Nutrition management of PKU with pegvaliase therapy: update of the web-based PKU nutrition management guideline recommendations.

BACKGROUND: The web-based GMDI/SERN PKU Nutrition Management Guideline, published before approval of pegvaliase pharmacotherapy, offers guidance for nutrition management of individuals with phenylketonuria (PKU) treated with dietary therapy and/or sapropterin. An update of this guideline aims to provide recommendations that improve clinical outcomes and promote consistency and best practice in the nutrition management of individuals with PKU receiving pegvaliase therapy. Methodology includes: formulation of a research question; review, critical appraisal, and abstraction of peer-reviewed studies and unpublished practice literature; expert input through Delphi surveys and a Nominal Group process; and external review by metabolic experts. RESULTS: Recommendations, summary statements, and strength of evidence are included for each of the following topics: (1) initiating a pegvaliase response trial, (2) monitoring therapy response and nutritional status, (3) managing pegvaliase treatment after response to therapy, (4) education and support for optimal nutrition with pegvaliase therapy, and (5) pegvaliase therapy during pregnancy, lactation, and adolescence. Findings, supported by evidence and consensus, provide guidance for nutrition management of individuals receiving pegvaliase therapy for PKU. Recommendations focus on nutrition management by clinicians, as well as the challenges for individuals with PKU as a result of therapy changes. CONCLUSIONS: Successful pegvaliase therapy allows the possibility for individuals with PKU to consume an unrestricted diet while still maintaining the benefits of blood phenylalanine control. This necessitates a perspective change in education and support provided to individuals in order to achieve healthy nutrient intake that supports optimal nutritional status. The updated guideline, and companion Toolkit for practical implementation of recommendations, is web-based, allowing for utilization by health care providers, researchers, and collaborators who advocate and care for individuals with PKU. These guidelines are meant to be followed always taking into account the provider's clinical judgement and considering the individual's specific circumstances. Open access is available at the Genetic Metabolic Dietitians International ( https://GMDI.org ) and Southeast Regional Genetics Network ( https://managementguidelines.net ) websites.

Anti-oxidant response of lipidom modulates lipid metabolism in Caenorhabditis elegans and in OxLDL-induced human macrophages by tuning inflammatory mediators.

Atherosclerosis is the main pathological process of several cardiovascular diseases. It may begin early in life and stay latent and asymptomatic for an extended period before its clinical manifestation. The formation of foamy macrophages due to dysregulated lipid metabolism is a key event in the development and progression of atherosclerotic plaque. The current pharmacotherapy for atherosclerosis is not able to address multiple aetiologies associated with the disease. Lipidom, an herbal prescription medicine, has anti-oxidant, lipid lowering and anti-inflammatory properties that lead to multifaceted treatment benefits against chronic inflammation, dyslipidaemia, and oxidative stress. The present study aimed to characterize the pharmacological effects of Lipidom using various experimental models. The phytochemical analysis of Lipidom was performed on ultra-high performance liquid chromatography (UHPLC) platform. Lipidom was evaluated for cytosafety, IL-1ß and MCP-1 release, modulation of NLRP3 pathway, NFκB activity, ROS generation, lipid accumulation and gene expression in THP1 macrophages. Furthermore, Lipidom evaluation was also performed in the N2, CF1553, and TJ356 strains of Caenorhabditis elegans (C. elegans). The evaluation of brood size, adult (%), lipid accumulation, triglyceride levels, SOD-3 GFP signal, MDA formation, DAF-16 nuclear translocation, and gene expression was performed in C. elegans. Lipidom treatment significantly reduced the inflammatory mediators, lipid accumulation, oxidative stress, and normalized genes involved in the development of foamy macrophages. Lipidom treated C. elegans showed a significant decline in lipid accumulation and oxidative stress. Taken together, Lipidom treatment showed a multifaceted approach in the modulation of several mediators responsible for the development and progression of atherosclerotic plaque.

Modulation of psoriatic-like skin inflammation by traditional Indian medicine Divya-Kayakalp-Vati and Oil through attenuation of pro-inflammatory cytokines.

Background and aim: Psoriasis (Ps) is a chronic skin inflammatory disorder, that progresses to scaly-red dermal plaque formations associated with inflammation. Divya-Kayakalp-Vati (DKV) and Divya-Kayakalp-Oil (DKO) are traditional Ayurveda herbo-mineral formulations, that are prescribed for the treatment of inflammatory dermal ailments. In the present study, we evaluated the efficacy of Divya-Kayakalp-Vati and Divya-Kayakalp-Oil (DKV-O) combined treatment in ameliorating Ps-like skin inflammation under in-vitro and in-vivo conditions. Experimental procedure: Efficacy of DKV-O was analyzed in λ-carrageenan-treated Wistar rats paw edema and 12-O-tetradecanoylphorbol 13-acetate (TPA)-treated CD-1 mouse ear edema models through physiological and histopathological analysis. Mode of action for the DKV-O was studied in LPS-stimulated THP-1 cells through pro-inflammatory cytokine analysis. Observed effects were correlated to the phytochemicals constituents of DKV-O analyzed using the HPLC method. Result and conclusion: DKV and DKO formulations were individually found to contain phytochemicals Gallic acid, Catechin, Berberine, Curcumin, Phenol and Benzoic acid. DKV-O treatment significantly reduced the paw volume and edema in Wistar rats stimulated through λ-carrageenan-treatment. Furthermore, DKV-O treatment significantly reduced the ear edema and enhanced biopsy weight, epidermal thickness, inflammatory lesions and influx of neutrophils stimulated by TPA-treatment in CD-1 mice. DKV alone ameliorated the LPS-stimulated release of Interleukin (IL)-6, IL-17A, IL-23, and Tumor Necrosis Factor-alpha cytokines in the THP-1 cells.Taken together, DKV-O showed good efficacy in ameliorating acute systemic inflammation stimulated by effectors such as, λ-carrageenan and TPA in animal models. Hence, Divya-Kayakalp-Vati and Divya-Kayakalp-Oil co-treatment can be further explored as an anti-inflammatory treatment against dermal diseases like psoriasis and atopic dermatitis.

Herbo-metallic ethnomedicine 'Malla Sindoor' ameliorates lung inflammation in murine model of allergic asthma by modulating cytokines status and oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Asthma is the leading inflammatory disease of the airways with inadequate therapeutic options. 'Malla Sindoor' (MS) is a metal-based ethnomedicinal formulation that has been prescribed in the ancient traditional medicinal system for treating chronic inflammations. AIM OF THE STUDY: Here, we validated the anti-inflammatory and anti-asthmatic properties of traditional metallic medicine MS in asthmatic mice model and in LPS stimulated human monocytic THP-1 cells, by examining the relevant cellular, biochemical and molecular intermediates. MATERIALS AND METHODS: Scanning Electron Microscope (SEM), Electron Dispersive X-ray (EDX), and X-Ray Diffraction (XRD) were performed to characterize MS particles. Allergic asthma was induced in Balb/c mice through intraperitoneal ovalbumin (OVA) injection. Experimental groups include, normal control, disease control, Dexamethasone (2 mg/kg) and three MS treated groups: 4.3 mg/kg, 13 mg/kg, and 39 mg/kg. Quantitative PCR, inflammatory cytokines and anti-oxidant enzymes, and histological analysis were performed, in the treated mice and LPS stimulated human monocytic THP-1 cells for determining the MS efficacy. RESULTS: SEM image analysis showed the MS to be heterogenous in shape with a particle size distribution between 100 nm-1 µm. Elemental composition showed the presence of mercury (Hg), arsenic (As), and sulphur (S) along with other elements in the forms of mercury sulfide, arsenic trioxide, and their alloy crystals. OVA-challenge of the Balb/c mice resulted in the development of overt pathological features for allergic asthma including smooth muscle thickening and collagen deposition. Mice receiving MS-exhibited alleviation of allergic asthma features. BAL fluid analysis showed a decrease in the total cell count and decreases in neutrophils, monocytes, lymphocytes, and eosinophils. Further, the stimulated levels of interleukin (IL)-1ß, -6, and TNF-α cytokines and antioxidant levels were also reduced upon MS-treatment. At the molecular level, MS-treatment reduced stimulated mRNA expression levels for IL-4, -5, -10, -13, -33, and IFN-γ cytokines. Histological analysis following MS-treatment of OVA-stimulated mice lungs showed a reduction in mucus accumulation in airways, decreases in peribronchial collagen deposition, bronchial smooth muscle thickening, and attenuation of inflammatory cell infiltration. In addition, under in-vitro conditions, MS-treatment attenuated the LPS induced secretion of IL-1ß, -6, and TNF-α from THP-1 cells. CONCLUSION: Collectively, the results suggest that MS acts as an effective anti-asthmatic and anti-inflammatory agent, by regulating various cellular, biochemical and molecular intermediates.

Enteric-Coated Cologrit Tablet Exhibit Robust Anti-Inflammatory Response in Ulcerative Colitis-like In-Vitro Models by Attuning NFκB-Centric Signaling Axis.

Ulcerative colitis (UC) is an inflammatory bowel disease that affects the patients' colorectal area culminating in an inflamed 'leaky gut.' The majority of UC treatments only provide temporary respite leading to its relapse. Therefore, this study investigated the efficacy of the enteric-coated 'Cologrit' (EC) tablet in alleviating UC-like inflammation. Cologrit is formulated using polyherbal extracts that have anti-inflammatory qualities according to ancient Ayurveda scriptures. Phytochemical profiling revealed the presence of gallic acid, rutin, ellagic acid, and imperatorin in Cologrit formulation. Cologrit treatment decreased inflammation in LPS-induced transformed THP-1 macrophages, and TNF-α-stimulated human colorectal (HT-29) cells through the modulation of NFκB activity, IL-6 production, and NFκB, IL-1ß, IL-8, and CXCL5 mRNA expression levels. Cologrit also lessened human monocytic (U937) cell adhesion to HT29 cells. Methacrylic acid-ethylacrylate copolymer-coating of the enteric Cologrit tablets (EC) supported their dissolution, and the release of phytochemicals in the small intestine pH 7.0 environment in a simulated gastrointestinal digestion model. Small intestine EC digestae effectively abridged dextran sodium sulfate (2.5% w/v)-induced cell viability loss and oxidative stress in human colon epithelial Caco-2 cells. In conclusion, the enteric-coated Cologrit tablets demonstrated good small intestine-specific phytochemical delivery capability, and decreased UC-like inflammation, and oxidative stress through the regulation of TNF-α/NFκB/IL6 signaling axis.

Natural history of children and adults with phenylketonuria in the NBS-PKU Connect registry.

PURPOSE: Phenylalanine hydroxylase deficiency, or phenylketonuria (PKU), is a rare autosomal recessive metabolic disorder. Early diagnosis via newborn screening (NBS) and initiation of treatment prevent the development of cognitive impairment and other co-morbidities. The purpose of this study is to describe the natural history of PKU in the United States, including prevalence of co-morbidities and predictors of outcomes. METHODS: We analyzed data from a self-report survey in the NBS-PKU Connect online registry. We describe the participants' nutrition management strategies, barriers to management, outcomes of bone disorders, skin, and psychological co-morbidities, and the use of special education or other special services. Predictors of outcomes were identified and assessed, including the impact of sex, age, age at diagnosis, blood phenylalanine concentration, use of sapropterin, use of medical food, adherence to prescribed diet, use of low protein modified foods, whether they had ever been off-diet, and use of tyrosine supplementation. RESULTS: The 219 respondents included individuals with PKU or hyperphenylalanemia (n = 78), or their caregivers (n = 141). Most (84.3%) started treatment before the age of two weeks. About one-third indicated that they had been off-diet at some point in their lives, and 81.4% reported that they currently adhered to their prescribed diet, with adherence to prescribed diet decreasing with age. Blood phenylalanine concentration was under the recommended threshold of 360 µmol/L for 68.5% of participants. One-quarter of respondents reported psychological co-morbidities, with anxiety and ADD/ADHD being the most common. The incidence of psychological co-morbidities increased with age and with ever having been off diet. Special education or other special services were more likely to be reported by individuals who were diagnosed after one week of age. Skin disorders such as acne and eczema were more common in females than males, and a minority of participants reported bone disorders. CONCLUSIONS: Despite recommendations to maintain blood phenylalanine concentrations in the therapeutic range throughout life, it is not uncommon for adults with PKU to discontinue dietary management of their disorder. Early diagnosis was associated with reduced need for special education or other special services, and continuous treatment was associated with decreased psychological co-morbidities.

Biotite-Calx Based Traditional Indian Medicine Sahastraputi-Abhrak-Bhasma Prophylactically Mitigates Allergic Airway Inflammation in a Mouse Model of Asthma by Amending Cytokine Responses.

PURPOSE: Asthma is a heterogeneous airway inflammatory disease with limited therapeutic options. Traditional medicine is extensively used for treating various ailments including asthma. Sahastraputi-Abhrak-Bhasma (SPAB) is a biotite-calx based Indian medicine. METHODS: We have tested for the anti-inflammatory and anti-asthmatic properties of SPAB, using a mouse model of ovalbumin-induced allergic asthma in-vivo and cell-based assays in-vitro. Histological analysis, qPCR and ELISA were performed to assess the pathology. SEM, EDX and XRD-analysis were performed to characterize the SPAB particles. RESULTS: SEM, EDX and XRD-analysis identified the presence of SPAB particle of 100 nm-~1µm diameter and contains annite-1M, aluminium silicate, kyanite, aluminium oxide, magnesium silicate, and maghemite in the samples. Ova-challenge resulted in severe inflammatory responses, airway remodelling and increased oxidative burden in lungs. Importantly, prophylactic treatment with SPAB significantly attenuated allergen induced leukocyte infiltration specifically eosinophils, lymphocytes, macrophages and neutrophils in BALF. Ova-induced mucus hypersecretion, peri-bronchial collagen deposition, inflammatory cell infiltration and bronchial epithelial thickening were significantly abrogated upon SPAB treatment. qPCR and ELISA analysis identified that allergen induced increases in IL-5, IL-13, IL-33, IFN-γ and IL-1ß cytokines mRNA in whole lungs and the levels of IL-6, IL-1ß and TNF-α proteins in BALF were significantly attenuated upon oral SPAB treatment. SPAB restored allergen induced decreases in anti-oxidant markers in lungs. In-vitro, SPAB attenuated the secretion of IL-6, and TNF-α from human bronchial epithelial cells and modestly inhibited NF-kB/AP-1 pathway in HEK cells. CONCLUSION: Taken together, our results experimentally validated the prophylactic ameliorative potential of the Indian classical medicine Sahastraputi-Abhrak-Bhasma against asthma associated airway inflammation.

The Use of Telemedicine and Other Strategies by Registered Dietitians for the Medical Nutrition Therapy of Patients With Inherited Metabolic Disorders During the COVID-19 Pandemic.

The clinical management of patients with inherited metabolic disorders (IMDs) includes medical nutrition therapy (MNT) by a registered dietitian (RD). We utilized an online quantitative and qualitative survey to characterize the practices of RDs treating patients with IMDs during the COVID-19 pandemic and to identify challenges and unmet needs. We received responses from 117 RDs. Results indicate that RDs are using alternate methods to engage this vulnerable population and provide MNT during the pandemic, including offering telemedicine appointments. Barriers to implementation of telemedicine include the limitations of virtual visits (inability to conduct physical exams and collect blood samples), time, patient knowledge of technology, audio problems, and patient access to internet, computers, or smartphones. RDs have addressed these barriers by extending prescriptions without a medical exam, relying on local facilities for blood draws, increasing the number of patients that use at-home filter papers for blood monitoring, and expanding the use of phone calls and emails. RDs identified patient education materials to facilitate telemedicine visits as a primary unmet need. Despite the reported barriers and limitations of telemedicine for MNT of IMDs, there was widespread satisfaction with the approach among RDs, with 96.9% reporting that they were somewhat or very satisfied with telemedicine. Although this survey focused on barriers, benefits of telemedicine for both RDs and patients were also reported. Identification of barriers and unmet needs can help clinics plan strategies to maximize telemedicine delivery models, to improve efficiency and patient outcomes, and to support sustained use of telemedicine post-pandemic.

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis.

The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.

Tri-Herbal Medicine Divya Sarva-Kalp-Kwath (Livogrit) Regulates Fatty Acid-Induced Steatosis in Human HepG2 Cells through Inhibition of Intracellular Triglycerides and Extracellular Glycerol Levels.

Steatosis is characterized by excessive triglycerides accumulation in liver cells. Recently, application of herbal formulations has gained importance in treating complex diseases. Therefore, this study explores the efficacy of tri-herbal medicine Divya Sarva-Kalp-Kwath (SKK; brand name, Livogrit) in treating free fatty acid (FFA)-induced steatosis in human liver (HepG2) cells and rat primary hepatocytes. Previously, we demonstrated that cytosafe SKK ameliorated CCl4-induced hepatotoxicity. In this study, we evaluated the role of SKK in reducing FFA-induced cell-death, and steatosis in HepG2 through analysis of cell viability, intracellular lipid and triglyceride accumulation, extracellular free glycerol levels, and mRNA expression changes. Plant metabolic components fingerprinting in SKK was performed via High Performance Thin Layer Chromatography (HPTLC). Treatment with SKK significantly reduced the loss of cell viability induced by 2 mM-FFA in a dose-dependent manner. SKK also reduced intracellular lipid, triglyceride accumulation, secreted AST levels, and increased extracellular free glycerol presence in the FFA-exposed cells. SKK normalized the FFA-stimulated overexpression of SREBP1c, FAS, C/EBPα, and CPT1A genes associated with the induction of steatosis. In addition, treatment of rat primary hepatocytes with FFA and SKK concurrently, reduced intracellular lipid accumulation. Thus, SKK showed efficacy in reducing intracellular triglyceride accumulation and increasing extracellular glycerol release, along with downregulation of related key genetic factors for FFA-associated steatosis.

Optimising amino acid absorption: essential to improve nitrogen balance and metabolic control in phenylketonuria.

It has been nearly 70 years since the discovery that strict adherence to a diet low in phenylalanine prevents severe neurological sequelae in patients with phenylalanine hydroxylase deficiency (phenylketonuria; PKU). Today, dietary treatment with restricted phenylalanine intake supplemented with non-phenylalanine amino acids to support growth and maintain a healthy body composition remains the mainstay of therapy. However, a better understanding is needed of the factors that influence N balance in the context of amino acid supplementation. The aim of the present paper is to summarise considerations for improving N balance in patients with PKU, with a focus on gaining greater understanding of amino acid absorption, disposition and utilisation. In addition, the impact of phenylalanine-free amino acids on 24 h blood phenylalanine/tyrosine circadian rhythm is evaluated. We compare the effects of administering intact protein v. free amino acid on protein metabolism and discuss the possibility of improving outcomes by administering amino acid mixtures so that their absorption profile mimics that of intact protein. Protein substitutes with the ability to delay absorption of phenylalanine and tyrosine, mimicking physiological absorption kinetics, are expected to improve the rate of assimilation into protein and minimise fluctuations in quantitative plasma amino acid levels. They may also help maintain normal glycaemia and satiety sensation. This is likely to play an important role in improving the management of patients with PKU.

One-year follow-up of B vitamin and Iron status in patients with phenylketonuria provided tetrahydrobiopterin (BH4).

BACKGROUND: People with Phenylketonuria (PKU) who respond to tetrahydrobiopterin (BH4) often decrease dependence on medical food (MF) following increased phenylalanine (phe) tolerance. Responders to BH4 may experience a reduction in certain nutrients if not compensated through intact foods or supplements. This study investigated B6, B12, folate, and iron status based on blood levels and dietary intake in patients with PKU responsive to BH4 over 1 year. METHODS: Fifty-eight patients with PKU, ages 4-50 years were recruited and initiated on BH4 therapy. Patients were monitored for BH4 response, and nutritional status was recorded at regular intervals over 12 months. The analysis included 33 patients with known BH4 response status and complete nutritional data. Nutrient intake was determined by National Data System for Research (NDSR) analysis of self reported 3 day diet records and compared to Dietary Reference Intakes (DRIs). Blood biomarkers were analyzed by Quest Diagnostics and compared to laboratory reference ranges. Patient laboratory values were compared to controls from the National Health and Examination Survey (NHANES). Differences in nutrient intakes across time points were examined, stratified by age, using nonparametric methods. Statistical analyses were completed with SAS 9.4, with significance set at α = 0.05. RESULTS: Medical food intake declined among pediatric (p < 0.01) and adult (p = 0.06) BH4 responders over 1 year. Among those < 18 years of age, mean percent of calories obtained from MF declined from 21.3 to 4.7%. In adults, percent calories from MF dropped from 19.5 to 4.0%. Though maintaining laboratory and dietary values within reference ranges, responders < 18 years experienced a significant decline in serum B12 (p = 0.01), dietary folate (p = 0.006), and dietary iron (p = 0.004) over the study. CONCLUSION: Although mean dietary and laboratory values for B12, B6, folate, and iron in BH4 responders and non-responders were adequate at baseline and 12-month follow-up, responders experienced a significant decline in serum B12 over 1 year, which may be explained by decreased intake of fortified MF. Both response groups had lower serum B12 than NHANES controls at baseline and 12 months. Results indicate a need to monitor B12 concentrations and consider micronutrient supplementation, with special attention to pediatric patients with PKU.

Development of newborn screening connect (NBS connect): a self-reported patient registry and its role in improvement of care for patients with inherited metabolic disorders.

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

Protein intake and physical activity are associated with body composition in individuals with phenylalanine hydroxylase deficiency.

OBJECTIVE: Determine whether body composition as it relates to dietary protein in patients with phenylalanine hydroxylase (PAH) deficiency is associated with genotype, dietary factors, and lifestyle choices. METHODS: We examined associations between protein intake (intact and medical foods: MF) and body composition in PAH-deficient patients along with, physical activity, and genotype. Protein intakes (total, intact, and MF) were analysed from three-day food records with Nutrition Data System for Research (NDSR) in 59 children and 27 adults (N=86, median age=16.0years). The severity of PAH deficiency was classified using the genotype assigned value method (AV sum). Physical activity was assessed using a study-developed question (light vs. intense activity). Body composition was measured by DXA, including android:gynoid ratio (A:G), fat-free mass index (FFMI), fat mass index (FMI), and FMI:FFMI ratio. RESULTS: High intact protein intake was associated with high FFMI (rs=0.75, p=0.008) and low FMI:FFMI (rs=-0.59, p=0.04) in adults. Only in children, MF protein (rs=0.38, p=0.04) was directly proportional to FFMI. Median intact protein intakes of adults (25.1 vs. 9.9g/d, p<0.001) and children (11 vs. 6g/d, p<0.001) were higher than prescribed. Only in adults, the actual median MF protein intake was lower than prescribed (53 vs. 60g/d, p=0.03). In adults and children, light activity was associated with higher fat mass indices compared to intense activity (adults: FMI:FFMI: ß=1.1, p=0.001, children: FMI:FFMI: ß=1.1, p=0.007; FMI ß=2.1, p=0.01; A:G ß=1.1, p=0.04). All associations remained significant after covariate adjustment. Genotype was not associated with body composition. CONCLUSIONS: Although fat-free mass in adults was positively associated with intact protein intake, it should be consumed as prescribed per individual tolerance to maintain plasma Phe concentrations within treatment range. In children, total protein maximized with MF should be encouraged to promote lean mass. Nutrition counselling could be complemented with physical activity recommendations for optimal clinical outcomes.

Updated, web-based nutrition management guideline for PKU: An evidence and consensus based approach.

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

Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach.

In an effort to increase harmonization of care and enable outcome studies, the Genetic Metabolic Dietitians International (GMDI) and the Southeast Regional Newborn Screening and Genetics Collaborative (SERC) are partnering to develop nutrition management guidelines for inherited metabolic disorders (IMD) using a model combining both evidence- and consensus-based methodology. The first guideline to be completed is for maple syrup urine disease (MSUD). This report describes the methodology used in its development: formulation of five research questions; review, critical appraisal and abstraction of peer-reviewed studies and unpublished practice literature; and expert input through Delphi surveys and a nominal group process. This report includes the summary statements for each research question and the nutrition management recommendations they generated. Each recommendation is followed by a standardized rating based on the strength of the evidence and consensus used. The application of technology to build the infrastructure for this project allowed transparency during development of this guideline and will be a foundation for future guidelines. Online open access of the full, published guideline allows utilization by health care providers, researchers, and collaborators who advise, advocate and care for individuals with MSUD and their families. There will be future updates as warranted by developments in research and clinical practice.

Insurance coverage of medical foods for treatment of inherited metabolic disorders.

PURPOSE: Treatment of inherited metabolic disorders is accomplished by use of specialized diets employing medical foods and medically necessary supplements. Families seeking insurance coverage for these products express concern that coverage is often limited; the extent of this challenge is not well defined. METHODS: To learn about limitations in insurance coverage, parents of 305 children with inherited metabolic disorders completed a paper survey providing information about their use of medical foods, modified low-protein foods, prescribed dietary supplements, and medical feeding equipment and supplies for treatment of their child's disorder as well as details about payment sources for these products. RESULTS: Although nearly all children with inherited metabolic disorders had medical coverage of some type, families paid "out of pocket" for all types of products. Uncovered spending was reported for 11% of families purchasing medical foods, 26% purchasing supplements, 33% of those needing medical feeding supplies, and 59% of families requiring modified low-protein foods. Forty-two percent of families using modified low-protein foods and 21% of families using medical foods reported additional treatment-related expenses of $100 or more per month for these products. CONCLUSION: Costs of medical foods used to treat inherited metabolic disorders are not completely covered by insurance or other resources.

A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria.

Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R = .32, P = .03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA.

BH(4) therapy impacts the nutrition status and intake in children with phenylketonuria: 2-year follow-up.

The impact of tetrahydrobiopterin (BH(4)) treatment on phenylalanine tolerance, medical-food consumption, and nutrition status in patients with phenylketonuria (PKU) was investigated. Six children (5-12 years) with well-controlled PKU, responding to a BH(4) dose of 20 mg/kg per day, were assessed for 24 months. Mean dietary phenylalanine tolerance increased from 421 ± 128 to 1470 ± 455 mg/day. Height Z scores significantly improved from 0.25 ± 0.99 at baseline to 0.53 ± 1.16 at 24 months (p for trend < 0.001). Patients tolerated more phenylalanine and more intact protein and required less medical food (protein supplement). Improved linear growth and nutrition status was seen over the course of the 24-month follow-up. Due to the variation in phenylalanine tolerance, dietary recommendations should be tailored to the patient's individual requirements.

Docosahexaenoic acid status in females of reproductive age with maple syrup urine disease.

Individuals with maple syrup urine disease (MSUD) have impaired metabolism of branched-chain amino acids (BCAA) valine, isoleucine, and leucine. Life-long dietary therapy is recommended to restrict BCAA intake and thus prevent poor neurological outcomes and death. To maintain adequate nutritional status, the majority of protein and nutrients are derived from synthetic BCAA-free medical foods with variable fatty acid content. Given the restrictive diet and the importance of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in neurological development, this study evaluated the dietary and fatty acid status of females of reproductive age with MSUD attending a metabolic camp. Healthy controls of similar age and sex were selected from existing normal laboratory data. Total lipid fatty acid concentration in plasma and erythrocytes was analyzed using gas chromatography-mass spectroscopy. Participants with MSUD had normal to increased concentrations of plasma and erythrocyte alpha linolenic acid (ALA) but significantly lower concentrations of plasma and erythrocyte docosahexaenoic acid (DHA) as percent of total lipid fatty acids compared with controls (plasma DHA: MSUD 1.03 +/- 0.35, controls 2.87 +/- 1.08; P = 0.001; erythrocyte DHA: MSUD 2.58 +/- 0.58, controls 3.66 +/- 0.80; P = 0.011). Dietary records reflected negligible or no DHA intake over the 3-day period prior to the blood draw (range 0-2 mg). These results suggest females of reproductive age with MSUD have lower blood DHA concentrations than age-matched controls. In addition, the presence of ALA in medical foods and the background diet may not counter the lack of preformed DHA in the diet. The implications of these results warrant further investigation.