Phenylketonuria Research Articles

Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria.

Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomised, placebo-controlled crossover trial, we investigated the impact of a four-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19-48 years) underwent magnetic resonance imaging before and after the four-week phenylalanine and placebo interventions (four timepoints). Structural T1-weighted images were preprocessed and evaluated using DL+DiReCT, a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume, and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four timepoints, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441µmol/L) than after the placebo period (873µmol/L, P<0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 out of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate=-0.095mm, P<0.001) and the left lingual gyrus (point estimate=-0.070mm, P<0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the Phe-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs=0.43 to 0.51, P≤0.036) and decreased cortical thickness (rs=-0.62 to -0.39, not surviving FDR correction) after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs=-0.54 to -0.40, not surviving FDR correction). These findings provide evidence that a four-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.

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.

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

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

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

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

Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria

Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively.

Unmet needs in phenylketonuria: an exploratory Italian survey among patients and caregivers

Objective Patients with phenylketonuria (PKU) require a strict diet to maintain phenylalanine (Phe) levels within the desired range. However, the diet can be onerous, resulting in poor adherence. We carried out the first online national survey in Italy to better understand the perceptions, knowledge, and experiences of both patients with PKU and caregivers with the goal of improving patient outcomes. Methods An online survey of 35 questions to patients and 36 questions to caregivers was distributed in September 2022 through physicians and relevant Italian associations. The information collected included knowledge and impact of PKU, unmet needs, knowledge of available drugs, and satisfaction with therapy. Results Overall, 241 questionnaires were completed by 85 patients and 156 caregivers (96.0% were parents). Knowledge of the pathogenic basis of PKU was generally high. The most common patient-reported symptoms were agitation/anxiety (48.8%), fatigue (41.1%), mood disorders (39.8%), and difficulty concentrating (33.4%). Different perspectives on adherence to a low-Phe diet were observed (22.9% of patients reported strict adherence vs. 47.0% of caregivers). Drugs that allow more freedom were needed by 49.4% of patients and 61.7% of caregivers, along with a wider range of choices of non-dietary treatments (48.2% and 60.0%, respectively). Unmet informational needs of patients included PKU and pregnancy, complications, travel, sports, and transition into adult care. Conclusions Our data showed that patients with PKU and their caregivers reported difficulties in adherence to diet therapy and indicated interest in new therapeutic approaches. Apparent differences between patient and caregiver perspectives were identified. More informational resources on PKU are needed.

The relationship between working memory and anxiety in individuals with early treated phenylketonuria (PKU).

Although early diagnosis and treatment prevent the severe impairments associated with untreated phenylketonuria (PKU), individuals with early treated PKU (ETPKU) nonetheless experience significant neurocognitive and psychological sequelae, including difficulties in working memory (WM) and increased risk of anxiety. The primary objective of the present study was to examine the extent to which anxiety may moderate the relationship between ETPKU and WM performance. A sample of 40 adults with ETPKU and a demographically comparable sample of 40 healthy adults without PKU completed a comprehensive assessment of WM performance and anxiety symptomatology. Data were collected using a variety of remote assessment methods (e.g., web-based neurocognitive tests, semistructured interview, report-based measures). The ETPKU group demonstrated significantly poorer WM performance as compared to the non-PKU group. The groups did not differ significantly in anxiety; however, high anxiety was more common in the ETPKU group (53% of sample) than the non-PKU group (33%). A significant interaction between anxiety, metabolic control (as reflected by Phe levels), and WM performance was observed for the ETPKU group. Individuals with high anxiety and/or high Phe levels (> 360 μmol/L) performed poorer than the non-PKU group. Individuals with low anxiety and relatively low Phe levels (< 360 μmol/L) performed comparably to the non-PKU group. Anxiety was found to moderate the relationship between Phe levels and WM performance in individuals with ETPKU. This finding underscores the importance of accounting for anxiety when evaluating neurocognitive performance in individuals with ETPKU whether for research or clinical purposes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Glycomacropeptide: A comprehensive understanding of its major biological characteristics and purification methodologies.

Glycomacropeptide (GMP) is a bioactive peptide derived from whey protein, consisting of 64 amino acids. It is a phenylalanine-free peptide, making it a beneficial dietary option for individuals dealing with phenylketonuria (PKU). PKU is an inherited metabolic disorder characterized by high levels of phenylalanine in the bloodstream, resulting from a deficiency of phenylalanine dehydrogenase in affected individuals. Consequently, patients with PKU require lifelong adherence to a low-phenylalanine diet, wherein a significant portion of their protein intake is typically sourced from a phenylalanine-free amino acid formula. GMP has several nutritional values, numerous bioactivity properties, and therapeutic effects in various inflammatory disorders. Despite all these features, the purification of GMP is an imperative requirement; however, there are no unique methods for achieving this goal. Traditionally, several methods have been used for GMP purification, such as thermal or acid treatment, alcoholic precipitation, ultrafiltration (UF), gel filtration, and membrane separation techniques. However, these methods have poor specificity, and the presence of large amounts of impurities can interfere with the analysis of GMP. More efficient and highly specific GMP purification methods need to be developed. In this review, we have highlighted and summarized the current research progress on the major biological features and purification methodologies associated with GMP, as well as providing an extensive overview of the recent developments in using charged UF membranes for GMP purification and the influential factors.

Measuring fecal neurotransmitter concentrations using Dried Fecal Spot (DFS)-based LC-MS/MS bioanalysis

Background: Guthrie implemented dried blood spot (DBS)-based bioanalytical techniques in the 1960s in order to screen for phenylketonuria (PKU) disease in neonates. Historically, the dominant matrix analyzed using the “Guthrie card” platform has been whole blood, but recent advances in device technology now allow for whole blood-to-plasma sample processing prior to drying and subsequent bioanalysis. This project aimed to use this dried matrix technologies in an entirely new direction by performing dried fecal spot (DFS)-based bioanalysis for analytical microbiology and microbiome applications. Homogenized fecal sample extracts were loaded onto quantitative DBS (qDBS) devices and were allowed to dry overnight, then were shipped at ambient shipping temperature. The DBS spots were processed and subjected to LC-MS/MS-based targeted metabolomics using our Glutamate Cycle method (Glu, Gln, and GABA). Methods &amp; Results: Fecal samples were collected from each of the five human subjects enlisted in the following cohorts: 1) healthy controls; 2) patients with diarrhea; and, 3) Clostridioides diffcile-infected (CDI) patients. A volume of ice-cold methanol:water (1:1, v:v) equivalent to a fecal density of 50 mg/mL was added into individual homogenization tubes that each contained 100 mg of 1.4 mm silica beads. Fecal samples were homogenized using 5 bead-beating cycles (4 m/s for each 20 s pulse). After centrifugation (@500 g), a 20-μL sample supernatant volume was loaded onto qDBS devices that yielded an exact 10-μL DFS spot volume on the embedded cards. Dried DFS spots were removed from the device and homogenized in a 200-μL volume of an IS solution. The Glu, Gln, and GABA concentration of each sample was compared against the concentrations measured in the matched frozen fecal extracts. We were able to successfully detect GABA in both the standard extraction method and in our processed DFS samples. Interestingly, we observed large variability between patient samples and there were no statistically significant differences between the cohorts. Conclusion: Collectively, these data demonstrate the utility of our method for measuring the concentrations of Glu, Gln and GABA contained in our processed DFS-based sample sets. This study was supported by the NIH K01K123195-01 (MAE). The Texas Children’s Hospital Department of Pathology provides salary support to Texas Children’s Microbiome Center-Metabolomics Lab staff, and purchased all of the reagents, the consumables and durable supplies, and the liquid chromatography-tandem mass spectrometry (LC-MS/MS) equipment described. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Rat PKU Model Display Gender-Based Neuroinflammatory Changes: Proinflamatuary Cytokines and Lipid Peroxidation

Phenylketonuria (PKU) results from congenital defects of amino acid metabolism. Accumulated phenylalanine crosses the blood-brain barrier and causes permanent brain damage, but the neuro-pathophysiology underlying phenylketonuria is not fully understood. Chemically-induced rat phenylketonuria model of both genders was generated to examine the role of inflammatory response, lipid peroxidation and oxidative stress in the prefrontal cortex. Our results showed that in phenylketonuria there was an increase in lipid peroxidation compared to controls, which was significantly different only in males (p&amp;lt;0.001). In male rat PKU groups, statistically significant differences were also observed in serum tryptophan (p&amp;lt;0.001) and interleukin-1β levels (p=0.014) as compared to male controls. In this study, gender-based changes in neuroinflammation and lipid peroxidation were reported for the first time in a PKU model.

Pediatrics 2 experience, Neuropediatrics and neurometabolic diseases unit on phenylcetonuria: About 36 patients

Phenylketonuria (PKU) is a hereditary metabolic disease of phenylalanine metabolism, linked to a deficiency of phenylalanine hydroxylase or its cofactor, an enzyme allowing the transformation of phenylalanine into tyrosine, resulting in an increase in blood and brain concentration. of PHA, comprising an intellectual disability with cognitive and behavioral disorders if it is not treated. We report 36 cases of phenylketonuria followed in the pediatric department 2, born to consanguineous parents in 58.4% of cases and non-consanguineous in 41.6%, the male sex represents the majority with 22 cases and female with 14 cases, The age of diagnosis minimum 3 days of life and maximum 16 years and the current age of patients minimum 4 years and maximum 37 years with comorbidities like epilepsy, motor disorders, behavioral disorders, Autism Spectrum Disorder and mental retardation and about 70% have a regular monitoring. Through this series we will support the epidemiological, clinical, paraclinical and therapeutic particularities of patients with phenylketonuria. Early diagnosis of the disease makes it possible to initiate treatment early, which is mainly based on a diet low in phenylalanine for life in order to improve the progressive prognosis and avoid irreversible after-effects.

Genetic Landscape and Clinical Features of Hyperphenylalaninemia in North Ossetia-Alania: High Frequency of P281L and P211T Genetic Variants in the PAH Gene.

This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population.

Pegvaliase for the treatment of phenylketonuria: Final results of a long-term phase 3 clinical trial program

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 μmol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer-term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the open-label extension study 165–304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of ≤600, ≤360, and ≤ 120 μmol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan-Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of ≤600, ≤360, or ≤ 120 μmol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of ≤600, ≤360, or ≤ 120 μmol/L, respectively. Longer-term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (≤6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of ≤600, ≤360, or ≤ 120 μmol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant-level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys.

Diagnosis and Treatment of Newborns Referred to the Metabolism Department From the National Newborn Screening Program in Türkiye: A 5-Year Single-Center Experience

Objective: The aims of this study were to investigate biochemical and genetic tests and treatment plans of newborns referred to our center with inherited metabolic disorders screened in Türkiye National Newborn Screening Program (NNSP). Material and Methods: The medical records of babies referred by the NNSP between January 2019 and November 2023 were scanned retrospectively. Plasma biotinidase activity and the biotinidase gene (BTD) analysis results for suspected biotinidase deficiency (BD), the plasma phenylalanine and phenylalanine hydroxylase gene (PAH) analysis for a suspicion of phenylketonuria (PKU) were documented with treatment information. Results: A total of 143 babies, 78 (54.5%) with suspected BD and 65 (45.5%) with suspected PKU were included. A PAH gene analysis was performed on 23 (35.4%) of those had high plasma phenylalanine levels, among which 86.9% were identified with the biallelic variant. Five patients were started on sapropterin-diet combined therapy, three on diet therapy and one on sapropterin therapy. In the first serum biotinidase activity measurement of babies referred with suspected BD, a heterozygous deficiency was detected in 48.7%, partial deficiency in 39.7% and profound deficiency in 10.3%. A BTD gene analysis was performed on 79.5% of those with suspected BD, and biallelic variants were detected in 50%. Forty-six patients (59.0%) underwent biotin treatment. Conclusion: In our study, approximately one-third of the babies referred from NNSP over the five-year course of the study had biallelic variants of the relevant disease. Our research is one of the few studies on NNSP in our country and presents the diagnosis and treatment process of PKU and BD.

Splice-Switching Antisense Oligonucleotides Correct Phenylalanine Hydroxylase Exon 11 Skipping Defects and Rescue Enzyme Activity in Phenylketonuria.

The PAH gene encodes the hepatic enzyme phenylalanine hydroxylase (PAH), and its deficiency, known as phenylketonuria (PKU), leads to neurotoxic high levels of phenylalanine. PAH exon 11 is weakly defined, and several missense and intronic variants identified in patients affect the splicing process. Recently, we identified a novel intron 11 splicing regulatory element where U1snRNP binds, participating in exon 11 definition. In this work, we describe the implementation of an antisense strategy targeting intron 11 sequences to correct the effect of PAH mis-splicing variants. We used an in vitro assay with minigenes and identified splice-switching antisense oligonucleotides (SSOs) that correct the exon skipping defect of PAH variants c.1199+17G>A, c.1199+20G>C, c.1144T>C, and c.1066-3C>T. To examine the functional rescue induced by the SSOs, we generated a hepatoma cell model with variant c.1199+17G>A using CRISPR/Cas9. The edited cell line reproduces the exon 11 skipping pattern observed from minigenes, leading to reduced PAH protein levels and activity. SSO transfection results in an increase in exon 11 inclusion and corrects PAH deficiency. Our results provide proof of concept of the potential therapeutic use of a single SSO for different exonic and intronic splicing variants causing PAH exon 11 skipping in PKU.

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

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

The establishment of a phenylketonuria (PKU) clinic in Iraq from Afar

The establishment of a phenylketonuria (PKU) clinic in Iraq from Afar

Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry.

The aim of this study was to observe the outcomes of newborn screening (NBS) in a certain population by using next-generation sequencing (NGS) as a first-tier screening test combined with tandem mass spectrometry (MS/MS). We performed a multicenter study of 29,601 newborns from eight screening centers with NBS via NGS combined with MS/MS. A custom-designed panel targeting the coding region of the 142 genes of 128 inborn errors of metabolism (IEMs) was applied as a first-tier screening test, and expanded NBS using MS/MS was executed simultaneously. In total, 52 genes associated with the 38 IEMs screened by MS/MS were analyzed. The NBS performance of these two methods was analyzed and compared respectively. A total of 23 IEMs were diagnosed via NGS combined with MS/MS. The incidence of IEMs was approximately 1 in 1287. Within separate statistical analyses, the positive predictive value (PPV) for MS/MS was 5.29%, and the sensitivity was 91.3%. However, for genetic screening alone, the PPV for NGS was 70.83%, with 73.91% sensitivity. The three most common IEMs were methylmalonic academia (MMA), primary carnitine deficiency (PCD) and phenylketonuria (PKU). The five genes with the most common carrier frequencies were PAH (1:42), PRODH (1:51), MMACHC (1:52), SLC25A13 (1:55) and SLC22A5 (1:63). Our study showed that NBS combined with NGS and MS/MS improves the performance of screening methods, optimizes the process, and provides accurate diagnoses.

Glycomacropeptide-Based Protein Substitutes for Children with Phenylketonuria in Italy: A Nutritional Comparison.

Advancements in food science technology have allowed the development of new products for the therapeutic management of inherited metabolic diseases such as phenylketonuria (PKU). Glycomacropeptide (GMP), a peptide derived from casein, is naturally low in phenylalanine (Phe) and, thus, adequate for protein substitutes (PSs) for the management of PKU in children. This review aims primarily to analyse the differences in the nutritional composition of GMP-based protein substitutes in different formulations (ready to drink, powdered, and bars), and secondarily to assess the quality of these products, comparing their nutritional composition with that of standard amino acid (L-AA) mixtures. Thirty-five GMP-based PSs produced by six different companies were included in this review: twenty-one powdered PSs, eight ready to drink, and six bars. The analysis revealed great heterogeneity not only among the different formulations (powdered, ready to drink, and bars) but also within the same group, in terms of energy content and nutritional composition. GMP-based PSs were shown to have higher contents of sugars and saturated fatty acids compared to L-AA PSs, especially in ready-to-drink formulations and bars. The latter also provided the highest amounts of energy among the GMP-based products. This finding may be related to a higher risk of developing overweight and obesity. The greater palatability of these GMP-based PSs, combined with improved nutritional quality, could not only improve adherence to diet therapy but also reduce the incidence of obesity-related comorbidities in PKU.

Generation of two lymphoblastoid-derived induced pluripotent stem cell (iPSC) lines from patients with phenylketonuria

We employed a Sendai virus-based reprogramming method to transform human lymphoblastoid cell lines (LCL) derived from two individuals diagnosed with phenylketonuria (PKU) into induced pluripotent stem cells (iPSC). This reprogramming process involved the expression of the four Yamanaka factors: KLF4, OCT4, SOX2, and C-MYC. The resulting patient-specific iPSCs exhibited a normal karyotype and expressed endogenous pluripotent markers NANOG and OCT-4. Notably, these iPSCs demonstrated strong differentiation capabilities, giving rise to cell populations representing the ectoderm, endoderm, and mesoderm germ layers.