Impact of pregnancy planning and preconceptual dietary training on metabolic control and offspring's outcome in phenylketonuria.

To prevent maternal phenylketonuria (PKU) syndrome low phenylalanine concentrations (target range, 120-360 µmol/L) during pregnancy are recommended for women with PKU. We evaluated the feasibility and effectiveness of current recommendations and identified factors influencing maternal metabolic control and children's outcome. Retrospective study of first successfully completed pregnancies of 85 women with PKU from 12 German centers using historical data and interviews with the women. Children's outcome was evaluated by standardized IQ tests and parental rating of child behavior. Seventy-four percent (63/85) of women started treatment before conception, 64% (54/85) reached the phenylalanine target range before conception. Pregnancy planning resulted in earlier achievement of the phenylalanine target (18 weeks before conception planned vs. 11 weeks of gestation unplanned, p < 0.001) and lower plasma phenylalanine concentrations during pregnancy, particularly in the first trimester (0-7 weeks of gestation: 247 µmol/L planned vs. 467 µmol/L unplanned, p < 0.0001; 8-12 weeks of gestation: 235 µmol/L planned vs. 414 µmol/L unplanned, p < 0.001). Preconceptual dietary training increased the success rate of achieving the phenylalanine target before conception compared to women without training (19 weeks before conception vs. 9 weeks of gestation, p < 0.001). The majority (93%) of children had normal IQ (mean 103, median age 7.3 years); however, IQ decreased with increasing phenylalanine concentration during pregnancy. Good metabolic control during pregnancy is the prerequisite to prevent maternal PKU syndrome in the offspring. This can be achieved by timely provision of detailed information, preconceptual dietary training, and careful planning of pregnancy.

[Dietary treatment of inborn errors of metabolism-a balancing act between indulgence and therapy]. / Ernährung bei angeborenen Stoffwechselerkrankungen ­ ein Spagat zwischen Genuss und Therapie.

For many inborn metabolic diseases, a lifelong diet is a crucial part of the therapy since pharmacological therapy is available for only a few conditions and patients. The implementation of a low natural protein diet with a reduced intake of natural protein and the complementary use of synthetic amino acid mixtures is described using the examples of phenylketonuria and urea cycle disorders focusing on children and adolescents. For phenylketonuria, the amino acid supplement is free of phenylalanine whereas for urea cycle disorders, it exclusively consists of essential amino acids. The dietary treatment aims to maintain metabolic stability and to prevent accumulation of toxic metabolites. At the same time, the nutritional requirements to ensure growth and development must be met. Therefore, patients need to follow strict rules regarding the choice of food products. This restrictive therapy interferes with the desire for autonomy and the joy of eating and often results in a reduced quality of life.Following the diet is crucial for a favorable outcome. To meet its requirements, patients and their families are provided with training. It is a great challenge not only to support the patients and their families in all practical aspects of dietary management, but also to motivate them to lifelong adherence in order to ensure the best possible outcome.

Hepatorenal Tyrosinaemia: Impact of a Simplified Diet on Metabolic Control and Clinical Outcome.

Background: Tyrosinaemia type 1 is a rare inherited metabolic disease caused by an enzyme defect in the tyrosine degradation pathway. It is treated using nitisinone and a low-protein diet. In a workshop in 2013, a group of nutritional specialists from Germany, Switzerland and Austria agreed to advocate a simplified low-protein diet and to allow more natural protein intake in patients with tyrosinaemia type 1. This retrospective study evaluates the recommendations made at different treatment centers and their impact on clinical symptoms and metabolic control. Methods: For this multicenter study, questionnaires were sent to nine participating treatment centers to collect data on the general therapeutic approach and data of 47 individual patients treated by those centers. Results: Dietary simplification allocating food to 3 categories led to increased tyrosine and phenylalanine blood concentrations without weighing food. Phenylalanine levels were significantly higher in comparison to a strict dietary regimen whereas tyrosine levels in plasma did not change. Non-inferiority was shown for the simplification and liberalization of the diet. Compliance with dietary recommendations was higher using the simplified diet in comparison to the stricter approach. Age correlates negatively with compliance. Conclusions: Simplification of the diet with increased natural protein intake based on three categories of food may be implemented in the diet of patients with tyrosinaemia type 1 without significantly altering metabolic control. Patient compliance is strongly influencing tyrosine blood concentrations. A subsequent prospective study with a larger sample size is necessary to get a better insight into the effect of dietary recommendations on metabolic control.

Dietary practices in methylmalonic acidaemia: a European survey.

Background The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim To describe the dietary management of patients with MMA across Europe. Methods A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0-6 months; 7-12 months; 1-10 years; 11-16 years; >16 years). Results Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice.

Management of three preterm infants with phenylketonuria.

Providing adequate amounts of protein in preterm infants suffering from a metabolic disease that requires a reduced intake of natural protein is challenging. Phenylketonuria (PKU) is an inborn error of metabolism affecting the enzymatic conversion of phenylalanine to tyrosine. The dietary treatment of PKU aims to lower phenylalanine concentrations in the blood by implementing a low-phenylalanine diet restrictive in natural protein. We describe the nutritional management of three preterm infants, two with very low birth weight, with PKU detected by newborn screening. All three infants tolerated high amounts of phenylalanine; two were breastfed unrestrictedly during late prematurity. We show that nutrition of preterm infants with PKU according to recommendations of early and intensive nutrition with a high intake of protein is feasible even in infants with impaired enteral feeding. Due to a high phenylalanine tolerance of PKU infants during prematurity, there is no need for a phenylalanine-free parenteral amino acid mixture. During the catabolic state of prematurity preterm infants with PKU have phenylalanine requirements comparable to healthy preterm infants.

Long-Term Growth in Phenylketonuria: A Systematic Review and Meta-Analysis.

There is an ongoing debate regarding the impact of phenylketonuria (PKU) and its treatment on growth. To date, evidence from studies is inconsistent, and data on the whole developmental period is limited. The primary aim of this systematic review was to investigate the effects of a phenylalanine (Phe)-restricted diet on long-term growth in patients with PKU. Four electronic databases were searched for articles published until September 2018. A total of 887 results were found, but only 13 articles met eligibility criteria. Only three studies had an adequate methodology for meta-analysis. Although the results indicate normal growth at birth and during infancy, children with PKU were significantly shorter and had lower weight for age than reference populations during the first four years of life. Impaired linear growth was observed until the end of adolescence in PKU. In contrast, growth impairment was not reported in patients with mild hyperphenylalaninemia, not requiring dietary restriction. Current evidence indicates that even with advances in dietary treatments, "optimal" growth outcomes are not attained in PKU. The majority of studies include children born before 1990s, so further research is needed to show the effects of recent dietary practices on growth in PKU.

A series of three case reports in patients with phenylketonuria performing regular exercise: first steps in dietary adjustment.

Background Phenylketonuria (PKU), a rare, inherited metabolic condition, is treated with a strict low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitute. The optimal nutritional management of a sporting individual with PKU has not been described. Therefore, guidelines for the general athlete have to be adapted. Case presentation Three clinical scenarios of sporting patients with PKU are given, illustrating dietary adaptations to usual management and challenges to attain optimal sporting performance. Therefore, the main objectives of sports nutrition in PKU are to (1) maintain a high carbohydrate diet; (2) carefully monitor hydration status; and (3) give attention to the timing of protein substitute intake in the immediate post-exercise recovery phase. Optimal energy intake should be given prior to, during and post exercise training sessions or competition. Fortunately, a usual low-Phe diet is rich in carbohydrate, but attention is required on the types of special low-protein foods chosen. Acute exercise does not seem to influence blood Phe concentrations, but further evidence is needed. Summary Well-treated PKU patients should be able to participate in sports activities, but this is associated with increased nutritional requirements and dietary adjustments. Conclusions It should be the goal of all sporting patients with PKU to maintain good metabolic Phe control and attain maximal athletic performance.

Weight Management in Phenylketonuria: What Should Be Monitored.

BACKGROUND: Severe intellectual disability and growth impairment have been overcome by the success of early and continuous treatment of patients with phenylketonuria (PKU). However, there are some reports of obesity, particularly in women, suggesting that this may be an important comorbidity in PKU. It is becoming evident that in addition to acceptable blood phenylalanine control, metabolic dieticians should regard weight management as part of routine clinical practice. SUMMARY: It is important for practitioners to differentiate the 3 levels for overweight interpretation: anthropometry, body composition and frequency and severity of associated metabolic comorbidities. The main objectives of this review are to suggest proposals for the minimal standard and gold standard for the assessment of weight management in PKU. While the former aims to underline the importance of nutritional status evaluation in every specialized clinic, the second objective is important in establishing an understanding of the breadth of overweight and obesity in PKU in Europe. KEY MESSAGES: In PKU, the importance of adopting a European nutritional management strategy on weight management is highlighted in order to optimize long-term health outcomes in patients with PKU.

Human lactation: oxidation and maternal transfer of dietary (13)C-labelled α-linolenic acid into human milk.

The origin of fatty acids in milk has not been elucidated in detail. We investigated the contribution of dietary α-linolenic acid (ALA) to human milk fat, its oxidation and endogenous conversion to long-chain polyunsaturated fatty acids. Ten lactating women were given (13)C-ALA orally, and breath and milk samples were collected for a five-day period, while dietary intakes were assessed. 37.5 ± 2.7 % (M ± SE) of the tracer was recovered in breath-CO2, and 7.3 ± 1.1 % was directly transferred into milk. About 0.25 % of the tracer was found in milk long-chain polyunsaturated fatty acids. Combining intake and milk data, we estimate that about 65 % of milk ALA is directly derived from maternal diet. Thus, the major portion of milk ALA is directly derived from the diet, but dietary ALA does not seem to contribute much as a precursor to milk n-3 long-chain polyunsaturated fatty acids within the studied time period.

Special low protein foods for phenylketonuria: availability in Europe and an examination of their nutritional profile.

BACKGROUND: Special low protein foods (SLPF) are essential in the nutritional management of patients with phenylketonuria (PKU). The study objectives were to: 1) identify the number of SLPF available for use in eight European countries and Turkey and 2) analyse the nutritional composition of SLPF available in one of these countries. METHODS: European Nutritionist Expert Panel on PKU (ENEP) members (Portugal, Spain, Belgium, Italy, Germany, Netherlands, UK, Denmark and Turkey) provided data on SPLF available in each country. The nutritional composition of Portuguese SLPF was compared with regular food products. RESULTS: The number of different SLPF available in each country varied widely with a median of 107 [ranging from 73 (Portugal) and 256 (Italy)]. Food analysis of SLPF available from a single country (Portugal) indicated that the mean phenylalanine content was higher in low protein baby cereals (mean 48 mg/100 g) and chocolate/energy bars/jelly (mean 41 mg/100 g). The energy content of different foods from a sub-group of SLPF (cookies) varied widely between 23 and 96 kcal/cookie. Low protein bread had a high fat content [mean 5.8 g/100 g (range 3.7 to 10)] compared with 1.6 g/100 g in regular bread. Seven of the 12 SLPF sub-groups (58 %) did not declare any vitamin content, and only 4 (33 %) identified a limited number of minerals. CONCLUSIONS: Whilst equal and free access to all SLPF is desirable, the widely variable nutritional composition requires careful nutritional knowledge of all products when prescribed for individual patients with PKU. There is a need for more specific nutritional standards for special low protein foods.

Optimising growth in phenylketonuria: current state of the clinical evidence base.

Patients with phenylketonuria (PKU) must follow a strict low-phenylalanine (Phe) diet in order to minimise the potentially disabling neuropsychological sequelae of the disorder. Research in this area has unsurprisingly focussed largely on managing blood Phe concentrations to protect the brain. Protein requirements in dietary management of PKU are met mostly from Phe-free protein substitutes with the intake of natural protein restricted to patient tolerance. Several reports have suggested that growth in early childhood in PKU is sub-optimal, relative to non-PKU control groups or reference populations. We reviewed the literature searching for evidence regarding PKU and growth as well as possible links between dietary management of PKU and growth. The search retrieved only limited evidence on the effect of PKU and its dietary management on growth. Physical development in PKU remains an under-studied aspect of this disorder.

Adjusting diet with sapropterin in phenylketonuria: what factors should be considered?

The usual treatment for phenylketonuria (PKU) is a phenylalanine-restricted diet. Following this diet is challenging, and long-term adherence (and hence metabolic control) is commonly poor. Patients with PKU (usually, but not exclusively, with a relatively mild form of the disorder) who are responsive to treatment with pharmacological doses of tetrahydrobiopterin (BH4) have either lower concentrations of blood phenylalanine or improved dietary phenylalanine tolerance. The availability of a registered formulation of BH4 (sapropterin dihydrochloride, Kuvan®) has raised many practical issues and new questions in the dietary management of these patients. Initially, patients and carers must understand clearly the likely benefits (and limitations) of sapropterin therapy. A minority of patients who respond to sapropterin are able to discontinue the phenylalanine-restricted diet completely, while others are able to relax the diet to some extent. Care is required when altering the phenylalanine-restricted diet, as this may have unintended nutritional consequences and must be undertaken with caution. New clinical protocols are required for managing any dietary change while maintaining control of blood phenylalanine, ensuring adequate nutrition and preventing nutritional deficiencies, overweight or obesity. An accurate initial evaluation of pre-sapropterin phenylalanine tolerance is essential, and the desired outcome from treatment with sapropterin (e.g. reduction in blood phenylalanine or relaxation in diet) must also be understood by the patient and carers from the outset. Continuing education and support will be required thereafter, with further adjustment of diet and sapropterin dosage as a young patient grows.

Dietary management practices in phenylketonuria across European centres.

BACKGROUND: Dietary phenylalanine restriction is the cornerstone of phenylketonuria (PKU) management. However, there are no European consensus guidelines for its optimal dietary care. METHODS: Detailed information on the routine dietary management of PKU was obtained from 10 European centres using structured questionnaires. Each centre was represented by one dietitian/nutritionist or physician (European Nutritionist Expert Panel). RESULTS: All centres screened for PKU within the first 10 days of life. PKU prevalence was highest in Turkey. The training, roles and responsibilities of dietitians and nutritionists varied widely; in some centres dietitians were responsible for managing the diet, while in others this was performed by a physician. There were marked differences in target blood phenylalanine concentrations, the dosages of protein substitutes, systems for allocating daily phenylalanine allowance, and the definition of foods that could be eaten without restriction ('free foods'). Eighty percent (n=8/10) of centres encouraged breastfeeding together with protein substitute in infants with PKU. CONCLUSIONS: Important differences exist among centres across Europe in the dietary management of PKU, and in support systems designed to assist patients in managing their diets. Further studies are needed to compare different dietary treatments with the aim of identifying best practice to optimise phenylalanine control and dietary adherence.