A. Daly

Protein substitute dosage in pku: How much do young patients need?

Background: The optimal dose of protein substitute has not been determined in children with phenylketonuria (PKU). Aim: To determine if a lower dose of protein substitute could achieve the same or better degree of blood phenylalanine control when compared to the dosage recommended by the UK MRC.1 Methods: In a six week randomised, crossover study, two doses of protein substitute (Protocol A: 2 g/kg/day of protein equivalent; Protocol B: 1.2 g/kg/day protein equivalent) were compared in 25 children with well controlled PKU aged 2–10 years (median 6 years). Each dose of protein substitute was taken for 14 days, with a 14 day washout period in between. Twice daily blood samples (fasting pre-breakfast and evening, at standard times) for plasma phenylalanine were taken on day 8–14 of each protocol. The median usual dose of protein substitute was 2.2 g/kg/day (range 1.5–3.1 g/kg/day). Results: When compared with control values, median plasma phenylalanine on the low dose of protein substitute increased at pre-breakfast by 301 μmol/l (95% CI 215 to 386) and in the evening by 337 μmol/l (95% CI 248 to 431). On the high dose of protein substitute, plasma phenylalanine concentrations remained unchanged when compared to control values. However, wide variability was seen between subjects. Conclusions: A higher dosage of protein substitute appeared to contribute to lower blood phenylalanine concentrations in PKU, but it did have a variable and individual impact and may have been influenced by the carbohydrate (+/− fat) content of the protein substitute.

Protein substitutes for PKU: What's new?

Summary: Protein substitutes are an essential component in the management of phenylketonuria. A series of studies at Birmingham Childrens Hospital have investigated their optimal dosage, timing and practical administration as well as the efficacy and tolerance of novel protein substitutes. The key findings are as follows. (1) Lower dosages of protein substitute (1.2 g/kg per day of protein equivalent) adversely affect blood phenylalanine control in children aged 1–10 years. (2) There is wide variability in 24 h blood phenylalanine concentrations. (3) Adjusting protein substitute timing during daytime does not reduce blood phenylalanine variability. (4) Repeated 4 h administration of protein substitute throughout 24 h markedly reduces phenylalanine variability and leads to lower phenylalanine concentrations. (5) The new, concentrated, low-volume protein substitutes and amino acid tablet preparations are efficacious and well tolerated by patients. (6) Administration of protein substitute as a gel or paste has reduced difficulties with administration of protein substitute in children. These findings are important in rationalizing treatment strategies, improving patient compliance and overall in improving blood phenylalanine control.

Breast feeding in IMD

SummaryBreast feeding has proven benefits for many infants with inherited metabolic disorders (IMDs) but, with the exception of phenylketonuria, there are few reports in other conditions. A questionnaire, completed by dietitians and clinicians from 27 IMD centres from 15 countries (caring for a total of over 8000 patients with IMDs on diet) identified breast feeding experience in IMD. Successful, demand breast feeding (in combination with an infant amino acid formula free of precursor amino acids) was reported in 17 infants with MSUD, 14 with tyrosinaemia type I, and 5 with homocystinuria. Eighty-nine per cent were still breast fed at 16 weeks. Fewer infants with organic acidaemias were demand breast fed (7 with propionic acidaemia; 6 with methylmalonic acidaemia and 13 with isovaleric acidaemia) (usually preceded by complementary feeds of a protein-free infant formula or infant amino acid formula free of precursor amino acids). Only 12 infants with urea cycle disorders were given demand breast feeds, but this was unsuccessful beyond 8 days in CPS deficiency. Further work is needed in developing guidelines for feeding and for clinical and biochemical monitoring for breast-fed infants with IMDs.

The micronutrient status of patients with phenylketonuria on dietary treatment: an ongoing challenge.

Background: In phenylketonuria (PKU), phenylalanine-free L-amino acid supplements are the major source of dietary micronutrients. Methods: Four hundred fifty-two retrospective annual/bi-annual non-fasting blood samples for nutritional markers (plasma zinc, selenium, and serum folate) from 78 subjects aged 1-16 years (median number of blood samples: 6, range 1-14) were analysed over 12 years. Longitudinal blood result data were available for 51 subjects (65%). The dietary intake from supplements was calculated. Results: The median intakes of all of the micronutrients studied were >200% of the reference nutrient intakes (RNI). There was no statistical correlation between dietary intake and nutritional markers outside of the normal reference range (RR) except for selenium, but there was a correlation between a lower plasma zinc, plasma selenium and haemoglobin status and better blood phenylalanine control in 1- to 4-year-old children. On at least one occasion, the individual plasma concentrations of zinc (71%, n = 54/76) and selenium (21%, n = 16/75) were below the RR; however, the concentrations of selenium (41%, n = 31/75) and serum folate (83%, n = 34/41) were also above the RR. Dietary intakes exceeded the upper tolerable intakes for zinc and copper (32%, n = 25) and folate (65%, n = 51). Individual longitudinal data demonstrated little change in micronutrient status over time. Conclusions: In PKU, biochemical micronutrient deficiencies are common despite micronutrient intakes above the RNI. Further study of the nutritional profiling of L-amino acid supplements in PKU is needed.

A new, low-volume protein substitute for teenagers and adults with phenylketonuria

Summary: Some older patients with phenylketonuria (PKU) fail to consume their protein substitute (with or without vitamin and mineral supplements) in prescribed amounts, which contributes to poor blood phenylalanine control. PKU Express (Vitaflo), is a new low-volume (amino acids 72 g/100 g), low-carbohydrate, phenylalanine-free protein substitute with added vitamins and minerals designed for people with PKU over 8 years of age. In an open intervention study, the aim was to investigate its acceptability and effectiveness in a group of teenagers and adults with PKU. Twenty-three subjects (15 female; 8 male) with PKU, who had a median age of 17 years (range 8–37 years) took the substitute for 8weeks. A 3-day prospective diet diary, height, weight, plasma amino acids, biochemical and haematological nutritional analytes were measured at weeks 0 and 8. Skin-puncture bloods for plasma phenylalanine were collected every 2 weeks. The median weight of protein substitute (with or without vitamin and mineral supplements) consumed decreased by 33% from 150 g (range 140–180) daily to 100 g (range 100–125) daily (p<0.001). Median change in energy intake decreased by a median of 10% (95% CI 2.0 to 18.0) when compared to intake on original protein substitute. On PKU Express, the intakes of all nutrients exceeded the dietary reference values but none was excessively high. Blood phenylalanine decreased by a mean of 37 µmol/L (95% CI-27 to 102) during the trial. Body mass index decreased in 40% of subjects. Changes in blood phenylalanine or body mass index were not statistically significant. Most of the nutritional, haematological and biochemical indices stayed within normal reference ranges for the analytes studied. Sixteen (70%) of the subjects had low plasma selenium at the start, but only 13 (57%) at the study end. Plasma vitamin B12 was high in 8 subjects at the start of the study and 9 at the end. Twenty-one subjects (96%) stated that the product was convenient and easy to prepare. However, 7 (32%) described the smell and 9 (46%) the texture as the same as or worse than those of previous protein substitutes. Because of the use of the premeasured sachets, some subjects were able to prepare their own protein substitute for the first time. PKU Express is a safe, efficacious, protein substitute that significantly reduces the daily volume of prescribed protein substitute.

Fibre content of enteral feeds for the older child

BACKGROUND There is currently a lack of clinical data on fibre requirements in UK children. Subsequently, the ideal fibre profile for enteral formulae designed to meet the requirements of older children is unknown. The present study aimed to investigate the effect of fibre supplementation on gastrointestinal function of children aged 7-12 years (or weight 21-45 kg) receiving an age-specific high-energy enteral feed. METHODS In this double-blind randomised crossover study, 25 home enterally tube-fed children with a range of medical conditions (including cystic fibrosis, neurological conditions, liver transplant and bone marrow transplant) were given a 1.5 kcal mL(-1) formula with or without added dietary fibre (1.13 g per 100 mL). Each formula was taken for 6 weeks, followed by 6 months on the second randomly assigned formula. Anthropometry, blood biochemistry, stool characteristics, tolerance and oral dietary intake were assessed. RESULTS Despite a higher median fibre intake on the fibre-containing formula (84% versus 26% of recommended intake; P = 0.003), most children did not meet existing international recommendations for fibre as a result of small feed volumes (median 800 mL day(-1); 9 g fibre day(-1)). There was some evidence of reduced constipation, laxative reliance and abdominal pain on the fibre-containing formula. CONCLUSIONS Given the poor fibre intakes and absence of adverse effects, the use of fibre-containing formulae should become standard practice for the majority of children on enteral feeds. Larger trials in children are required to further evaluate the effect of amount and blend of fibre in enteral formulae for older children. However, it is likely that current formulae require higher levels of fibre.

Long-term efficacy of ‘ready-to-drink’ protein substitute in phenylketonuria

BACKGROUND In phenylketonuria (PKU), protein substitute is an essential part of dietary treatment. Short-term studies have demonstrated that liquid protein substitutes (LPS) are efficacious, and improve compliance in teenagers and adults with PKU, although there are no data available to demonstrate that their effectiveness is sustained over time. The present retrospective study aimed to evaluate the long-term efficacy of ready-to-drink protein substitute in a group of people with PKU. METHODS Thirty-four patients (17 females and 17 males, median age 14.9 years, range 7.2-53.8 years) with PKU on dietary management were recruited from Birmingham Childrens Hospital. All patients who were taking a LPS for a median of 2.4 years (range 6 months to 4.1 years), had their plasma phenylalanine concentrations, anthropometric and nutritional biochemical markers reviewed, both before and when taking the LPS. RESULTS There was a significant improvement in median plasma phenylalanine (P < 0.05), vitamin B(12) (P < 0.01), calcium (P < 0.05) and albumin (P < 0.05) concentrations in subjects (n = 13) aged >18 years when taking the LPS. In the children aged 7-18 years (n = 21), median plasma phenylalanine concentrations were maintained on LPS. Their plasma selenium concentrations (P < 0.05) deteriorated, but calcium (P < 0.05), albumin (P < 0.01), haemoglobin (P < 0.01) and haematocrit (P < 0.01) significantly improved. CONCLUSIONS This retrospective review suggested that, in adult patients, the long-term use of LPS is associated with better compliance by lowering blood phenylalanine and improving nutritional biochemical markers.

Diurnal variation of phenylalanine concentrations in tyrosinaemia type 1: should we be concerned?

BACKGROUND Tyrosinaemia type 1 (HT1) is treated with a tyrosine and phenylalanine-restricted diet, amino acids free of phenylalanine and tyrosine, and nitisinone (NTBC). Treatment guidelines recommend plasma tyrosine between 200-400 μm and phenylalanine at least >30 μm. There is little information on the diurnal variation of plasma tyrosine or phenylalanine in HT1. Low plasma phenylalanine <30 μm may be associated with poor growth and cognitive delay. The present study aimed to document diurnal variation of tyrosine and phenylalanine plasma concentrations and growth in children with HT1. METHODS Median tyrosine and phenylalanine plasma concentrations were reviewed retrospectively over 3 years in 11 subjects (median age 4 years) with HT1. Subjects routinely collected morning fasting blood samples but afternoon nonfasted samples were taken in the clinic (<10% of samples). Growth Z-scores were calculated. RESULTS The percentage of all plasma phenylalanine concentrations <30 μm was 8.6% and <40 μm was 13.6%. Only 2% of fasting morning phenylalanine concentrations were <30 μm, compared to 83% of nonfasting afternoon samples. All but one child had a height Z-score <0. CONCLUSIONS Blood phenylalanine concentrations were consistently lower in the afternoon. Taking blood samples at variable time points in the day may lead to variation in interpreting dietary control. A detailed study is necessary to examine the 24-h diurnal variation of plasma phenylalanine and tyrosine in HT1. It is possible that phenylalanine concentrations may be very low for a substantive time over 24 h and the potential impact that this may have on cognitive development and growth in children is unknown.

Accuracy of home enteral feed preparation for children with inherited metabolic disorders

BACKGROUND Many children with rare chronic disorders require home enteral tube feeds (HETF) consisting of multiple modular ingredients. Feeds are often complex and the risk of errors during their preparation is high. The consequences of over- or under-concentration can be critical. The aim of the present prospective observation study was to assess the accuracy, skills and technique of caregivers when preparing and administering HETF. METHODS Fifty-two HETF patients (median age 7.5 years, range 0.7-18.0 years) with inherited metabolic disorders (IMD) requiring special feeds were recruited. Using observation and a structured questionnaire, a practical assessment of feed preparation and storage by the main caregiver was undertaken by an independent dietitian and nurse in the childs home, including hygiene practices, accuracy of measuring recipe ingredients, and storage of both ingredients and prepared feeds. RESULTS The majority (85%; n = 44) of feeds were based on >1 ingredient (median 3; range 1-6). Almost half (48%; n = 25) of caregivers measured feed ingredients inaccurately. Of the 31% (n = 16) using scoops, 31% used incorrect measuring spoons and 25% did not level scoops appropriately. Some 45% (n = 20/44) of carers measured liquid ingredients inaccurately. Hygiene practices during feed preparation were poor, including a lack of hand washing (31%: n = 16) and incorrect storage procedures for unused feed ingredients (56%; n = 29). CONCLUSIONS Practices in the preparation of modular HETF for children with IMD were not ideal. A combination of inaccuracy, poor hygiene, inappropriate storage, and long feed hanging times increases both metabolic and microbial risk. Better education, regular monitoring and the development of ready-to-use or preweighed ingredients would be beneficial.

Errors in emergency feeds in inherited metabolic disorders: a randomised controlled trial of three preparation methods

Objective Glucose polymer-based emergency feeds (EF), used during illness to prevent metabolic decompensation and encephalopathy in inherited metabolic disorders, should be produced accurately and safely. Design In a randomised, prospective, controlled study, the aim was to investigate if when preparing age-appropriate EF, a pre-measured sachet of glucose polymer, compared with scoops and weighing (using digital scales), decreased carer errors. Subjects 47 carers (3 men, 44 women) of 52 inherited metabolic disorders patients were recruited. Setting and intervention The carers made EF using all three techniques (weighing, scoops and pre-measured sachets) under supervision in controlled and home conditions. A 100-ml aliquot of each EF was analysed for carbohydrate concentration. Results Under controlled preparation conditions, with 1 litre EFs, the % median glucose polymer concentration closest to target amounts was (1) pre-measured sachets (105%), (2) weighing (107%) and (3) scoops (118%; p<0.001). Similarly, under home conditions, the closest method was (1) pre-measured sachets (111%), (2) weighing (112%) and (3) scoops (118%; p<0.05). Under home preparation conditions, with 200 ml EFs, the pre-measured sachets were more likely to be within 20% of target weight than weighing (p<0.05), but there was no difference with scoops. Common errors observed were inaccurate water measurements (40% controlled and home conditions), incorrect scoop measurements and difficulty using digital scales. Conclusions Overall, using pre-measured sachets was more accurate in EF production. Pre-measured sachets are likely to decrease preparation error and, therefore, reduce the risk of feed intolerance, particularly osmotic diarrhoea and consequential metabolic decompensation and encephalopathy.