A food pyramid for adult patients with phenylketonuria and a systematic review on the current evidences regarding the optimal dietary treatment of adult patients with PKU.

Early dietary treatment is mind-saving in patients with phenylketonuria. A "diet-for-life" is advocated, aimed to prevent effects of chronic exposure to hyperphenylalaninemia. While adherence to diet is significant during childhood as patients are followed-up at specialized metabolic centers, during adolescence and adulthood percentage of patients discontinuing diet and/or lost at follow-up is still high. The process of passing skills and responsibilities from pediatric team to adult team is defined "transition". The goal of transition clinics is to set up specific multidisciplinary care pathways and guarantee continuity of care and compliance of patients to care. In 2017, "The complete European guidelines on phenylketonuria" were published. These guidelines, however, do not provide an easy way to illustrate to adult patients how to follow correct dietary approach. The purpose of this review is to evaluate current evidence on optimum dietary treatment of adults with phenylketonuria and to provide food pyramid for this population. The pyramid built shows that carbohydrates should be consumed every day (3 portions), together with fruits and vegetables (5 portions), extra virgin olive oil, and calcium water (almost 1 L/day); weekly portions can include 150 g potatoes walnuts and hazelnuts (20 g). At top of pyramid, there are two pennants. The green means that, based on individual metabolic phenotype and daily phenylalanine tolerance, patients need personalized supplementation (specific phenylalanine free amino acid mixtures, vitamins and omega 3 fatty acids); the one red indicates foods that are banned from diet (aspartame and protein foods exceeding individual dietary phenylalanine tolerance).

Accidental Consumption of Aspartame in Phenylketonuria: Patient Experiences.

Aspartame is a phenylalanine containing sweetener, added to foods and drinks, which is avoided in phenylketonuria (PKU). However, the amount of phenylalanine provided by aspartame is unidentifiable from food and drinks labels. We performed a cross-sectional online survey aiming to examine the accidental aspartame consumption in PKU. 206 questionnaires (58% female) were completed. 55% of respondents (n = 114) were adults with PKU or their parent/carers and 45% (n = 92) were parents/carers of children with PKU. 74% (n = 152/206) had consumed food/drinks containing aspartame. Repeated accidental aspartame consumption was common and more frequent in children (p < 0.0001). The aspartame containing food/drinks accidentally consumed were fizzy drinks (68%, n = 103/152), fruit squash (40%, n = 61/152), chewing gum (30%, n = 46/152), flavoured water (25%, n = 38/152), ready to drink fruit squash cartons (23%, n = 35/152) and sports drinks (21%, n = 32/152). The main reasons described for accidental consumption, were manufacturers' changing recipes (81%, n = 123/152), inability to check the ingredients in pubs/restaurants/vending machines (59%, n = 89/152) or forgetting to check the label (32%, n = 49/152). 23% (n= 48/206) had been prescribed medicines containing aspartame and 75% (n = 36/48) said that medicines were not checked by medics when prescribed. 85% (n = 164/192) considered the sugar tax made accidental aspartame consumption more likely. Some of the difficulties for patients were aspartame identification in drinks consumed in restaurants, pubs, vending machines (77%, n = 158/206); similarities in appearance of aspartame and non-aspartame products (62%, n = 127/206); time consuming shopping/checking labels (56%, n = 115/206); and unclear labelling (55%, n = 114/206). These issues caused anxiety for the person with PKU (52%, n = 106/206), anxiety for parent/caregivers (46%, n = 95/206), guilt for parent/carers (42%, n = 87/206) and social isolation (42%, n = 87/206). It is important to understand the impact of aspartame and legislation such as the sugar tax on people with PKU. Policy makers and industry should ensure that the quality of life of people with rare conditions such as PKU is not compromised through their action.

Preliminary Investigation to Review If a Glycomacropeptide Compared to L-Amino Acid Protein Substitute Alters the Pre- and Postprandial Amino Acid Profile in Children with Phenylketonuria.

In Phenylketonuria (PKU), the peptide structure of the protein substitute (PS), casein glycomacropeptide (CGMP), is supplemented with amino acids (CGMP-AA). CGMP may slow the rate of amino acid (AA) absorption compared with traditional phenylalanine-free amino acids (Phe-free AA), which may improve nitrogen utilization, decrease urea production, and alter insulin response. AIM: In children with PKU, to compare pre and postprandial AA concentrations when taking one of three PS's: Phe-free AA, CGMP-AA 1 or 2. METHODS: 43 children (24 boys, 19 girls), median age 9 years (range 5-16 years) were studied; 11 took CGMP-AA1, 18 CGMP-AA2, and 14 Phe-free AA. Early morning fasting pre and 2 h postprandial blood samples were collected for quantitative AA on one occasion. A breakfast with allocated 20 g protein equivalent from PS was given post fasting blood sample. RESULTS: There was a significant increase in postprandial AA for all individual AAs with all three PS. Postprandial AA histidine (p < 0.001), leucine (p < 0.001), and tyrosine (p < 0.001) were higher in CGMP-AA2 than CGMP-AA1, and leucine (p < 0.001), threonine (p < 0.001), and tyrosine (p = 0.003) higher in GCMP-AA2 than Phe-free AA. This was reflective of the AA composition of the three different PS's. CONCLUSIONS: In PKU, the AA composition of CGMP-AA influences 2 h postprandial AA composition, suggesting that a PS derived from CGMP-AA may be absorbed similarly to Phe-free AA, but this requires further investigation.

The Impact of a Slow-Release Large Neutral Amino Acids Supplement on Treatment Adherence in Adult Patients with Phenylketonuria.

The gold standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet supplemented with Phe-free protein substitutes. Adherence to therapy becomes difficult after childhood. Supplementing with large neutral amino acids (LNAAs) has been proposed as an alternative medication to Phe-free protein substitutes (i.e., amino acid mixtures). The aim of this study was to evaluate adherence to therapy and quality of life (QoL) in a cohort of sub-optimally controlled adult PKU patients treated with a new LNAA formulation. Twelve patients were enrolled in a 12-month-trial of slow-release LNAAs (1g/kg/day) plus a Phe-restricted diet. Medication adherence was measured with the Morisky Green Levine Medication Adherence Scale; the QoL was measured using the phenylketonuria-quality of life (PKU-QoL) questionnaire. Phe, tyrosine (Tyr) levels, and Phe/Tyr ratios were measured fortnightly. Before treatment, 3/12 patients self-reported a 'medium' adherence to medication and 9/12 reported a low adherence; 60% of patients reported a full adherence over the past four weeks. After 12 months of LNAA treatment, all patients self-reported a high adherence to medication, with 96% reporting a full adherence. Phe levels remained unchanged, while Tyr levels increased in most patients. The Phy/Tyr ratio decreased. All patients had a significant improvement in the QoL. LNAAs may give patients a further opportunity to improve medication adherence and, consequently, their QoL.

Clinical efficacy of a novel topical formulation for vitiligo: compared evaluation of different treatment modalities in 149 patients.

Current vitiligo treatments are not always satisfactory for both patients and dermatologists. Recently, combination therapies have been introduced in order to obtain better results and reduce risks in the management of the disease. Novel efficacious products are needed to improve the therapeutic possibilities of dermatologists in the respect of safety for the patients. The objective of the present study was to evaluate the effects of a novel topical in a gel formulation containing phenylalanine, cucumis melo extract, and acetyl cysteine in vitiligo. The present study used an open observational study to evaluate the efficacy and safety of the investigated product, given alone or in combination with 311-nm narrow band microphototherapy. Results were compared with those obtained treating a matched patient population with microphototherapy alone and with clobetasol propionate 0.05% ointment alone. One hundred forty-nine patients suffering from symmetrical vitiligo affecting less than 10% of the skin surface were evaluated. Patients affected by acral vitiligo only were excluded from the analysis. Treatment duration was scheduled for 12 weeks. Excellent repigmentation (>75%) was achieved by 38-73% of patients, depending on the treatment regimen. Mild to moderate side effects were observed only in patients treated with clobetasol 0.05% ointment. The tested gel formulation showed a good efficacy in improving vitiligo repigmentation. No side effects were observed.

Food products made with glycomacropeptide, a low-phenylalanine whey protein, provide a new alternative to amino Acid-based medical foods for nutrition management of phenylketonuria.

Phenylketonuria (PKU), an inborn error in phenylalanine metabolism, requires lifelong nutrition management with a low-phenylalanine diet, which includes a phenylalanine-free amino acid-based medical formula to provide the majority of an individual's protein needs. Compliance with this diet is often difficult for older children, adolescents, and adults with PKU. The whey protein glycomacropeptide (GMP) is ideally suited for the PKU diet because it is naturally low in phenylalanine. Nutritionally complete, acceptable medical foods and beverages can be made with GMP to increase the variety of protein sources for the PKU diet. As an intact protein, GMP improves protein use and increases satiety compared with amino acids. Thus, GMP provides a new, more physiologic source of low-phenylalanine dietary protein for people with PKU.

Weaning infants with phenylketonuria: a review.

Careful weaning is particularly important in phenylketonuria (PKU). Dietary phenylalanine intake is severely restricted, and the diet is supplemented with phenylalanine-free amino acids and special low protein foods. In PKU, there are no evidence-based weaning guidelines and no studies assessing the introduction of solid foods. We critically review the literature and examine current UK weaning practices. Ideally, weaning in PKU should closely reflect the 'model' for healthy infants. However, the requirement for optimal blood phenylalanine control and the demands of diet therapy overshadow the social aspects of weaning. Solid food intake is established with very low protein foods first, and then 50 mg phenylalanine exchanges (equivalent to 1 g of intact protein) gradually replace breast/formula feeds. Introducing solids before the recommended 6 months of age may be advantageous because there is a less persistent neophobic food response, possibly leading to better food acceptance. Infants with PKU also require a special phenylalanine-free protein substitute. Between 6 and 12 months, a second concentrated source of phenylalanine-free protein substitute is required. This is commonly given as an additional liquid, although the prescribed volume may adversely affect appetite. Alternatively, a second-stage protein substitute administered as a paste may better suit feeding development. Further research aiming to examine the weaning process in PKU with a focus on biological, maternal, infant, social and environmental factors is required. This will help provide evidence for the effect of protein substitute on appetite and help in the development of evidence-based guidelines.

Pyruvate and creatine prevent oxidative stress and behavioral alterations caused by phenylalanine administration into hippocampus of rats.

Phenylketonuria is characterized by a variable degree of mental retardation and other neurological features whose mechanisms are not fully understood. In the present study we investigated the effect of intrahippocampal administration of phenylalanine, isolated or associated with pyruvate or creatine, on rat behavior and on oxidative stress. Sixty-day-old male Wistar rats were randomly divided into 6 groups: saline; phenylalanine; pyruvate; creatine; phenylalanine + pyruvate; phenylalanine + creatine. Phenylalanine was administered bilaterally in the hippocampus one hour before training; pyruvate, at the same doses, was administered in the hippocampus one hour before phenylalanine; creatine was administered intraperitoneally twice a day for 5 days before training; controls received saline solution at same volumes than the other substances. Parameters of exploratory behavior and of emotionality were assessed in both training and test sessions in the open field task. Rats receiving phenylalanine did not habituate to the open field along the sessions, indicating deficit of learning/memory, but parameters of emotionality were normal, not interfering in the habituation process. Pyruvate or creatine administration prevented the lack of habituation caused by phenylalanine. Pyruvate and creatine also prevented alterations provoked by phenylalanine on lipid peroxidation, total content of sulfhydryls, total radical-trapping antioxidant potential and total antioxidant reactivity. The results suggest that the behavioral alterations provoked by intra-hippocampal administration of phenylalanine may be caused, at least in part, by oxidative stress and/or energy deficit. If this also occurs in PKU, it is possible that pyruvate and creatine supplementation to the phenylalanine-restricted diet might be beneficial to phenylketonuric patients.

Adult patients with well-controlled phenylketonuria tolerate incidental additional intake of phenylalanine.

BACKGROUND/AIMS: In patients with phenylketonuria (PKU), target ranges of blood phenylalanine (Phe) concentrations have been tightened in order to improve long-term outcomes. We investigated day-to-day and week-to-week variations in blood Phe concentration and the effect of an additional Phe load. METHODS: We performed a longitudinal study in 6 adult PKU patients. The study was divided in five 7-day periods: 1 period without any intervention (period I) and 4 periods with a Phe load on day 3 equivalent to 100% (periods II and III) and to 200% (periods IV and V) of each patient's individual daily Phe intake. Phe loading was given as encapsulated L-Phe. Blood spots to measure blood Phe concentration were taken each morning before breakfast in all periods. RESULTS: Day-to-day and week-to-week blood Phe concentrations varied considerably with and without intervention in Phe intake. Equal loads of Phe did not result in comparable effects in blood Phe concentrations in all patients. In periods II-IV, mean blood Phe concentrations of days 1-3 (pre-load) were not significantly different from days 4-7 (post-load). The 200% load resulted in a significantly larger variation. CONCLUSION: These results showed that patients with well-controlled PKU can incidentally tolerate 100% - and in some cases 200% - of their normal daily Phe intake.

Phenylalanine-pyruvate aminotransferase activity in chicks subjected to phenylalanine imbalance or phenylalanine toxicity.

Two experiments were done to determine the influence of Phe imbalance and excess on Phe-pyruvate aminotransferase (PAT) activity in the chick. Five replicates of 3 chicks (experiment 1) or 2 chicks (experiment 2) of a commercial brown egg layer strain were fed a semipurified diet for 1 wk and then received experimental diets for 10 d. Three diets were used in experiment 1: the basal diet contained 0.46% Phe; the imbalance diet was similar to the basal diet except that it contained a 10% mixture of indispensable amino acids lacking Phe (IAA - Phe) to create a Phe imbalance; the imbalance corrected diet was similar to the imbalance diet except that it was supplemented with 1.12% Phe to correct the imbalance. A 3 x 2 factorial arrangement of treatments in experiment 2 provided 3 dietary levels (0.46, 1.58, and 2.46%) of Phe and either no supplement or 10% supplement of IAA - Phe. Nonfasted chicks were killed and livers were sampled in experiment 1, and livers, kidneys, brains, and pectoralis major muscles were sampled in experiment 2. In experiment 1, liver PAT activity per gram of liver was 80 and 55% higher (P < 0.01) in chicks fed the imbalance and imbalance corrected diets than in chicks fed the basal diet. In experiment 2, the livers and kidneys, but not brains and muscles, of chicks that received the 10% supplement of IAA - Phe had higher activities of PAT per gram of tissue per minute and per milligram of tissue protein extract per minute than chicks that did not receive IAA - Phe (P < 0.001). No effect of dietary Phe on PAT activity was detected (P > 0.05). Phenylalanine-pyruvate aminotransferase activity appears to be regulated in response to dietary content of indispensable amino acids but not by the dietary level of Phe.

Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause?

In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.

Effects of L-phenylalanine on energy intake in overweight and obese women: interactions with dietary restraint status.

L-Phenylalanine (Phe), is a potent releaser of the satiety hormone, cholecystokinin (CCK) and previous studies, conducted primarily in men, show that ingestion of Phe reduces energy intake. The objective of the current study was to test the effects of Phe on energy intake in overweight and obese women. Subjects (n=32) received three treatments (high-dose (10 g Phe), low-dose (5 g Phe and 5 g glucose) or control (10 g glucose)) 20 min before an ad libitum lunch and dinner meal in a within-subjects', counterbalanced, double-blind study. No effect of Phe was found, however, interactions with dietary restraint status were detected in post-hoc analyses. Energy intake over the day was 11% lower following high-dose Phe versus control for women classified in the lower tertile of rigid restraint, a subscale of the dietary restraint scale, whereas no effects were noted for women in the middle and upper tertiles. High-dose Phe increased ratings of nausea, however, reduced energy intake in the high-dose condition was noted only for subjects with low nausea ratings. These results suggest that the satiety response to Phe is modulated by rigid restraint status and that reductions in food intake occur independently of Phe's effects on nausea.

Safety and efficacy of nateglinide/metformin combination therapy in the treatment of type 2 diabetes.

UNLABELLED: The increasing prevalence of type 2 diabetes provides impetus for both development of new drugs to improve glycemic control and for reconsideration of treatment strategies with existing agents. Combination therapy with complementary drug classes that act on different aspects of glycemic control has been a particularly effective strategy. This work reviews the published literature reporting efficacy and safety/tolerability of nateglinide, a rapid-onset insulinotropic agent with a predominant effect to reduce postprandial glucose, when combined with metformin, a first-line agent that suppresses hepatic glucose production and thereby reduces fasting plasma glucose. The nateglinide/metformin combination has consistently been found to be both efficacious and well tolerated, whether given as initial combination therapy in drug-naïve patients or when added to metformin monotherapy. Maximum efficacy (Delta glycosylated hemoglobin [HbA(1c)]= -1.4% to -1.9%, sustained for up to 2 years of treatment) was seen in studies of drug-naïve patients in whom pharmacotherapy was initiated with the combination of nateglinide and metformin, and modest reductions in HbA(1c) (Delta = -0.5% to -1.2%, sustained for up to 24 weeks) were found when nateglinide was added to ongoing metformin monotherapy. CONCLUSION: the combination of nateglinide and metformin provides a sustained degree of glycemic control not achievable with either agent given as monotherapy.

[Pharmacological treatment of postprandial hyperglycemia in hypertensive patients with type 2 diabetes mellitus].

Several epidemiological studies have shown an association between postprandial hyperglycemia and mortality from cardiovascular disease. Postprandial hyperglycemia is frequently associated with visceral obesity which plays a key role in metabolic abnormalities such as dyslipidemia and hypertension. Inhibitors of alpha-glucosidase and nateglinide have beneficial effects on the metabolic syndrome associated with visceral obesity. Voglibose in combination with diet therapy reduces visceral fat deposition and ameliorates insulin resistance. Acarbose slightly reduces blood pressure of hypertensive diabetic patients. Nateglinide, a rapidly acting insulin secretagogue, lowers postprandial glucose levels without significant body weight gain. These drugs may protect pancreatic beta-cells from postprandial glucose toxicity and prevent the progression of diabetes.

A single-site, double-blind, placebo-controlled, dose-ranging study of YKP10A--a putative, new antidepressant.

BACKGROUND: YKP10A is a novel, new antidepressant that may affect dopamine neurotransmission. We present results from the first Phase II clinical trial of YKP10A antidepressant activity in patients with major depression. METHODS: This was a single-site, placebo-controlled, dose-ranging study. Patients with major depression were randomly assigned to one of four double-blind treatment conditions: YKP10A 100-300 mg/day, YKP10A 400-600 mg/day, YKP10A 700-900 mg/day, or placebo for 8 weeks. RESULTS: 43 patients were screened and 35 were randomized. Nineteen patients (54.3%) completed the entire 8-week study. Five YKP10A-treated patients (19%) discontinued treatment for adverse events. Thirty-eight percent of patients in the medium dose YKP10A group had a reduction in baseline HAM-D17 score > or = 50% compared with the low-dose (13%), high-dose (13%), and placebo (29%) groups. A similar nonsignificant 'signal' for therapeutic activity was also seen in the medium-dose YKP10A group on the HAM-D28 and the Montgomery-Asberg Depression Rating Scale (MADRS). Headaches, nervousness, agitation, insomnia, and gastrointestinal complaints were the most commonly reported side effects. Two cases of hypomania were observed. LIMITATIONS: This preliminary, single-site study was not powered to detect a statistically significant difference from placebo among treatment groups. CONCLUSION: YKP10A may have antidepressant activity at a daily dose range of 400-600 mg.

Phenylketonuria: tyrosine supplementation in phenylalanine-restricted diets.

Treatment of phenylketonuria (PKU) consists of restriction of natural protein and provision of a protein substitute that lacks phenylalanine but is enriched in tyrosine. Large and unexplained differences exist, however, in the tyrosine enrichment of the protein substitutes. Furthermore, some investigators advise providing extra free tyrosine in addition to the tyrosine-enriched protein substitute, especially in the treatment of maternal PKU. In this article, we discuss tyrosine concentrations in blood during low-phenylalanine, tyrosine-enriched diets and the implications of these blood tyrosine concentrations for supplementation with tyrosine. We conclude that the present method of tyrosine supplementation during the day is far from optimal because it does not prevent low blood tyrosine concentrations, especially after an overnight fast, and may result in largely increased blood tyrosine concentrations during the rest of the day. Both high tyrosine enrichment of protein substitutes and extra free tyrosine supplementation may not be as safe as considered at present, especially to the fetus of a woman with PKU. The development of dietary compounds that release tyrosine more slowly could be beneficial. We advocate decreasing the tyrosine content of protein substitutes to approximately 6% by wt (6 g/100 g protein equivalent) at most and not giving extra free tyrosine without knowing the diurnal variations in the blood tyrosine concentration and having biochemical evidence of a tyrosine deficiency. We further advocate that a better daily distribution of the protein substitute be achieved by improving the palatability of these products.

Aspartame: clinical update.

Since the introduction of aspartame into the American food supply in 1981, it has grown to become the most widely used and accepted artificial sweetener. However, recent published and unpublished reports of headaches, seizures, blindness, and cognitive and behavioral changes with long-term, high-dose aspartame may be cause for concern. Physician awareness of the present clinical and research status of aspartame is important.

[Use of screening for amino acid disorders in the study of the nutrition of the newborn infant: various milk formulas and changes in plasma amino acids]. / Utilizzazione dello "screening" per le aminoacidopatie nello studio dell'alimentazione del neonato: formule lattee diverse e variazioni degli aminoacidi plasmatici.

A sample of 1326 new-born babies has been studied regarding the influence of the milk diet over some plasma-serum amino acids. The Authors have make use of the screening of the congenital errors of the protein metabolism. New-born babies were bled on the fifth or sixth day of life and their blood was analysed at first with the Guthrie test and then with automatic chromatographic determination. New-born babies have been arranged according to their gestational age, birth weight and intrauterine growth. More then 90% of the sample was formed by normal for gestational age new-born babies. We have make use of five different milk formulas: a mixed one (human milk with adapted milks), three powdered milks with three different casein-serum proteins ratio and finally cow's milk with 50% water. The best formula among these ones has been the human milk mixed with adapted milks. The completely artificial formulas, but with casein/serum proteins ratio lower or equal to one, has given rise to a few amino acid alterations, too. On the contrary, the cow's milk mixed with water and the artificial powdered milks with a casein-serum proteins ratio equal to 4.5 shouldn't be utilized in the new-born baby's diet, as they may provoke remarkable alteration in the amino acid metabolism.