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Pharmacists have a major role in multidisciplinary team management of phenylketonuria. Early diagnosis and treatment of this inborn protein metabolism error forestall severe learning difficulties, allowing normal development
Fiona White
BSc(Hons)
Chief Metabolic
Dietitian
Sophie Farooq
BSc(Hons)
Clinical Pharmacist
Royal Manchester
Children’s Hospital
Pendlebury
Manchester
UK
Phenylketonuria (PKU) is the commonest inborn error of protein metabolism, with an incidence of up to 1 in 10,000. It is an autosomal recessive disorder caused by mutations within the gene for the hepatic enzyme phenylalanine hydroxylase. The resulting enzyme deficiency prevents the normal metabolism of phenylalanine to tyrosine, causing accumulation of phenylalanine and relative tyrosine deficiency. Accumulation of phenylalanine is neurotoxic, preventing normal postnatal brain
development and leading to irreversible neurological damage. Different mutations of the gene produce different levels of residual enzyme activity and consequently varying degrees of hyperphenylalaninaemia.
Infants with PKU are normal at birth. Signs of serious developmental delay only appear at a few months of age when the baby is not reaching normal developmental milestones. Early diagnosis and treatment prevent severe learning difficulties, leading to a normal developmental outcome. Since 1969 newborn screening for PKU has been offered to all babies in the UK. Screening is recommended 5–8 days after birth, aiming to commence dietary treatment by 21 days of age.[1] Dietary management involves the use of prescription products (phenylalanine- free protein substitutes and low-protein products). In addition, information is required on the presence of aspartame as a medicine excipient. Pharmacists have an important role in the multidisciplinary team (MDT) management of PKU.
Management of PKU
Individuals should be cared for by a multidisciplinary team experienced in managing PKU.[1,2] Management involves a phenylalanine-restricted diet to control blood levels within age-related limits.[3] This prevents toxic effects from high levels while providing sufficent phenylalanine (an essential amino acid) for normal growth and development. Diet should be nutritionally adequate, palatable, varied and compatible with a normal lifestyle. Principles are:
- Avoidance of high-protein foods such as meat, fish, eggs, dairy products, pulses, nuts, soya, ordinary flour, artificial sweeteners containing aspartame (aspartame [E951]/salt of aspartame and acesulfame K [E962]).
- A daily allowance of phenylalanine (depending upon phenylalanine tolerance) from foods containing small amounts of protein. An exchange system is used based on portions of food containing 50 mg phenylalanine (equivalent to 1 g protein)-for example, 80 g boiled potato, 45 g chips, 10 g wheat-based cereal biscuits.
- Use of a phenylalanine-free protein substitute, with added tyrosine. These are essential to ensure adequate total protein. They normally contain complete vitamins, minerals and trace elements. If not, a separate supplement is required. There are many different products available, of which some are age-related.[4,5]
- Foods low in protein to provide normal energy requirements and variety in the diet, such as fruit, some vegetables, sugars and fats, and low-protein prescription products, such as flour, bread, pasta, biscuits and milk substitutes (more than 100 items are prescribable).[4,5]
Phenylalanine levels are monitored regularly, and phenylalanine intake is adjusted if indicated, together with regular clinic review of dietary intake, growth, development and knowledge of diet and condition.
The current UK recommendation is to continue treatment into adulthood.[3] Good phenylalanine control throughout childhood is important to optimise developmental outcome. Some adults
notice worsening concentration, memory, behaviour or performance of specific tasks with high phenylalanine levels. Others notice no difference. Achieving dietary compliance is not easy, and at present there is no compelling evidence in favour of making recommendations in adulthood mandatory. The absolute exception is for females wishing to become pregnant. Strict phenylalanine control (100-250 microlitremol/l) is essential prior to conception and throughout pregnancy to prevent adverse effects on the fetus, such as cardiac malformations, facial dysmorphism,microcephaly and growth retardation.
Pharmaceutical issues
The main issues affecting pharmacists are awareness of artificial sweeteners in medicines and of the needto dispense the correct phenylalanine-free protein substitute and low-protein food product.
Aspartame (E951) is a sweetener included in medicines to improve palatability. Aspartame is metabolised to aspartic acid and phenylalanine, contributing to phenylalanine intake and possibly affecting phenylalanine control. Some commonly prescribed medicines contain aspartame or phenylalanine-such as granules or powders for reconstitution, chewable tablets, gums and orodispersible tablets (such as paracetamol “melts”) and, surprisingly, erythropoietin syringes. Community and hospital pharmacists may receive prescriptions for short- or long-term treatment of co-morbid conditions. We may only discover the patient has PKU if the patient or carer volunteers this information. Prescriptions may not necessarily be endorsed with “PKU”. Most pharmacists know to avoid aspartame and phenylalanine in PKU and can check whether a preparation contains either. Information sources include the British National Formulary for Children (BNFc) and the regular BNF, which indicate the presence of either excipient but may not include quantity.[4,5] Other sources include summaries of product characteristics, manufacturers’ medical information departments and the certificate of analysis (for unlicensed products).
Short-term use of antibiotics containing aspartame can be disregarded, as high phenylalanine levels due to infection will lessen with treatment. Medication for long-term use where a phenylalanine-free preparation is not available should be discussed with the dietitian/prescriber, as the phenylalanine content may need to be taken into account. Patients must not be denied a medicine without discussion with the dietitian/prescriber.
Care is needed to ensure the protein substitute dispensed
is for PKU and not another condition, as these substitutes would contain phenylalanine. Many substitutes have an affix to the name denoting the disorder they are designed for (eg, XP/PKU); some may also be colour-coded. Care is needed to ensure solely glutenfree food products are not supplied, as these contain a significant protein load.
Conclusion
Pharmacists have an important role in managing PKU as part of the multidisciplinary team. This involves our usual roles of educating and providing medical information to patients/carers and healthcare professionals. Careful records highlighting known patients and awareness of the issues affecting them enable us to contribute to safe and effective treatment.
Box 1 Summary. Pharmacists’ roles in managing
patients with phenylketonuria
- Awareness of the importance of supplying the correct protein substitute and low-protein products
- Checking medicines-prescribed and over-the-counter
- (OTC)-for aspartame or phenylalanine content
- Educating patients/carers to ask for information on any medicine (prescribed or OTC)
- Liaising with dietitians/prescribers if medicines contain aspartame or phenylalanine; advising on alternative preparations or therapy choices
- Highlighting regular patients on pharmacy records
- Advising on prepayment certificates.
References
1. UK Newborn Screening Program Centre. Newborn bloodspot screening in the UK. London: DoH; 2005.
2. National Society for Phenylketonuria. The management of PKU. London: NSPKU; 2004.
3. Anonymous. Recommendations on the dietary management of phenylketonuria. Arch Dis Child 1993;68(3):426-7.
4. BMA/RPS. British national formulary for children. London: BMJ publishing/RPS publishing; 2006.
5. BMA/RPS. British national formulary 52. London: BMJ Publishing/RPS Publishing; 2006.
