testing than venous blood draws. The system shows strong promise for routine home monitoring of blood phe levels by patients.

Current Advances and Material Innovations in the Search for Novel Treatments of Phenylketonuria.

Phenylketonuria (PKU) is a genetically inherited disease caused by a mutation of the gene encoding phenylalanine hydroxylase (PAH) and is the most common inborn error of amino acid metabolism. A deficiency of PAH leads to increased blood and brain levels of phenylalanine (Phe), which may cause permanent neurocognitive symptoms and developmental delays if untreated. Current management strategies for PKU consist of early detection through neonatal screening and implementation of a restrictive diet with minimal amounts of natural protein in combination with Phe-free supplements and low-protein foods to meet nutritional requirements. For milder forms of PKU, oral treatment with synthetic sapropterin (BH4), the cofactor of PAH, may improve metabolic control of Phe and allow for more natural protein to be included in the patient's diet. For more severe forms, daily injections of pegvaliase, a PEGylated variant of phenylalanine ammonia-lyase (PAL), may allow for normalization of blood Phe levels. However, the latter treatment has considerable drawbacks, notably a strong immunogenicity of the exogenous enzyme and the attached polymeric chains. Research for novel therapies of PKU makes use of innovative materials for drug delivery and state-of-the-art protein engineering techniques to develop treatments which are safer, more effective, and potentially permanent.

The association of aromatic amino acids with coronary artery disease and major adverse cardiovascular events in a Chinese population

This study aimed to evaluate the relationship between aromatic amino acids (AAAs), – phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp) – and coronary artery disease (CAD) in a prospective study involving 2970 participants undergoing coronary angiography at Beijing Hospital. Serum levels of Phe, Tyr and Trp were analysed. The cross-sectional data revealed that serum Tyr and Trp levels were significantly and inversely associated with CAD. During a median follow-up period of 44 months, 343 major adverse cardiovascular events (MACEs) and 138 all-cause deaths were recorded. MACE included myocardial infarction, stroke, revascularisation and all-cause mortality. Low serum Trp levels predicted an increased risk of MACE and death. High serum Phe levels were linked to an increased risk of MACE, while low Tyr levels were associated with a higher risk of death. Collectively, our findings underscore a close correlation between AAAs and CAD, as well as their potential predictive value for adverse cardiovascular outcomes.

Evaluation of Exposure to Bisphenol A, Bisphenol F, and Phthalates in Patients with Phenylketonuria and Its Differences According to Dietary Status.

Phenylketonuria (PKU) is the most common amino acid metabolism disorder. Patients with blood phenylalanine (Phe) levels of ≥6 mg/dL require treatment, and the most definitive treatment is the Phe-restricted diet. Bisphenols and phthalates are widely used endocrine-disrupting chemicals (EDCs) found in personal care products, baby bottles, and food packaging. In this study, we evaluated the possible routes of exposure to these EDCs in patients diagnosed with PKU (n = 105, 2-6 years of age) and determined the relationship between the plasma levels of bisphenol A (BPA), bisphenol F (BPF), di-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP), mono-(2ethylhexyl) phthalate (MEHP), and dietary regimens. Participant characteristics and exposure routes were evaluated according to their dietary treatment status. Thirty-four of these patients were on a Phe-restricted diet, while the remaining 71 had no dietary restrictions. DBP and DEHP levels were higher in those using plastic tablecloths (p = 0.049 and p = 0.04, respectively). In addition, plasma DBP levels were higher in those who used bottled water (p = 0.01). Being under 4 years of age, using plastic food containers, and using plastic shower curtains were characteristics associated with higher MEHP levels (p = 0.027, p = 0.019, and p = 0.014, respectively). After adjustment for baseline characteristics (Model 1), the odds of having a plasma BPA level in the upper tertile were 3.34 times higher in the free-diet group (95% CI = 1.09-10.25). When we additionally adjusted for plastic exposure (Model 2), the odds ratio was found to be 18.64 (95% CI = 2.09-166.42) for BPA. In the free-diet group, the probability of having plasma DEHP levels in the upper tertile was increased by a relative risk of 3.01 (p = 0.039, 95% CI = 1.06-8.60). Our results indicate that exposure to bisphenols and phthalates varies with dietary treatment. The difference in sources of exposure to EDCs between the diet and non-diet groups indicates that diet plays an important role in EDC exposure.

Parents’ Perspectives of Children with PKU: Assessing Parental Stress and Psychological Adjustment

Phenylketonuria (PKU) is an inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase enzyme activity. Diagnosis in the first days of life allows early initiation of dietary therapy. The maintenance of this treatment raises demanding management issues in everyday life, often resulting in a psychological burden for patients and families. In this brief report, we aimed to investigate parenting stress and parents’ perceptions of their child’s adjustment, focusing on correlations between the perspectives of mothers and fathers. We conducted an observational study, enrolling parents of pediatric patients (aged 2–18) diagnosed with PKU and treated from birth. A total of 20 parenting couples of 20 PKU-affected children were included. The mean Phe level was 301.60 µmol/L (SD = 128.39). Most PSI-SF and SDQ-P scores were below the clinically relevant threshold. Significant correlations emerged between paternal parenting stress and the child’s Phe level and, additionally, between mothers’ and fathers’ scores. Parents of PKU-affected children reported acceptable levels of parenting stress and their children’s psychological adjustment. However, fathers perceived greater stress in maintaining adequate Phe levels for their children. Our results suggest a similar perspective of both parents in relation to their child’s psychological adjustment. Therefore, the psychological well-being of PKU patients and their parents must be monitored to provide family-centered care and psychological support in the process of accepting a rare disease.

Meta-analysis of bone mineral density in adults with phenylketonuria

BackgroundLifelong management of phenylketonuria (PKU) centers on medical nutrition therapy, including dietary phenylalanine (Phe) restriction in addition to Phe-free or low-Phe medical foods/protein substitutes. Studies have reported low bone mineral density (BMD) in mixed-age PKU populations, possibly related to long-term Phe restriction. Therefore, a meta-analysis investigating BMD specifically in adults with PKU was conducted.MethodsStudies reporting BMD-related outcomes were identified from a systematic literature review evaluating somatic comorbidities experienced by adults with PKU on a Phe-restricted diet (searched February 1, 2022, updated November 1, 2023). Risk of study bias was assessed (Scottish Intercollegiate Guidelines Network checklists). The primary outcome of the meta-analysis was pooled mean BMD Z-scores of different bones. Secondary outcomes were the prevalence of low BMD Z-scores at pre-specified thresholds. Subgroup analyses of mean BMD Z-scores (decade of study publication, controlled versus uncontrolled blood Phe levels, gender) were conducted.ResultsBMD-related data from 4097 individuals across 10 studies rated as at least acceptable quality were included. Mean BMD Z-scores were statistically significantly lower compared with an age-matched control or reference (non-PKU) population, across bones, but still within the expected range for age (> -2.0): lumbar spine (seven studies, n = 304), -0.63 (95% confidence interval (CI): -0.74, -0.52); femoral neck (four studies, n = 170), -0.74 (95% CI: -1.25, -0.22); radius (three studies, n = 114), -0.77 (95% CI: -1.21, -0.32); total body (four studies, n = 157), -0.61 (95% CI: -0.77, -0.45). The small number of observations in the subgroup analyses resulted in a high degree of uncertainty, limiting interpretation. Estimated prevalence of BMD Z-scores ≤ -2.0 was 8% (95% CI: 5%, 13%; four studies, n = 221) and < -1.0 was 42% (95% CI: 35%, 51%; five studies, n = 144).ConclusionsAdults with PKU had lower BMD Z-scores than the reference (non-PKU) population but < 1 in 10 were below the expected range for age. The low number of studies prevents identification of which population characteristics are most impacting BMD.This meta-analysis was supported by BioMarin Pharmaceutical Inc., Novato, CA and is registered with the Research Registry (reviewregistry1476).

High-level L-Gln compromises intestinal amino acid utilization efficiency and inhibits protein synthesis by GCN2/eIF2α/ATF4 signaling pathway in piglets fed low-crude protein diets

Gln, one of the most abundant amino acids (AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters, protein synthesis, and underlying mechanisms in vivo is scarce. The present study aimed to explore the effects of low-crude protein diet inclusion with differential doses of L-Gln on intestinal AA levels, transporters, protein synthesis, and potential mechanisms in weaned piglets. A total of 128 healthy weaned piglets (Landrace × Yorkshire) were randomly allocated into four treatments with four replicates. Pigs in the four groups were fed a low-crude protein diet containing 0%, 1%, 2%, or 3% L-Gln for 28 d. L-Gln administration markedly (linear, P < 0.05) increased Ala, Arg, Asn, Asp, Glu, Gln, His, Ile, Lys, Met, Orn, Phe, Ser, Thr, Tyr, and Val levels and promoted trypsin activity in the jejunal content of piglets. Moreover, L-Gln treatment significantly enhanced concentrations of colonic Gln and Trp, and serum Thr (linear, P < 0.01), and quadratically increased serum Lys and Phe levels (P < 0.05), and decreased plasma Glu, Ile, and Leu levels (linear, P < 0.05). Further investigation revealed that L-Gln administration significantly upregulated Atp1a1, Slc1a5, Slc3a2, Slc6a14, Slc7a5, Slc7a7, and Slc38a1 relative expressions in the jejunum (linear, P < 0.05). Additionally, dietary supplementation with L-Gln enhanced protein abundance of general control nonderepressible 2 (GCN2, P = 0.010), phosphorylated eukaryotic initiation factor 2 subunit alpha (eIF2α, P < 0.001), and activating transcription factor 4 (ATF4) in the jejunum of piglets (P = 0.008). These results demonstrated for the first time that a low crude protein diet with high-level L-Gln inclusion exhibited side effects on piglets. Specifically, 2% and 3% L-Gln administration exceeded the intestinal utilization capacity and compromised the jejunal AA utilization efficiency, which is independent of digestive enzyme activities. A high level of L-Gln supplementation would inhibit protein synthesis by GCN2/eIF2α/ATF4 signaling in piglets fed low-protein diets, which, in turn, upregulates certain AA transporters to maintain AA homeostasis.

Longitudinal Dietary Intake Data in Patients with Phenylketonuria from Europe: The Impact of Age and Phenylketonuria Severity.

In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1-57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities.

The value of phenylalanine in predicting atrial fibrillation risk in chronic heart failure.

Atrial fibrillation (AF) is a common complication of chronic heart failure (HF). Serum phenylalanine (Phe) levels are related to inflammation disorder. It is meaningful to study the circulating Phe with AF occurrence in HF. The cross-sectional study recruited 300 patients (78.0% male; mean age, 65 ± 13 years) with HF (left ventricular ejection fraction of ≤50%, containing 70 AF patients) and 100 normal controls. Serum Phe value was measured by liquid chromatography-tandem mass spectrometry. Logistic regression analysis was conducted to measure the association between Phe and AF risk in HF. The association between Phe and high-sensitivity C-reactive protein (hsCRP) was assessed by simple correlation analysis. In the prospective study, the 274 HF subjects (76.6% male; mean age, 65 ± 13 years) were followed up for a mean year (10.99 ± 3.00 months). Serum Phe levels increased across the control, the HF without AF, and the HF with AF groups (77.60 ± 8.67 umol/L vs. 95.24 ± 28.58 umol/L vs. 102.90 ± 30.43 umol/L, ANOVA P < 0.001). Serum Phe value was the independent risk factor for predicting AF in HF [odds ratio (OR), 1.640; 95% CI: 1.150-2.339; P = 0.006]. Phe levels were correlated positively with hsCRP value in HF patients with AF (r = 0.577, P < 0.001). The elevated Phe levels were associated with a higher risk of HF endpoint events in HF patients with AF (log-rank P = 0.005). In HF with AF subjects, elevated Phe value confers an increased risk for prediction AF and was more related to poor HF endpoint events. Phe can be a valuable index of AF in HF.

Do early‐treated adults with phenylketonuria sense high phenylalanine levels?

AbstractThis study aimed to analyze whether early‐treated adults with phenylketonuria (PKU) can subjectively sense high phenylalanine (Phe) concentrations and whether a possible impact of Phe on objective measures of cognitive performance and mood reflects patients' self‐perception. Data from the PICO study, a randomized, placebo‐controlled, double‐blind, crossover trial, were analyzed. Twenty‐eight adults with PKU received either Phe capsules or placebo in two 4‐week intervention periods in a randomized order, with a 4‐week washout in between. The median Phe level increased from 852 μmol/L (interquartile range: 345) to 1455 μmol/L (interquartile range: 369). Neuropsychological assessments were performed at four study visits. At the end of the last study visit, patients were asked whether they could discern the Phe intervention period. Seven of 28 (25%) patients stated that they could not discern between the Phe and the placebo period. Twenty‐one of 28 (75%) patients subjectively thought to sense high Phe levels. Of the 21 patients, 12 (57%) correctly identified the Phe period, whereas 9 (43%) received placebo at the time when they thought they would receive the high Phe load. Binomial tests showed that the probability of 12 out of 21 is p = 0.140, and 12 out of 28 is p = 0.113. The “Right‐Guess” group showed significantly higher Phe changes than the “Wrong‐Guess” group. Cognitive performance and standardized mood assessment did not significantly differ, and both groups reported similar subjective negative impact on cognition and mood. In conclusion, adults with early‐treated PKU cannot effectively identify high Phe levels, although some individuals may be able to perceive more pronounced increases in Phe levels.

Influence of Different Feed Particle Sizes on the Growth Performance and Nutrition Composition in Crayfish, Procambarus clarkii Larvae.

A suitable feed size has a positive effect on animal feeding. For aquatic larvae, the correct feed size is very important for their growth. This experiment analyzed and compared the effect of different particle sizes of feed for larval stages on the growth performance, whole body composition, and muscle amino acid and fatty acid composition of crayfish. Five larval crayfish diets of different particle sizes, namely < 0.40 mm (Group A, control group), 0.40-0.50 mm (Group B), 0.71-0.85 mm (Group C), 0.90-1.00 mm (Group D) and 1.5 mm (Group E), were fed to 2000 crayfish (initial weight 0.0786 ± 0.0031 g) for 100 d. The results showed that as the particle size increased, final weight, weight gain (WG, p = 0.001) and specific growth rate (SGR, p = 0.000) of the crayfish tended to increase and then leveled off, with the control group being the lowest. The feed conversion ratio (FCR, p = 0.000) showed a decreasing and then equalizing trend with increasing particle size, but there was no significant difference between the groups except the control group. Broken-line regression analysis showed that the critical values for the appropriate particle feed size for crayfish larvae were 0.55 mm and 0.537 mm using SGR and FCR as indicators. Groups B, C and D had the highest crude protein content and were significantly higher than the control group (p = 0.001). Group E had the highest umami amino acid (UAA) and was significantly higher than the control group (p = 0.026). The content of isoleucine (Ile, p = 0.038) and phenylalanine (Phe, p = 0.038) was highest in group C and significantly higher than in the control group. Through principal component analysis, groups C and D were shown to contain leucine (Leu), glutamic (Glu), methionine (Met), valine (Val), histidine (His), Phe, and Ile levels significantly induced. The content of linoleic acid (C18:2n6, p = 0.000), linolenic acid (C18:3n3, p = 0.000), saturated fatty acid (SFA, p = 0.000), monounsaturated fatty acid (MUFA, p = 0.001), polyunsaturated fatty acid (PUFA, p = 0.000) and n-6 PUFA (p = 0.000) in group C was the highest and significantly higher than the control group. Principal component analysis showed that group C significantly induced the levels of C18:2n6, C18:3n3, DHA, EPA, n-3 PUFA and n-6 PUFA in muscle. Therefore, our results suggest that appropriate feed particle size can improve the growth performance and nutrient composition of crayfish. Based on the broken-line regression analysis of SGR and FCR, the critical values of optimal particle size for crayfish are 0.55 mm and 0.537 mm, and when the particle size exceeds these critical values (not more than 1.5 mm commercial feed), growth performance and FCR of the crayfish are no longer changed. Nevertheless, group C has high protein and low lipid content, as well as better nutrition with amino acids and fatty acids. Overall, combined with growth performance and nutrient composition, it is recommended that the particle size of the diet at the larval stage for crayfish is between 0.71 and 0.85 mm.

Are Carriers Unaffected? A Literature Review of Metabolic and Health Outcomes among Genetic Carriers of Phenylketonuria.

Phenylketonuria (PKU) is an autosomal recessive genetic condition that results in reduced enzymatic functioning within the phenylalanine hydroxylase (PAH) pathway, which is involved in the metabolism of phenylalanine (Phe) into tyrosine (Tyr). Without dietary intervention, individuals with PKU exhibit significantly elevated levels of Phe, which is presumed to cause severe neurological dysfunction and other associated health risks. Carriers of PKU are heterozygotes for a PAH gene mutation and are typically described in the literature as "unaffected." However, decades of existing research challenges this classical thinking and it is plausible that these individuals currently classified as carriers may present with an intermediate phenotype or may be "moderately affected." The purpose of this scoping review was to explore this hypothesis further, by searching for and summarizing existing literature on metabolism and health outcomes among PKU carriers. Preliminary research has suggested that some PKU carriers exhibit reduced PAH enzyme function, and relatedly, elevated circulating Phe levels compared to noncarriers. In addition, Phe dosing trials have further demonstrated that carriers have increased Phe levels and decreased Tyr levels compared to noncarriers. Because of these metabolic perturbations, it is biologically plausible for carriers to experience an intermediate phenotype in terms of metabolic consequences and clinical outcomes. While these outcomes have yet to be thoroughly explored, early research has found associations between PKU carrier status and lower IQs as well as decreased executive functioning, memory, processing speed, and inhibitory control. The PAH pathway is also involved in melanogenesis, and research has demonstrated increased melanoma risk among PKU carriers. However, there are many limitations to this research, and thus whether or not carriers are clinically impacted cannot yet be conclusively determined. Overall, while preliminary research suggests a possible intermediate phenotype among PKU carriers, the current available research is limited and PKU carriers are still clinically considered "unaffected." This review outlines the current literature while discussing future research endeavors related to the metabolism and health of PKU carriers.

Seizure Outcome and Predicting Factors in Adult Patients with Phenylketonuria: Single-center Experience

ABSTRACT Objective: Phenylketonuria (PKU) is one of the most common metabolic disorders worldwide. If left untreated, it causes neuropsychiatric sequelae, with seizures being a common occurrence. There is little information about the clinical features of epilepsy, electroencephalography (EEG) findings, and factors related to seizure outcomes in adult patients. We aimed to investigate these variables in adult PKU patients. Methods: We conducted a retrospective search in our database using the keywords “PKU and epilepsy” for the period between 2008 and 2022. Demographic, clinical, EEG, and cranial magnetic resonance imaging (MRI) findings of the patients were extracted from the electronic health records. Scalp EEG and MRI findings were reassessed. Phenylalanine (Phe) levels of the cases were retrieved. The potential correlation between seizure outcome and laboratory findings was analyzed. Results: Ten patients (4 females; aged: 19–55 years) were included. Seizure onset was various. The most common seizure type was bilateral tonic-clonic. Nine patients were on antiseizure medications (ASMs); seven were seizure-free. EEG background activity was slow in four patients, with paroxysmal discharges in eight individuals. The most frequent MRI finding was periventricular white matter hyperintensity. No correlation existed between seizure outcome and clinical, EEG, MRI results, or Phe levels. Seizure freedom was more common in patients with good dietary compliance. Conclusion: Bilateral tonic–clonic seizures were the most common type of seizure, accompanied by frequent paroxysmal activity in EEG. MRI scans revealed periventricular white matter hyperintensity. Seizure freedom was commonly achieved with ASMs, irrespective of blood Phe levels. Nevertheless, dietary compliance may play a role in seizure control.

Blood Phenylalanine Levels in Patients with Phenylketonuria from Europe between 2012 and 2018: Is It a Changing Landscape?

In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications. A total of 1323 patients (age range:1-57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU (n = 625, 48%), followed by mild PKU (n = 357, 27%) and hyperphenylalaninemia (HPA) (n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2-5 years: 84%; 6-12 years: 73%; 13-18 years: 85%; 19-30 years: 64%; 31-40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher (p < 0.001) in patients with HPA (290 ± 325 μmol/L; 96 ± 24%) and mild PKU (365 ± 224 μmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 μmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels (p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6-12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13-18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31-40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin (n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 μmol/L; percentage within target 84 ± 39% vs. 406 ± 334 μmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control (p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 μmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 μmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 μmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 μmol/L, (70 ± 58%). Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.

Volumetric brain reductions in adult patients with phenylketonuria and their relationship with blood phenylalanine levels

BackgroundContinued dietary treatment since early diagnosis through newborn screening programs usually prevents brain-related complications in phenylketonuria (PKU). However, subtle neurocognitive and brain alterations may be observed in some adult patients despite early treatment. Nevertheless, neuropsychological and neuroimaging studies in the field remain scarce.ObjectivesThis work aimed to determine possible neuropsychological and structural brain alterations in treated adult patients with PKU.MethodsThirty-five patients with PKU and 22 healthy controls (HC) underwent neuropsychological assessment and T1-weighted magnetic resonance imaging on a 3 T scanner. FreeSurfer (v.7.1) was used to obtain volumetric measures and SPSS (v27.0.1.0) was used to analyze sociodemographic, neuropsychological, volumetric, and clinical data (p < 0.05).ResultsAdult patients with PKU showed significantly lower performance than HC in Full Scale IQ (t = 2.67; p = .010) from the WAIS-IV. The PKU group also showed significantly lower volumes than HC in the pallidum (U = 224.000; p = .008), hippocampus (U = 243.000; p = .020), amygdala (U = 200.000; p = .002), and brainstem (t = 3.17; p = .006) as well as in total cerebral white matter volume (U = 175.000; p = .001). Blood phenylalanine (Phe) levels in PKU patients were negatively correlated with the pallidum (r = -0.417; p = .013) and brainstem (r = -0.455, p = .006) volumes.ConclusionsAdult patients with early-treated PKU showed significantly lower global intelligence than HC. Moreover, these patients showed reduced global white matter volume as well as reductions in the volume of several subcortical grey matter structures, which might be related to the existence of underlying neurodevelopmental alterations. Higher blood Phe levels were also negatively correlated with pallidum and brainstem, suggesting a higher vulnerability of these structures to Phe toxicity.

The struggle that is phenylketonuria: What do the patients and caregivers suffer from.

To assess stress levels and life hardships of patients with phenylketonuria and their parents. Between January 2020 and June 2020, 156 patients with PKU and their parents who arrived for regular examinations were included. Parents were asked to complete the parenting stress index, Zarit Burden Scale, and the Strengths and Difficulties Questionnaire (SDQ), and children over the age of 11 were asked to fill the Rosenberg Self-Esteem Scale, the State-Trait Anxiety Inventory, and the SDQ. We found a significant negative correlation between the Rosenberg Self-Esteem Scale and age at diagnosis (r = -0.27, P = .035), mother's age (r = -0.33, P = .009), and father's age (r = -0.38, P = .004). There was a significant positive correlation between the State-Trait Anxiety Inventory and patient's age (r = 0.36, P = .006), mother's age (r = 0.29, P = .031) and father's age (r = 0.38, P = .024). In the child form of the SDQ, emotional problems were significantly positively correlated with serum phenylalanine (Phe) levels at diagnosis (r = 0.35, P = .036), total points were significantly positively correlated with serum Phe levels at clinical examination (r = -0.34, P = .004), and social problems were significantly negatively correlated with the father's age (r = -0.34, P = .047). We found a significant positive correlation between the Zarit Burden Scale and number of siblings (r = 0.195, P = .023). In the parent form of the SDQ, emotional problems were significantly positively correlated with patient age (r = 0.217, P = .032), peer problems were significantly positively correlated with age at diagnosis (r = 0.211, P = .037), behavioral problems (r = 0.203, P = .045), and attention deficit and hyperactivity (r = 0.203, P = .045) were significantly positively correlated with serum Phe levels at diagnosis. Phenylketonuria is difficult to cope with both for the patients and their parents because of diet obligation, high expenditures for the formulas required for the diet, requirement of regular clinical examinations, and possible development of mental disability and psychiatric disorders. Patients and their families should be psychologically evaluated and support should be provided if needed.

Pre-analytic decrease of phenylalanine in plasma of patients with phenylketonuria treated with pegvaliase

Treatment of phenylketonuria (PKU) has evolved since the initial introduction of a phenylalanine (Phe) restricted diet. The most recent option for adults affected with PKU is treatment with an alternate enzyme, phenylalanine ammonia lyase (PAL), that metabolizes excess Phe. Proper management of all patients with PKU relies on accurate measurement of Phe levels in blood, to comply with guidance intended to minimize the neurological symptoms. Recently, our laboratory was notified of discrepant results for a patient with PKU who is treated with pegvaliase. Two specimens were collected at the same time but yielded unexpectedly different Phe concentrations. After exclusion of specimen mix-ups or analytical errors, we suspected that there was residual pegvaliase activity in the specimens continuing to degrade Phe after collection. To investigate this possibility, we performed spiking studies that showed the degradation of Phe over time at ambient temperatures. Sample preparation by protein crash appears to deactivate pegvaliase and prevents further Phe degradation. However, because pegvaliase deactivation would be required immediately following blood collection, appropriate mitigation measures must be implemented, including stringent pre-analytical requirements, alternate sample matrices such as dried blood spots, or point of care testing. Until then, health care professionals need to be cautious in their interpretation of Phe levels in their patients with PKU that are treated with pegvaliase.

Interação fungicida-requeima na síntese de compostos fenólicos e atividade de enzimas de defesa em tomateiro

Due to the significant impact of late blight (LB) (Phytophthora infestans [Mont.]) on tomato (Solanum lycopersicum L.), we investigated the interaction between fungicides and this disease to understand how some plant defense mechanisms are affected over time. Following a randomized design, we evaluated the synthesis of phenolic compounds (PHE) and the activity of phenylalanine ammonium lyase (PAL), peroxidases (POX) and superoxide dismutase (SOD). The experiment involved the application of fosetyl-Al and fluoxastrobin (fungicides with dual modes of action) on healthy and infected tomato plants. LB severity was assessed weekly and leaf samples were collected at various intervals for biochemical analysis. The Kruskal-Wallis test (α = 0.05) analyzed main effects of infection, fungicide, and time on response variables, followed by Bonferroni post hoc for significant group differences and regression models to evaluate variable effects over time. The application of fungicides had no effect on enzymatic activity or PHE accumulation. While PAL and SOD activities were not significantly affected by infection, POX activity was significantly higher in healthy plants (4793.8 U g-1 fresh weight) compared to infected plants (1858.1 U g-1 fresh weight). A complex interaction between PHE accumulation in relation to LB severity and time was observed, with a notable increase in PHE levels at 50 days after transplant when disease severity was between 25 and 50%. Future studies should consider including a broader range of genotypes and isolates of P. infestans, a more extensive set of biochemical responses, and evaluations of the overexpression of genes related to plant defense.

Delays in Newborn Screening for Phenylketonuria from Birth to Diagnosis and Factors Affecting This.

This study aims to evaluate the process of neonatal phenylketonuria (PKU) screening from birth to admission to the pediatric metabolism polyclinic, determining delays in the screening program and the factors influencing them. This study was conducted during 2021-2023. Blood collection dates, results, and probable parameters causing delays in the screening program were recorded. This study included 118 infants. Admission time to the polyclinic was (mean ± SD) 25.2 ± 12.6 days (min-max: 3.4-78.9 days). Admission time was significantly high for refugees, those whose parents were consanguineous, and those who had more heel-prick blood samples taken (p < 0.001, p = 0.005, and p < 0.001, respectively). The first heel-prick blood phenylalanine (phe) level was significantly negatively correlated with the admission time (p < 0.001). Patients' admission time whose first blood phe level < 240 μmol/L was statistically significantly higher than in those with ≥240 μmol/L (p < 0.001). We determined that there were delays in PKU screening from birth to admission to the polyclinic. Being a refugee, the presence of consanguineous marriages, the increase in the number of heel-prick tests, and blood phe levels at a range of 120-240 μmol/L were the factors that played a role in this delay. Taking steps to reduce the impact of these parameters can prevent delays in newborn PKU screening and increase the success of the screening program.