PKU dietary handbook to accompany PKU guidelines.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. MAIN BODY: In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. CONCLUSION: This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Dietary management of maternal phenylketonuria with glycomacropeptide and amino acids supplements: A case report.

BACKGROUND: In maternal PKU, protein substitute (PS) is provided by phenylalanine (PHE)-free l-amino acids (AA), but glycomacropeptide-based protein substitute (GMP) is an alternative consideration. OBJECTIVE: To describe the first Portuguese Maternal Phenylketonuria (MPKU) partially managed with GMP. CASE REPORT: A 31 year old MPKU female with classical PKU (mutations P281L/P281L), diagnosed by newborn screening, had a lifelong history of poor metabolic control. She has a history of partial bicornuate uterus and had a previous miscarriage in the first trimester. Pre-conception, her median blood PHE was 462 µmol/L but throughout pregnancy the median reduced to 258 µmol/L. GMP provided 30 g/day protein equivalent (46 mg/day PHE). Total protein equivalent from PS increased from 58 to 86 g/day during pregnancy but AA provided all additional protein equivalent intake. Both GMP and AA were well tolerated with no morning sickness. Normal morphologic evaluation and adequate fetal growth with cephalic biometry near the 5th percentile was determined. The infant was born at 39.3 weeks: weight 2570 g (3rd percentile), length 47.5 cm (10th percentile) and head circumference (HC) of 31.5 cm (1st percentile). In the neonatal period, the infant had craniofacial dimorphism with metopic suture prominence. Father also had bitemporal narrowing. By 12 months of age, the infant's weight (15th percentile), length (50th percentile) and HC (10th-50th percentile) were normal although bitemporal narrowing persisted. CONCLUSIONS: This is the first case reporting the use of GMP in MPKU. Its PHE content did not adversely affect metabolic control although it only provided part of the PS intake. Some intrauterine development delay occurred in the last trimester, although we consider that this is unlikely to be associated with MPKU syndrome or the use of GMP. More published data is essential to examine the impact of using GMP in MPKU on morning sickness severity and aversion, maternal weight gain, blood amino acid concentrations and variability of blood PHE concentrations.

Nutritional status in patients with phenylketonuria using glycomacropeptide as their major protein source.

BACKGROUND/OBJECTIVES: Low phenylalanine (PHE), glycomacropeptide-based protein substitute (GMP) is an alternative to traditional L-amino acid supplements (AA) used in the dietary management of phenylketonuria (PKU). In a retrospective, longitudinal study, we report the nutritional status of PKU patients taking AA and GMP. SUBJECTS/METHODS: Eleven PKU patients aged 27±10 years (1 HPA, 4 mild and 6 classical PKU) on dietary treatment were evaluated (anthropometry, body composition, blood pressure measurements, biochemical markers including vitamin, mineral, lipids, carbohydrates and protein status/metabolism, and nutritional intake assessment) at two different annual reviews. The mean time taking AA was 13±5 months and GMP 13±7 months. Blood phenylalanine (PHE) and tyrosine (TYR) were analysed before and after GMP introduction. RESULTS: Both GMP and AA protein substitutes provided similar protein equivalent intake (0.85 vs 0.75 g/kg/day, P=0.182). In the GMP group, it contributed 57% (27-100%) of the protein substitute intake (with AA delivering the rest of protein substitute intake), providing an additional 34±12 mg/day PHE. Nutritional intake, anthropometry and body composition measurements were similar in both the groups. Median blood PHE did not change (P=0.594), although values within target range improved (36 vs 46%), but this was not statistically significant. Mean blood TYR increased (52.0±19.2 vs 63.2±25.6 µmol/l, P=0.033), and all biochemical markers remained stable, except for a lower A1C haemoglobin (P=0.011). CONCLUSIONS: Partial GMP contribution to total protein substitute intake did not affect nutritional status in patients with PKU. Blood PHE control was not adversely affected. The increased blood TYR after GMP introduction necessitates further study.

Protein substitutes for phenylketonuria in Europe: access and nutritional composition.

BACKGROUND/OBJECTIVES: Protein substitutes (PS) are an essential component in the dietary management of phenylketonuria (PKU). PS are available as phenylalanine-free amino-acid mixtures (AAM), glycomacropeptide-based PS (GMP) and large neutral amino acids (LNAA). There is a lack of information regarding their availability in different countries and comparison of their nutritional composition is limited. The objectives of this study were to identify the number of PS available in different European countries and Turkey and to compare their nutritional composition. SUBJECTS/METHODS: Members of the European Nutritionist Expert Panel on PKU (ENEP) (Portugal, Spain, Belgium, Italy, Germany, Netherlands, United Kingdom, Denmark and Turkey) provided data on PS available in each country. The nutritional composition of PS available in Portugal was analyzed. RESULTS: The number of PS available in each country varied from 30 (Turkey) to 105 (Germany), with a median of 64. GMP was available only in Portugal, whereas LNAA was an option in Portugal, Italy, Turkey and Denmark. Some PS were designed for weaning. Many PS did not contain added fat and fiber. GMP contained the highest carbohydrate (CHO) and energy content as well as higher LNAA content compared with AAM. Only one AAM contained added fructo-oligosaccharides and galacto-oligosaccharides. AAM designed for the first year of life had the highest CHO, fat and LNAA contribution. Liquid AAM had lower CHO and fat contents compared with powdered AAM, but contained higher LNAA. CONCLUSIONS: There was widely dissimilar numbers of PS available in different countries. Nutritional composition of different PS was variable and should be considered before prescription.

Nutrition education tools used in phenylketonuria: clinician, parent and patient perspectives from three international surveys.

BACKGROUND: Three international surveys were developed aiming to identify the current nutrition educational tools used in the management of phenylketonuria (PKU) and the perceived effectiveness of these tools by clinicians, parents and patients. METHODS: The first two surveys were distributed through the Metabolic Dietitians ListServe (pno-metabl@listserv.cc.emory.edu), and the third survey was distributed by international clinics and the National PKU Alliance website (www.npkua.org). A total of 888 responses (S1, n = 88; S2, n = 81; S3, n = 719) were collected from all three surveys. The surveys represent participants from 17 countries, in Europe; North America (USA and Canada); Mexico; Argentina; Turkey; Australia; and Africa (Tunisia). RESULTS: A consistent decline in 'parents as role models' as an educational tool was observed starting at age 10 years. Patients responded they feel their families are the most effective form of education, whereas handouts were selected as the least effective educational tool by patients. Parents responded they feel the most effective educational tool is one-on-one counselling. Patients and parents show a desirable trend in wanting to attend group clinic, even in centres where this type of educational tool is not offered. CONCLUSIONS: There was a discrepancy between clinicians and patient views regarding the perceived effectiveness of the nutrition education tools. Future research is needed surrounding the impact nutrition education may have on improved dietary compliance in patients with PKU.

Dietary practices in pyridoxine non-responsive homocystinuria: a European survey.

BACKGROUND: Within Europe, the management of pyridoxine (B6) non-responsive homocystinuria (HCU) may vary but there is limited knowledge about treatment practice. AIM: A comparison of dietetic management practices of patients with B6 non-responsive HCU in European centres. METHODS: A cross-sectional audit by questionnaire was completed by 29 inherited metabolic disorder (IMD) centres: (14 UK, 5 Germany, 3 Netherlands, 2 Switzerland, 2 Portugal, 1 France, 1 Norway, 1 Belgium). RESULTS: 181 patients (73% >16 years of age) with HCU were identified. The majority (66%; n=119) were on dietary treatment (1-10 years, 90%; 11-16 years, 82%; and >16 years, 58%) with or without betaine and 34% (n=62) were on betaine alone. The median natural protein intake (g/day) on diet only was, by age: 1-10 years, 12 g; 11-16 years, 11 g; and >16 years, 45 g. With diet and betaine, median natural protein intake (g/day) by age was: 1-10 years, 13 g; 11-16 years, 20 g; and >16 years, 38 g. Fifty-two percent (n=15) of centres allocated natural protein by calculating methionine rather than a protein exchange system. A methionine-free l-amino acid supplement was prescribed for 86% of diet treated patients. Fifty-two percent of centres recommended cystine supplements for low plasma concentrations. Target treatment concentrations for homocystine/homocysteine (free/total) and frequency of biochemical monitoring varied. CONCLUSION: In B6 non-responsive HCU the prescription of dietary restriction by IMD centres declined with age, potentially associated with poor adherence in older patients. Inconsistencies in biochemical monitoring and treatment indicate the need for international consensus guidelines.

Micronutrient status in phenylketonuria.

Patients with phenylketonuria (PKU) encompass an 'at risk' group for micronutrient imbalances. Optimal nutrient status is challenging particularly when a substantial proportion of nutrient intake is from non-natural sources. In PKU patients following dietary treatment, supplementation with micronutrients is a necessity and vitamins and minerals should either be added to supplement phenylalanine-free l-amino acids or given separately. In this literature review of papers published since 1990, the prevalence of vitamin and mineral deficiency is described, with reference to age of treatment commencement, type of treatment, dietary compliance, and dietary practices. Biological micronutrient inadequacies have been mainly reported for zinc, selenium, iron, vitamin B12 and folate. The aetiology of these results and possible clinical and biological implications are discussed. In PKU there is not a simple relationship between the dietary intake and nutritional status, and there are many independent and interrelated complex factors that should be considered other than quantitative nutritional intake.

Dietary management of urea cycle disorders: European practice.

BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Main issues in micronutrient supplementation in phenylketonuria.

For almost all patients with PKU, a low phenylalanine diet is the basis of the treatment despite a widely varying natural protein tolerance. A vitamin and mineral supplement is essential and it is commonly added to a phenylalanine-free (phe-free) source of L-amino acids. In PKU, many phe-free L-amino acid supplements have age-specific vitamin and mineral profiles to meet individual requirements. The main micronutrient sources are chemically derived and their delivery dosage is usually advised in three or more doses throughout the day. Within the EU, the composition of VM (vitamin and mineral) phe-free L-amino acid supplements is governed by the Foods for Special Medical Purposes (FSMP) directive (European Commission Directive number 1999/21/EC and amended by Directive 2006/141/EC). However the micronutrient composition of the majority fails to remain within FSMP micronutrient maximum limits per 100 kcal due to their low energy content and so compositional exceptions to the FSMP directive have to be granted for each supplement. All patients with PKU require an annual nutritional follow-up, until it has been proven that they are not at risk of any vitamin and mineral imbalances. When non-dietary treatments are used to either replace or act as an adjunct to diet therapy, the quality of micronutrient intake should still be considered important and monitored systematically. European guidelines are required about which micronutrients should be measured and the conditions (fasting status) for monitoring.

Large neutral amino acids supplementation in phenylketonuric patients.

Phenylketonuria is an inborn error of amino acid metabolism that results in severe mental retardation if not treated early and appropriately. The traditional treatment, consisting of a low-phenylalanine diet, is usually difficult to maintain throughout adolescence and adulthood, resulting in undesirable levels of blood phenylalanine and consequent neurotoxicity. The neurotoxicity of phenylalanine is enhanced by its transport mechanism across the blood-brain barrier, which has the highest affinity for phenylalanine compared with the other large neutral amino acids that share the same carrier. The supplementation of large neutral amino acids in phenylketonuric patients has been showing interesting results. Plasma phenylalanine levels can be reduced, which may guarantee important metabolic and clinical benefits to these patients. Although long-term studies are needed to determine the efficacy and safety of large neutral amino acids supplements, the present state of knowledge seems to recommend their prescription to all phenylketonuric adult patients who are non-compliant with the low-phenylalanine diet.

Ex vivo evaluation of the percutaneous penetration of proanthocyanidin extracts from Guazuma ulmifolia using photoacoustic spectroscopy.

In this work photoacoustic spectroscopy has been applied to determine ex vivo the percutaneous penetration of proanthocyanidins present in extracts obtained from Guazuma ulmifolia, in rats. Lotion formulations containing 0.0663 mg of procyanidin B2 day(-1)animal(-1) were topically applied during 7, 10 and 13 days in each group of the animals. After the end of treatment the animals were killed, the skin dissected to remove the basal content, and the measurements were carried out as a function of the period of time of treatment. The results showed that despite the very low concentration of the active principle (procyanidin B2) in the lotion, the photoacoustic method was able to show the presence of optical absorption bands from this substance in the dermis region, evidencing once again that this method may be useful for studies of topically applied formulations of interest in the pharmacokinetic area.

Dietary medium-chain triacylglycerol prevents the postprandial rise of plasma triacylglycerols but induces hypercholesterolemia in primary hypertriglyceridemic subjects.

BACKGROUND: Previous studies showed divergent results concerning the influence of medium-chain triacylglycerol (MCT) on lipoprotein metabolism. OBJECTIVE: The objective of this study was to compare the effects of MCT and corn oil on plasma lipids in primary hypertriglyceridemic patients. DESIGN: Ten subjects ate different proportions of corn oil and MCT for 12 wk. The subjects first ate a low-fat diet for 2 wk and during the next 4 wk, corn oil was added as the sole source of fat. Thereafter, for 2-wk periods, the subjects were sequentially fed corn oil and MCT mixed in the following proportions: 3:1, 1:1, and 0:1. Fasting plasma total cholesterol, triacylglycerol, and HDL-cholesterol concentrations were measured at the end of each period. At the end of the 100%-corn oil and of the 100%-MCT periods, subjects were fed a test meal containing the respective oil (40 g fat/m(2) body surface area) and total cholesterol and triacylglycerols were measured at 2-h intervals over 8 h; fasting lipoprotein composition was also measured. RESULTS: Compared with corn oil, MCT was associated with a higher mean (+/-SD) fasting total cholesterol concentration (6.39 +/- 1.14 compared with 5.51 +/- 0.98 mmol/L, respectively; P < 0. 05); non-HDL-cholesterol concentrations were also higher with MCT (5. 36 +/- 1.11 mmol/L) than with corn oil (4.51 +/- 0.92 mmol/L; P < 0. 005). In response to the liquid test meal, plasma total cholesterol did not change with either diet but triacylglycerols increased with the 100%-corn oil diet. CONCLUSIONS: MCT prevents the risk of pancreatitis due to postprandial hypertriglyceridemia but has the inconvenience of raising total cholesterol concentrations in primary hypertriglyceridemic subjects.