Improving phenylalanine and micronutrients status of children with phenylketonuria: a pilot randomized study

Background Children with Phenylketonuria (PKU) need a special diet to avoid a variety of physical and psychological complications. The aim of this study was to compare and assess the effects of two interventions on and levels of phenylalanine and micronutrients in children with PKU. Methods Forty-six children with PKU (ages 1–12 years) and their caregivers were randomly assigned to one of two 10-week interventions: a caregiver educational intervention based on the Integrative Model of Behvioral Prediction (IMBP) and supplementary low-protein-modified foods. Outcomes consisted of Children's plasma phenylalanine and micronutrients (i.e., vitamin B12, vitamin D3, and zinc) and hemoglobin levels. To assess the sustainability of outcomes, we also compared the children’s phenylalanine level at five-time points including baseline and 10-week, 6 months, 12 months, and 24 months follow-ups. In addition, caregivers of both groups were asked to complete a questionnaire to assess how well the interventions were implemented as well as satisfaction with interventions. Results While a large percentage of children had phenylalanine levels out of range indicating non-adherence (69.6% and 81% in the educational and food items group, respectively), micronutrient deficiencies were not prevalent in the patient cohort. The levels of phenylalanine in both groups decreased significantly over time. However, conducting a repeated-measures ANOVA to evaluating the change in groups across five-time points, revealed a significant difference between groups (F = 4.68, p = 0.03). That is, the educational intervention was more effective in lowering the children's phenylalanine level. At 24-month follow-up, the percentage of children with a normal range of phenylalanine level in the educational and food items groups increased to 73.9 and 57.1 percent, respectively, from 26 and 38 percent at baseline. There were no significant changes in children's micronutrients level following the interventions, except in the hemoglobin. In this way, at 10-week follow-up, the mean hemoglobin of children in the educational group reduced significantly (P = 0.041). However, there was no significant difference between the two groups. In general, all caregivers completed the process evaluation checklist, the feedback was largely positive. Conclusions The results of this study demonstrated that both educational and providing food item interventions resulted in a significant reduction in phenylalanine levels. Empowering caregivers of patients, creating and fortifying social networks, providing favorable social supports, and providing access to special food items may be effective in controlling PKU. Clinical trial registration: Iranian Registry of Clinical Trials (IRCT20180506039548N1). Registered 6th Jun 2018, https://www.irct.ir/trial/30977.

Does Dietary Treatment Cause Obesity in Phenylketonuria? Comparison of Obesity Ratios of Patients Receiving Dietary Treatment and Tetrahydrobiopterin Treatment

Phenylketonuria is treated either with tetrahydrobiopterin (BH4) or with a phenylalanine-restricted diet. Patients in the diet group may tend to consume carbohydrate-rich foods which have a risk for obesity. In this study, the prevalence of obesity+overweight among phenylketonuria patients either treated with phenylalanine-restricted diet or with BH4 were compared.Patients with phenylketonuria were divided into two groups on dietary treatment and BH4 treatment. Body mass index (BMI), BMI-percentile, and z-score values of patients were calculated and classified as underweight, normal-weight, overweight, and obese according to their nutritional status. The annual mean phenylalanine level of each patient is also evaluated. The study was done retrospectively.A total of 130 patients was included. 77 were receiving diet (female (n,%):37, 48.1%; male (n,%):40, 51.9%) and 53 were receiving BH4 (female (n,%):33, 62.3%; male (n,%):20, 37.7%) respectively. According to BMI-z-score, the sum of the ratio of obesity+overweight was found to be 35.1% in the diet group, 16.9% in the BH4 group. Ratio was significantly higher in diet group (p=0.02). When obesity+overweight ratios were examined in terms of female/male distribution, no significant difference was found. Considering the correlation of obesity+overweight ratios with age in two groups, the median age of the patients with normal weight+underweight in the BH4 group were found as 46-months, and the median age of obese+overweight patients was 137-months (p=0.001). For the same situation, there was no significant difference in the dietary treatment group (p=0.92). Mean annual phenylalanine levels were significantly higher in obese+overweight patients (p=0.047) in the BH4 treatment group but this difference was not significant in the diet group (p=0.051).Patients on the phenylalanine-restricted diet have a risk of obesity or overweight. Therefore, attention should be paid not only to the phenylalanine levels of these patients but also to their weight control and dietary content

Integrative biology defines novel biomarkers of resistance to strongylid infection in horses

The widespread failure of anthelmintic drugs against nematodes of veterinary interest requires novel control strategies. Selective treatment of the most susceptible individuals could reduce drug selection pressure but requires appropriate biomarkers of the intrinsic susceptibility potential. To date, this has been missing in livestock species. Here, we selected Welsh ponies with divergent intrinsic susceptibility (measured by their egg excretion levels) to cyathostomin infection and found that their divergence was sustained across a 10-year time window. Using this unique set of individuals, we monitored variations in their blood cell populations, plasma metabolites and faecal microbiota over a grazing season to isolate core differences between their respective responses under worm-free or natural infection conditions. Our analyses identified the concomitant rise in plasma phenylalanine level and faecal Prevotella abundance and the reduction in circulating monocyte counts as biomarkers of the need for drug treatment (egg excretion above 200 eggs/g). This biological signal was replicated in other independent populations. We also unravelled an immunometabolic network encompassing plasma beta-hydroxybutyrate level, short-chain fatty acid producing bacteria and circulating neutrophils that forms the discriminant baseline between susceptible and resistant individuals. Altogether our observations open new perspectives on the susceptibility of equids to strongylid infection and leave scope for both new biomarkers of infection and nutritional intervention.

Assessing Phenylalanine Blood Level in Children Having Phenylketonuria in Southern Khorasan Province, and Determining the Affecting Social and Demographic Factors

Background: Phenylketonuria is a metabolic disorder resulting from a defect in phenylalanine metabolism with a global prevalence of 1 in 10000. Delayed initiation of dietary modification leads to brain injury and cognitive and behavioral problems. The main objective of this study was to assess the demographic and social factors affecting metabolic control of patients having phenylketonuria in Southern Khorasan Province.Methods: In this cross-sectional descriptive analytic study which was performed during summer 2019, 32 out of 37 known children and adolescents having phenylketonuria in Southern Khorasan Province were assessed. The age of patients, the gender of patients, parents` marital status, parents` occupational status, parents` educational level, the distance between home and phenylketonuria clinic, and the number of affected siblings having phenylketonuria were documented. We were not able to contact five patients having phenylketonuria in Southern Khorasan Province. Data were analyzed by SPSS 16 software using Mann-Whitney U test and Kruskal-Wallis test. The significance level was considered as p <0.05.Results: 32 patients with a mean age of 6.6±4.7 years were enrolled in this study. 23 of them were male (71.9%) and 9 patients were females (28.1%). The mean phenylalanine level in this study group was 8.1±5.2 mg/dl. The disease was optimally controlled in 14 patients (43.3%) and poorly controlled in 18 of them (56.3%). There was not any statistically significant relation between the metabolic control of the disease and any of the assessed social and demographic factors.Conclusion: The disease was properly controlled in 43.3% of the assessed population, and 56.3% had poor metabolic control. There was not any statistically significant relation between the metabolic control of patients having phenylketonuria in Southern Khorasan Province and assessed demographic and social. As the number of known cases in South Khorasan province is limited, small sample size could be one of the main limitations of our study.

Integrative biology defines novel biomarkers of resistance to strongylid infection in horses

The widespread failure of anthelmintic drugs against nematodes of veterinary interest requires novel control strategies. Selective treatment of the most susceptible individuals could reduce drug selection pressure but requires appropriate biomarkers of the intrinsic susceptibility potential. To date, this has been missing in livestock species. Here, we selected Welsh ponies with divergent intrinsic susceptibility to cyathostomin infection and found that their potential was sustained across a 10-year time window. Using this unique set of individuals, we monitored variations in their blood cell populations, plasma metabolites and faecal microbiota over a grazing season to isolate core differences between their respective responses under worm-free or natural infection conditions. Our analyses identified the concomitant rise in plasmatic phenylalanine level and faecal Prevotella abundance and the reduction in circulating monocyte counts as biomarkers of the need for drug treatment. This biological signal was replicated in other independent populations. We also unravelled an immunometabolic network encompassing plasmatic beta-hydroxybutyrate level, short-chain fatty acid producing bacteria and circulating neutrophils that forms the discriminant baseline between susceptible and resistant individuals. Altogether our observations open new perspectives on the susceptibility of equids to cyathostomin infection and leave scope for both new biomarkers of infection and nutritional intervention.

Phenylalanine Response in Rice Kernel Under Chitosan Nanoparticles Spraying

Background: Since phenylketonuria patients have a metabolic defect, should use specific foods that have low phenylalanine levels. These foods are usually produced by hydrolysis processes. The most important problems of the foods are unpleasant to taste and expensive. The main objective of this study was to investigate the possibility of reducing the amount of phenylalanine in rice kernel under spraying of chitosan nanoparticles. Treatments were different concentrations of chitosan nanoparticles spraying (0,500,1000,1500 µlL-1). The treatments effects were studied in a randomized complete block design with four replications. Experimental variables were phenylalanine, phenylalanine ammonia-lyase activity and total grain protein. Results: The results showed that the total protein and phenylalanine level in rice kernel decreased under all concentrations of chitosan nanoparticles compared to the control, while the activity of phenylalanine ammonia-lyase was higher than that of the control. In this experiment, 1000 µlL-1 of chitosan nanoparticles was found as the optimum concentration, since minimum phenylalanine level and maximum phenylalanine ammonia-lyase activity were affected by this concentration. Conclusion: Our results indicated that chitosan nanoparticles spraying during the grain growth was able to reduce phenylalanine level in rice kernel.

Similarities and differences in key diagnosis, treatment, and management approaches for PAH deficiency in the United States and Europe

Background Individuals with phenylalanine hydroxylase (PAH) deficiency lack an enzyme needed to metabolize the amino acid, phenylalanine. This leads to an increase of phenylalanine in the blood, which is associated with changes in cognitive and psychological functioning. Skilled clinical management is essential for preventing complications and providing comprehensive care to patients. In the last decade, the American College of Genetics and Genomics (ACMG) and a group of European experts developed separate guidelines to provide recommendations for the management and care of persons with PAH deficiency. The purpose of this paper was to compare and contrast these guidelines in order to understand the different approaches to PAH deficiency care. Methods We examined the procedures used to develop both guidelines, then evaluated key areas in PAH deficiency care which included screening, diagnostic approaches, dietary treatment (initiation and duration), ongoing phenylalanine level/ nutritional monitoring, neurocognitive screening, adherence issues in treatment, and special populations (women and maternal PKU, late or untreated PAH deficiency, and transitioning to adult services). We conducted a scoping review of four key topics in PAH deficiency care to explore recent research studies performed since the publication of the guidelines. Results The ACMG and European expert group identified limited numbers of high quality studies to use as evidence for their recommendations. The ACMG and European guidelines had many similarities in their respective approaches PAH deficiency care and recommendations for the diagnosis, treatment, and management for persons with PAH deficiency. There were also a number of differences between the guidelines regarding the upper range for phenylalanine levels in adolescents and adults, the types of instruments used and frequency of neuropsychiatric examinations, and monitoring of bone health. Treatment adherence can be associated with a number of challenges, such as aversions to medical foods and formulas, as well as factors related to educational, social, and psychosocial issues. From the scoping review, there were many new studies addressing issues in treatment and management including new research on sapropterin adherence and increased dietary protein tolerance and pegvaliase on the reduction in phenylalanine levels and hypersensitivity reactions. Conclusions In the last decade, ACMG and European experts developed comprehensive guidelines for the clinical management of phenylalanine hydroxylase deficiency. The guidelines offered background and recommendations for clinical care of patients with PAH deficiency throughout the lifespan. New research evidence is available and updates to guidelines can keep pace with new developments. Evidence-based guidelines for diagnosis and treatment are important for providing expert care to patients.

Phenylalanine Is a Novel Marker for Radiographic Knee Osteoarthritis Progression: The MOST Study

Objective.To identify plasma markers associated with an increased risk of radiographic knee osteoarthritis(OA) progression using a metabolomics approach.Methods.Study participants were from the Multicenter Osteoarthritis Study (MOST) and were categorized into 2 groups based on the presence of baseline radiographic OA. Subjects in group 1 had unilateral knee OA and subjects in group 2 had bilateral knee OA. Progression was defined as a half-grade or greater worsening in joint space width at 30-month follow-up. For group 1, a participant progressed when their OA knee showed radiographic progression and the contralateral knee developed OA; for group 2, a participant progressed when both knees with OA showed radiographic progression. Metabolomic profiling was performed on plasma samples collected at baseline and logistic regression was performed to test the association between each metabolite and knee OA progression after adjustment for age, sex, BMI, and clinic site. Significance was defined as P ≤ 0.0003 in the combined analysis.Results.There were 234 progressors (57 in group 1 and 177 in group 2) and 322 nonprogressors (206 in group 1 and 116 in group 2) included in the analyses. Among 157 metabolites studied, we found that odds of progression were 1.46 times higher per SD increase of phenylalanine level (95% CI 1.20–1.77, P = 0.0001) in the combined analysis. Sex-specific analysis showed that an association was seen in women (P = 0.0002) but not in men.Conclusion.Our data suggest that phenylalanine might be a novel plasma marker for higher risk of bilateral radiographic knee OA progression in women.

Evaluation of the silkworm lemon mutant as an invertebrate animal model for human sepiapterin reductase deficiency

Human sepiapterin reductase (SR) deficiency is an inherited disease caused by SPR gene mutations and is a monoamine neurotransmitter disorder. Here, we investigated whether the silkworm lemon mutant could serve as a model of SR deficiency. A point mutation in the BmSPR gene led to a five amino acid deletion at the carboxyl terminus in the lemon mutant. In addition, classical phenotypes seen in SR deficient patients were observed in the lemon mutant, including a normal phenylalanine level, a decreased dopamine and serotonin content, and an increased neopterin level. A recovery test showed that the replenishment of l -dopa significantly increased the dopamine level in the lemon mutant. The silkworm lemon mutant also showed negative behavioural abilities. These results suggest that the silkworm lemon mutant has an appropriate genetic basis and meets the biochemical requirements to be a model of SR deficiency. Thus, the silkworm lemon mutant can serve as a candidate animal model of SR deficiency, which may be helpful in facilitating accurate diagnosis and effective treatment options of SR deficiency.

Infant Acute Lymphoblastic Leukemia with Atypical Presentation

Infant leukemia is a very rare disease and consists of 5% of all childhood leukemias. Infant leukemia usually presents with high leukocyte counts and numerous extra-hematological features including central nervous system and skin involvement. Herein, we report a 1-month-old girl presented with high phenylalanine level in national newborn screening program for phenylketonuria; and subsequently diagnosed to have acute lymphoblastic leukemia.