How does pku impact dietary recommendations

Children with untreated PKU suffer from severe physical and mental disability. Postnatal diagnosis by newborn screening and immediate initiation of a lifelong protein-restricted diet with substitution of a phe-free amino acid mixture result in normal cognitive development. The tolerated amount of phe is determined by the plasma phe concentration, which has to be monitored on a regular basis.

It depends on the residual activity of phe hydroxylase, and the patient's age and weight Scriver et al. As natural protein contains fairly high amounts of phe, almost all foods have to be severely restricted. This includes even those that are not typically regarded as protein providers, such as fruits and vegetables. It is therefore common practice in Germany and many other, but not all, countries to calculate phe intake from all foods to achieve tolerable phe plasma concentrations Burgard et al.

Living on a strict diet adversely influences the quality of life. As a consequence, eating disorders are not uncommon in PKU patients Burgard et al. If dietary restrictions can be eased without compromising metabolic control, this can be expected to improve the quality of life and may even enhance compliance. Such modifications will primarily affect those foods containing only small amounts of phe.

Although it is common practice in many European countries to restrict fruits and vegetables in the PKU diet Ahring et al. Fruits and vegetables contain little protein and carry the additional advantage of providing vitamins and being rich in dietary fibre. The latter may even inhibit complete resorption of protein Gilani et al. A study performed earlier with standardized meals demonstrated that it is safe to omit fruits and vegetables when calculating the daily phe tolerance Macdonald et al.

We wondered if this result also applies in a less-controlled everyday situation. We therefore conducted an open clinical trial on outpatients in order to analyse if the PKU diet can be eased with respect to fruit and vegetable intake for a limited time without compromising metabolic control.

The presented clinical trial was planned and carried out as an open trial in patients with classical PKU. The protocol was reviewed by the ethics committee of the University of Leipzig, Germany. Patients with additional diseases or abnormal signs at the general or neurological examination were excluded. At study entry, a 3-day diet diary was maintained by the parents and phe concentration in a dried-blood sample was determined daily. During this time, dietary control was followed according to the individual phe tolerance.

All food intake was included in the phe calculation. The target total protein intake, including protein from natural foods and protein substitutes, was calculated according to the recommendations of the German Society of Nutrition Deutsche Gesellschaft fuer Ernaehrung, Patients were instructed to continue on the specific protein substitute that they were using before the study.

On day 4 visit 1 , the patients were randomized and either continued on restricted consumption of fruits and vegetables, or started on a period of free fruits and vegetables study phase 1. On day 18 visit 2 , patients switched over to the other type of diet, for another 2 weeks study phase 2. No standardized meals were given throughout the study.

During restricted fruit and vegetable consumption, the patients followed the classic treatment of PKU. All foods were weighed and the phe content was calculated.

The amount of daily phe allowed was according to the individual tolerance. The phe-free amino-acid mixture was given in three portions throughout the day as advised by the treating physician. During free fruit and vegetable consumption, the patients were allowed to eat as much fruits and vegetables as they liked. The phe content of fruits and vegetables was not included in calculation of their daily tolerance.

However, the patients were advised to fully adhere to the same individual phe tolerance. They were not specifically asked to increase their consumption of fruits and vegetables, but were encouraged to do so if they liked. All other foods were again weighed and the phe content was calculated. The patients were instructed to remain on the same dosage of phe-free amino acid mixture as during the study phase with restricted intake of fruit and vegetables.

To investigate metabolic control, dried-blood phe content was analysed daily in a sample taken between and hours after an overnight fast. In addition, diet diaries were recorded on days 5, 6, 15, 16 and 17 study phase 1 , as well as on days 19, 20, 29, 30 and 31 study phase 2 Figure 1. Study design. Randomization of the patients at visit 1. Depending on the study arm beginning, the study was conducted in the group of free or restricted fruit and vegetable consumption.

After 14 days visit 2 change of regimen as indicated cross-over design. Evaluation of all data at visit 3. DD, diet diary; Phe DB, phenylalanine concentration in dried blood. A total of 28 PKU patients aged 2—10 years and treated at this center were screened for participation in the study.

Of these, 16 PKU patients met the inclusion criteria and were enrolled; two had to be excluded during the study Table 1. Fourteen patients completed the protocol mean age 5. The diagnosis of PKU had been established by newborn screening and was confirmed by further clinical testing and molecular genetics.

Dietary treatment had been initiated within the first 3 weeks of life in all patients. Patients were regularly followed up in our clinic for inborn metabolic diseases and adhered to a strict protein-restricted diet. All patients continued to use the same powdered phe-free amino-acid mixtures as before the study entry, of which some did and some did not contain vitamin C. Only foods actually eaten were recorded in the diary.

Intake of energy, protein, phe, carbohydrates, fat, vitamin C, fruits and vegetables was calculated as percentage of the recommendations issued by the German Research Institute of Child Nutrition Kersting and Alexy, All parents were familiar with the proper technique, having been trained during the newborn period of the patients. It may be the only treatment or used in combination with drug treatments.

This diet manual describes the practical application of the European PKU guidelines [ 1 ]. It provides additional references supporting the practical recommendations as listed in the European PKU Guidelines [ 1 ]. All protein substitutes are phenylalanine-free or very low in phenylalanine. Attainment of normal growth and nutritional status.

This is achieved by ensuring that the diet contains a balanced intake of all nutrients and energy. Vitamins and minerals supplements are either added to the protein substitute or given as a separate supplement.

Phenylalanine is an amino acid found in natural protein. Different foods contain different amounts of phenylalanine. In animal e. This means that the phenylalanine content of these foods can be estimated from the food protein labelling, without knowing the phenylalanine content.

Many fruits and vegetables have been analysed specifically for their phenylalanine content [ 2 , 3 , 4 ]. Phenylalanine tolerance is the amount of phenylalanine that can be eaten by an individual with PKU whilst maintaining blood phenylalanine concentrations within the target treatment range. It is also influenced by growth, pregnancy, and catabolic state during illness.

Initial phenylalanine tolerance is established in early infancy, with the amount of breast milk or standard infant formula being titrated with the blood phenylalanine levels.

In practice, it is better for individuals if their phenylalanine is maximized according to individual tolerance. The more phenylalanine that is tolerated, the more acceptable the diet will be, and it will ease the practical and social burden that the diet demands. Additionally, more natural protein will bring nutritional benefits. Physiologically, natural nutrients are more likely to be more efficiently utilized.

There is evidence to suggest that some individuals with PKU may tolerate more phenylalanine than they have been prescribed by their health professionals [ 8 , 9 , 10 ]. The only way that this can be tested is to systematically challenge individuals with additional phenylalanine.

It is particularly important that patients fully adhere with their prescribed dose of protein substitute as this will help stimulate protein synthesis. If blood phenylalanine levels remain within the lower half of the target blood phenylalanine range for a further 3 consecutive blood phenylalanine levels, consideration should be given to repeating this process. If blood phenylalanine levels increase above target range, then additional phenylalanine should be removed, and the patients should return to the original prescribed amount of phenylalanine.

These dietary changes should always be done under the supervision of a metabolic dietitian or physician. All individuals with PKU should be allocated a daily allowance of phenylalanine according to their individual tolerance. Throughout Europe, health professionals may use one of five systems to calculate the amount of phenylalanine eaten each day and all systems achieve acceptable blood phenylalanine control. This means they are not calculated as part of the daily phenylalanine analysis.

Examples of how to calculate the phenylalanine in each system are given in Appendix 1. For regular manufactured foods e. This can be challenging as sometimes protein labelling is confusing. Specific considerations when using protein labelling are given in Table 1. No studies have been conducted to give an indication of how much dietary change is needed when blood phenylalanine levels have been consistently above target range for many years.

The degree of change necessary may vary from individual to individual and will also be influenced by the presence of catabolism, growth and pregnancy. It may be that for some patients, strict adherence with the existing dietary prescription is enough to achieve the European PKU Guidelines target ranges.

Other patients may need a significant reduction in their phenylalanine intake. Several steps may be necessary to achieve blood phenylalanine concentrations within target recommendations:. Carefully document all intake of food, drink and protein substitute. Any dietary adjustment should be supervised by the health care team. If a patient is eating an unrestricted diet i. The minimum phenylalanine intake for adults with PKU remains undefined.

During any dietary change it is important to monitor blood phenylalanine levels regularly. Weekly blood spots are recommended. Giving adequate energy intake from very low protein sources is essential to meet energy requirements and to minimise catabolism that can lead to poor blood phenylalanine control.

There are many regular foods which are naturally very low in protein that can be eaten without measurement. These fruit and vegetable sources are not calculated in the daily phenylalanine allowance list of suitable fruits and vegetables in Table 3 , and are given without restriction.

Potatoes are an exception see Phenylalanine allocation in the diet section. Patients using sapropterin have less need for special low protein foods. The provision of an adequate dose of protein substitute, usually based on phenylalanine-free amino acids supplements, is essential to promote normal growth, prevent protein deficiency, provide a source of tyrosine, and help optimise blood phenylalanine control [ 1 ].

However, this amount is arbitrary and unconfirmed by research. If an individual with PKU is obese, the protein substitute requirement should be based on ideal body weight although this is an arbitrary measure, it is probably the most practical.

It is advised to give the protein substitute in small frequent doses, 3—4 times evenly throughout the day, rather than once or twice-daily [ 14 ].

This should be taken together with natural protein and a carbohydrate source [ 15 ]. Protein substitutes are in the form of amino acid powders, capsules, tablets, bars and liquids and may contain added carbohydrate, fat, vitamins and minerals.

The general types and features of protein substitutes are outlined in Table 4. Protein substitute adherence is an issue and it is important that a choice of age and nutritionally appropriate types and presentations are offered. Protein substitutes based on amino acids have a high osmolality. Osmolality is the concentration of a solution expressed as the total number of solute particles per kilogram. Products with a high osmolality may lead to delayed gastric emptying and cause diarrhoea.

Therefore, it is recommended that extra water is given with each dose of protein substitute, particularly if they are given more concentrated than recommended by the manufacturer. When water is added to a powdered protein substitute, the tyrosine is hydrophobic and forms an insoluble layer at the top of the solution making the product less acceptable.

Using a shaker beaker should produce a homogenous mixture. Ideally, all protein substitutes should be prepared immediately prior to use. Some preparations contain starch that thickens with time. Protein substitute quality may be less acceptable if it is close to its shelf life date or stored in warm conditions.

This is a low phenylalanine protein that is used as a protein substitute in PKU. It is a by-product of cheese whey, and although theoretically phenylalanine-free, due to the extraction process, some residual phenylalanine remains in the manufactured product. In humans, there is evidence that CGMP has a better taste, improves satiety and improves nitrogen retention.

In animal PKU mice studies, there is suggestion that CGMP reduces blood phenylalanine in the brain, improves bone health and acts as prebiotic [ 16 ]. One supplier provides most of the CGMP protein; this provides 1. However, it is now established that CGMP, when given for the entire dose of protein substitute, increases blood phenylalanine levels in well treated children with PKU, so care should be taken when replacing amino acids with CGMP [ 18 ].

Nevertheless, children with milder forms of PKU or on sapropterin therapy with a higher natural protein tolerance should tolerate the extra phenylalanine provided by CGMP. No significant increase in blood phenylalanine has been observed in adult patients using CGMP [ 16 ], although some patients may have had sub-optimal blood phenylalanine control prior to CGMP commencement or they may have received only a partial amount of their protein substitute intake from this source.

It is added to soft drinks, chewing gums, sweets, desserts, jelly and tabletop sweeteners. Although aspartame should always be included on food labels, the amount of phenylalanine it provides remains undisclosed. The types of foods that may contain phenylalanine from aspartame with the maximum amount per litre or kg of food is given in Appendix 2.

Aspartame is added to some medications. The European Medicines Agency summary of product characteristics may identify the amount of phenylalanine from aspartame added to a specific medication. Neotame contains aspartame but the production of phenylalanine is limited due to the inability to break down the peptide bond between aspartic acid and phenylalanine, reducing the production of phenylalanine. This sweetener is safe in PKU, but is more expensive, and therefore is used less by the industry.

Safe sweeteners for PKU are listed in Table 5. Taking the prescribed dose of protein substitute divided into at least 3 equal doses spread throughout the day. If vitamins, minerals and long chain fatty acids e.

If there is poor adherence with the protein substitute, then additional vitamins and minerals may be required and biochemical nutritional status should be carefully monitored, particularly vitamin B Encourage special low protein foods such as bread and pasta at most meals to provide calories, aid satiety, and variety.

Monitor blood phenylalanine levels regularly see European PKU guidelines for frequency , at the same time of day but preferably fasting. There are few studies that report the prevalence of dental caries in PKU with results of studies contradictory. There are certainly conflicting objectives in PKU care, i. Discourage infants from sleeping with a bottle or beaker in their mouth. Sweet foods and juices are better confined to mealtimes only. Using dummies after this age encourages an open bite which is when teeth move to make space for the dummy.

Tables 6 and 7 provide an overview of causes of high and low blood phenylalanine levels, including appropriate actions to take. During illness, poor appetite and low energy intake are common and high blood phenylalanine concentrations occur due to catabolism protein breakdown. There is little work defining the best management for illness in PKU, but the guidelines in Table 8 may be helpful.

All children should complete their child health vaccination program to protect them from infectious diseases which may otherwise impact on blood phenylalanine control. This involves controlling and lowering the amount of natural protein intake by giving less breast milk or standard infant formula in combination with a phenylalanine-free infant formula. The European PKU guidelines recommend that breast feeding is encouraged in preference to using standard infant formula as a source of phenylalanine; there is considerable experience of breast-feeding infants with PKU [ 19 , 20 , 21 ].

Acceptable blood phenylalanine control, growth and weight gain is attained provided it is administered alongside a phenylalanine- free infant formula. The most widely reported method of breast feeding is based on the principle of giving a measured volume of a phenylalanine- free infant formula before each breast feed.

Infants still feed on demand, varying the number of feeds from day to day, but the phenylalanine- free infant formula should always be given first. It is good practice to encourage parents to keep records of daily feeds taken.

Alternatively, breast feeds can be given alternately with the phenylalanine- free infant formula although there is less evidence to support this.

The number of breast feeds per day is based on the blood phenylalanine results [ 23 ]. At first, mothers may feel their baby is taking inadequate breast milk if they are slow to recommence suckling. Blood phenylalanine concentrations should be checked twice weekly until they have stabilised. Frequent weights help provide reassurance that the infant is gaining weight and by inference, taking enough breast milk.

Ideally, breast feeding should continue long term. When standard infant formula is used as the phenylalanine source, it is given in combination with phenylalanine free infant formula. The total daily amount of infant formula is divided between 6 and 7 feeds. The rest of the fluid requirements is provided by phenylalanine-free infant formula. The phenylalanine-free infant formula and the source of phenylalanine standard infant formula should be given at the same feed to deliver the correct balance of all essential amino acids.

Traditionally it is recommended the standard infant formula is given first to ensure the entire phenylalanine source is completed, followed by the phenylalanine-free infant protein substitute, which can be fed to appetite, with guidance on an acceptable minimal volume to provide total protein requirements. Alternatively, the calculated volume of normal infant formula and phenylalanine-free infant protein substitute can be mixed.

This is the most popular method in Europe [ 22 ]. A disadvantage of mixing the source of phenylalanine standard infant formula with phenylalanine-free infant formula is that the taste may be rejected when the amount of standard infant formula is reduced or removed.

These foods are high protein foods, such as milk, dairy products, meat, fish, chicken, eggs, beans, and nuts. These foods cause high blood phe levels for people with PKU. This target is an easy way to visualize the foods allowed on the diet for PKU. As the foods get further away from the bull's-eye, they are higher in phenylalanine. The foods outside the target are not included in the low-phenylalanine meal plan.

It is not unusual for someone who follows a low phe diet to have 2 kinds of vegetables and a baked potato for dinner. However, if these foods were the only foods a person consumed, his or her diet would be lacking protein, vitamins, and minerals. Nutritional management of phenylketonuria. Almost each country has their own food lists that report the estimated content of Phe, Tyr, and protein. A food equivalent is a specific portion that has a similar amount of nutrients, especially Phe, Tyr, protein, and energy.

This allows food to be exchanged within a list with multiple options, with the advantage that the patient and family can choose different food groups according to their preference, economic status, culture, availability, and diet prescription. In other countries, counting grams of intact protein is done as indirect control of the amount of Phe.

Management of phenylketonuria and hyperphenylalaninemia: the French guidelines [in French]. Arch Pediatr. In some other clinics, only recommendations of foods list are given to avoid high contents of Phe, and also free food lists are available, which includes fruits and vegetables that are not considered important sources of Phe. Unrestricted fruits and vegetables in the PKU diet: a 1 year follow up. Eur J Clin Nutr. All these approaches have advantages and disadvantages, and some of them are shown in Table 2.

Ahring et al reported the experience of 10 centers treating PKU in Europe analyzing patients with different systems of counting Phe, and no differences were found between methods regarding PKU control; it is important to notice that each center had different dietary managements and also their own Phe blood targets.

Blood phenylalanine control in phenylketonuria: a survey of 10 European centers. Effect of dietary regime on metabolic control in phenylketonuria: is exact calculation of phenylalanine intake really necessary? Mol Genet Metab Rep. Dietary protein counting as an alternative way of maintaining metabolic control in phenylketonuria. JIMD Rep. Tyrosine is a nonessential amino acid as it comes from Phe hydroxylation; however, in patients with PKU, it becomes essential because it cannot be synthesized.

It is important to provide an adequate supply of Tyr, as either a Phe-free supplemented formula or Tyr supplement to maintain blood levels in normal ranges. The Tyr deficiency can decrease dopamine, noradrenaline, and melanin synthesis. There are also age-specific Tyr recommendations, and it is suggested to calculate the contribution from medical Phe-free formula plus the contribution of food used as Phe source and most importantly to have Tyr blood concentrations frequently monitored.

It is pertinent to take into account that water solubility of this amino acid is poor, so it could precipitate and form a waste residue at the bottom of the container in which medical formula was prepared, so parents and patients must shake well the mixture to ensure the calculated Tyr intake.

There are recommended daily intakes RDIs for total protein in patients with PKU Table 1 ; however, optimal dosage depends on individual needs. Achieving optimal protein intake to maintain adequate levels of lean body mass is possible only with close biochemical and nutritional monitoring.

MacDonald et al studied 2 groups of patients with PKU with different amounts of Phe-free protein substitute, with and 1.

The higher dosage of protein was associated with lower blood Phe concentrations; however, variations were observed depending on its carbohydrate content.

Protein substitute dosage in PKU: how much do young patients need? Arch Dis Child. The Phe-free formula must be carefully selected because variations are wide in terms of carbohydrates, protein, fats, and Tyr contents. Protein status of infants with phenylketonuria undergoing nutrition management.

J Am Coll Nutr. Formula distribution throughout the day is important and a minimum intake of 3 servings is recommended; when it is given as a single dose, urinary nitrogen excretion, protein catabolism, and amino acids oxidation could increase with a concomitant protein synthesis decline. Utilisation of amino acid mixtures in adolescents with phenylketonuria. Eur J Pediatr. Growth and body composition in children with classical phenylketonuria: results in 34 patients and review of the literature.

Several studies have reported lower levels of total cholesterol in untreated patients with PKU, and there are different hypotheses for this; the first one is a low intake through diet because it is devoid of animal foods, which are the primary sources of cholesterol.

Another explanation is that high levels of Phe are associated with impairment of cholesterol synthesis due to downregulated expression of 3-hydroxymethylglutaryl-CoA reductase and inhibition of mevalonate 5-pyrophosphate decarboxylase, besides the high consumption of acetyl CoA to synthesize phenylacetylglutamine.

Inhibition of brain and liver 3-hydroxymethylglutaryl-CoA reductase and mevalonatepyrophosphate decarboxylase in experimental hyperphenylalaninemia. Neurochem Res. Recent data support that high Phe levels rather than an effect of a low protein diet lead to hypocholesterolemia in patients with PKU.

Plasma cholesterol in adults with phenylketonuria. Lower n-3 long-chain polyunsaturated fatty acid values in patients with phenylketonuria: a systematic review and meta-analysis. Nutr Res. Phenylketonuria diet is deficient in essential fatty acids; AA, DHA, and EPA supplementation and observance are necessary since these fatty acids play an important role in the brain and retina.

J Pediatr Gastroenterol Nutr. Diet history is a reliable predictor of suboptimal docosahexaenoic acid levels in adult patients with phenylketonuria.

A systematic review of literature showed that supplementation with DHA may be an effective way to increase the omega-3 long chain polyunsaturated fatty acid status. Even though the number of commercial Phe-free formulas supplemented with fatty acids has increased, currently some of them contain linoleic and linolenic acid but they do not have DHA, so it is important that health-care personnel treating PKU be aware of this situation to consider an optimal supplementation dosage.