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XXV ESPKU Conference

XXV ESPKU Conference
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

Resource type

Article

The 25th European Society for Phenylketonuria and Allied Disorders (ESPKU) Conference, held 14th to 15th October 2011 in Warsaw, Poland was opened by Prof Francjan van Spronsen and David Abeln, current president of the ESPKU. Prof van Spronsen thanked Stanislaw Macko­wiak, president of host-country Poland’s PKU patient association, Ars Vivendi, as the main sponsor for the organisation.

 

Untreated and late-treated PKU patients experience partial symptom relief from treatment

Dr Maria Gizewska of the Department of Paediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology, Pomeranian Medical University (Szczecin, Poland) discussed Phe neurotoxicity present even in early and continuously treated PKU patients (below 400 µmol/l). These patients were found to have slightly lower IQ and mild deficits in executive function compared with healthy subjects. Neurones and glial cells are involved, with altered cell metabolism and energy production, together with defective neurotransmitters and myelin synthesis. The overall result of these changes is a negative effect on cognitive and motor functions with psychiatric and psychological disturbances. Related nutritional deficits and the stress secondary to the diet have an exacerbating impact. Some studies using brain imaging show that, in untreated and late-treated PKU patients, these effects can be partly reversed, even in adults, by therapy and continuous control of Phe levels. These findings reinforce the need for early diagnosis and therapy, with a careful diet that should be maintained for life.


Maintaining appropriate Phe levels during pregnancy

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Prof Friedrich Trefz of the Medical Centre for Women, Children and Adolescents (Reutlingen, Germany) discussed the challenge of maternal PKU, advising a blood Phe target pre-conception and throughout pregnancy of below 360 µmol/l or even below 240 µmol/l to avoid risks to the fetus. A low Phe diet started early (within 8-12 weeks of gestation) with adequate caloric intake plus at least weekly Phe monitoring are all important for normal neurological and organ fetal development (e.g. to prevent heart defects), Prof Trefz stressed. Wide fluctuations of Phe levels due to poor adherence to therapy seem to be more harmful than constant moderate-to-high levels, he warned. Some case reports have outlined the benefits of supplementing with low doses of sapropterin (BH4) in responsive pregnant women, and it is hoped that this option will soon be approved. Psychological support and sex education should also be given to PKU women who want to become pregnant to improve newborn health status.


Ensuring adherence to treatment

Only half of all patients with PKU have appropriate blood Phe levels, warned Prof Peter Burgard from the Centre for Pediatric and Adolescent Medicine, University of Heidelberg (Heidelberg, Germany) in his talk about the challenge of adherence in PKU patients. A major objective is to help patients and their families understand about the disease and its therapy. If there are opportunities to assess understanding, outcomes may be improved and psychological stress minimised. Healthcare professional communications should be simple, effective and balanced, Prof Burgard recommended, reducing demands and increasing patients’ and relatives’ capacity to face the disease, even in adverse situations. Improving adherence is a continuous balance between healthcare professionals’ desire  to manage the patient’s Phe levels without triggering a negative reaction and patients who are trying to lead a normal life. Success is possible, Prof Burgard said, if appropriate behavioural, emotional and cognitive techniques are utilised.


The influence of genetic factors

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The type of genes that a person with PKU has can influence the severity of the disease, explained Prof Serap Sivri of the Department of Pediatrics, Hacettepe University Hospital (Ankara, Turkey). Prof Sivri presented the results of studies on genotyping and on the quality and duration of dietary treatment in patients diagnosed and treated late for classical PKU. Different genetic backgrounds can influence the degree of neurological impairment, she said, adding that this was probably due to diverse brain blood barrier permeability to amino acids and nutrients, variations in the repair capacity of the brain to insults and stresses, different responses to dietary restriction and supplementations as well as variable gestational, perinatal and growing-up age factors. Late-initiated and continuous therapy, including tailored formulations for each specific case, with attainment of target Phe levels, can partially reverse severe cognitive deficits, pointed out Prof Sivri, and even more the motor disabilities, thereby improving both quality and expectation of life in such late-treated PKU individuals.


Diet can help prevent the late consequences of PKU

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Dr John Walter from the Willink Biochemical Genetics Unit (Manchester, UK) highlighted the impact of PKU in older adolescents and adults who have been late- or inadequately treated. Cognitive, motor and mental disorders, early ageing, nutritional deficiencies, lower bone mineral density, increased cardiovascular risk and reduced quality of life are seen. Brain alterations observed on magnetic resonance imaging (MRI) scans seem to correlate with Phe levels above 600 µmol/l, which are accepted by most current adult treatment recommendations. Only 30% of PKU adults achieve target Phe levels, and over 50% of PKU women are not on a PKU diet when they become pregnant, with associated risks for the newborn. PKU patients should be followed throughout their life and treated with a Phe-restricted diet (target below 400 µmol/l) and nutritional supplements, advised Dr Walter.


Adopting an individualised approach to diet in PKU patients

Diet must be tailored to the indivi­dual patient while also responding to recommendations and guidelines, stressed Ms Eleanor Weetch of the National Society for Phenylketonuria (UK). Healthcare professionals should promote collaboration with other caregivers to support the patient and their families, communicating an empowering message that patients can do almost everything if they want to. Steps to success in PKU management include: explaining circumstances and teaching solutions; encouraging patient independence and consistency; a varied diet with enough calories, using acceptable protein substitutes and adequate supplements; developing a good routine in meals and activities; and trying not to be resentful about having the condition, but instead adopting a positive attitude despite the problems that are associated with having PKU.

 

Birth and progress of research in PKU

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Mr John Adams of Canadian PKU and Allied Disorders Inc. (Toronto, Canada) reminded the audience about how research into PKU had been strongly driven by families of children with unknown and untreated severe mental retardation. In the early 1930s in Norway, Mrs Borgny Egeland stimulated the discovery of the first diagnostic test for PKU, specifically phenyl ketones in urine samples of her two ill children, by Dr Asbjørn Følling who named the disease initially ‘imbecillitas phenylpyruvica’, soon changed to phenylketonuria (PKU) by Dr Lionel Penrose. In the 1950s in the UK, Mrs Laura Jones encouraged doctors to test for the first time a low Phe diet in her ill daughter, thereby successfully treating PKU behavioural symptoms; on this basis the first low Phe formula was produced. In the 1960s in the USA, Dr Robert Guthrie was motivated by his cou­sin’s illness to invent the first blood test for PKU, namely a dried spot on filter paper, to be used for di­sease diagnosis and management; later on the test was introduced for mass screening and early intervention for newborns.

 

Enzyme substitution therapy: the future of PKU treatment?

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In the future, it may be possible to take an enzyme supplement, rather than rely on diet to control PKU. Dr Cary Harding from the Department of Molecular and Medical Genetics, Oregon University (Oregan, USA) presented the results of his stu­dies on enzyme substitution therapy by using recombinant pegylated Anabaena variabilis phenylalanine ammonia lyase (rAvPAL-PEG), a bacterial-derived Phe-ammonia lyase, pegylated to reduce immunogenicity and given subcutaneously to avoid intestinal deactivation. PKU mouse models demonstrated the ability of the drug to decrease blood Phe levels by its degradation and production of harmless chemical products, and then clinical phase 1 studies showed its safety given at low doses once a week, with few minor side-effects and antibody production apparently not correlating with Phe levels after therapy. Ongoing phase II trials are testing different doses of rAvPAL-PEG and intervals of administration for better efficacy; they are also verifying patients’ tolerance to the drug. Preliminary but incomplete data seem encouraging, showing significant reduction of blood Phe levels, while not on a Phe-restricted diet.


Lifelong support for patients with PKU

A team approach is vital to help patients with PKU enjoy a near-normal life, pointed out Dr Laurie E. Bernstein of the Department of Pediatrics, University of Colorado (Denver, Colorado, USA). Her presentation focussed on the importance of lifelong learning in PKU, which in her clinic involves a team approach from healthcare professionals who provide patients and their families with continuous support in learning about and dealing with PKU. From the first weeks of life through to adolescence, easily understandable and age-appropriate education is provided on PKU aetiology, health consequences and on nutritional management, by teaching essential skills to live with the disease (e.g. selection and preparation of foods, use of formulations, regular testing of Phe levels) and by giving counselling (e.g. sex education, social impediments, disease-related stress). Reinforcement is achieved via participation in dedicated events (i.e. camps, courses, conferences) with the ultimate goal of improving compliance to therapy and thereby improving clinical outcomes.

 

Reaching a consensus in Europe

Common guidelines for PKU management are urgently needed in Europe, said Prof Francjan van Spronsen from the Beatrix Children’s Hospital, University Medical Center of Groningen (Groningen, the Netherlands) in closing the meeting. He thanked the orga­nisers and sponsors, as well as all participants, and reinforced the need for an homogeneous approach in the field, particularly with regard to targeting blood Phe levels, which today are quite homogeneous in childhood (from below 284 to 367 µmol/l at age 0-4 years, from below 363 to 446 µmol/l at age 4-9 years), but different in adolescence (from below 600 to 900 µmol/l at 10-16 years) and adulthood (from below 1200 to 1500 µmol/l in patients over 16 years). This challenge was accepted by the newly elected

ESPKU president Mr Eric Lange from the UK who will work on a consensus paper in 2012. Mr David Abeln, in ending his mandate, launched the benchmark report ‘PKU: Closing the Gaps’ for the EU community with the purpose of promoting uniformity in reimbursement of treatments and services. He also supported a draft consensus paper on optimal care from the patient’s perspective.


Workshop on psychological aspects of PKU

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Two workshops were held during the conference. The first was dedicated to the psychological aspects of PKU that strongly affect patients’ and families’ lives. For example: feeling different, anxiety, control, denial, social restriction, over- or under-caring is seen in patients with PKU. Appropriate educational, supportive and disease management programmes, run by trained certified healthcare professionals can help improve compliance and neurological outcomes while enabling patients to lead a near-normal life. This chronic care model includes community resources and specially designed health system structures and algorithms (e.g. to-do and check lists). Constant collaboration, exchange of information and sharing of problems among PKU patients, families and caregivers is required.


Workshop on daily PKU management

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The second workshop summarised the practical clinical aspects of daily PKU management from early life throughout adulthood: ruling out tetrahydrobiopterin deficiency, evaluating sapropterin responsiveness, performing genotype and nutritional analyses; leading to a correct diagnosis and patient’s classification and to tailored treatments. Monitoring blood Phe le­vels over time is crucial to define the patient’s Phe tolerance and to evaluate long-term treatment efficacy. Quantity and amplitude of Phe fluctuations and a high Phe:tyrosine ratio correlate with neurological symptoms more than mean Phe levels, fluctuations being less controllable and responsive to dietary restrictive changes. In the near future, approval of sapropterin for use in the first year of age and during pregnancy may improve PKU management and outcomes.

 

Introducing amino acid supplements in diet

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Dr Margreet van Rijn of the Beatrix Children’s Hospital, University Medical Center (Groningen, the Netherlands) reported on a study of newly-available amino acid supplements which have different flavours, are supplied in pre-packed portions of liquid or powder formulas and which also provide the correct energy intake in terms of fats and carbohydrates. A two-week trial is ongoing based on a taste training programme with repeated exposure in PKU patients divided into age groups (from age 4 to over 16 years), looking at patients’ compliance, formulation type, taste preferences and the occurrence of side-effects; collected by a detailed questionnaire. Preliminary results show that the majority of participants were able to finish the programme and continued the implementation of the amino acid supplements in their daily routine.

 

Benefits of amino acid supplementation

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Dietary restrictions may become a thing of the past if current research into amino acid supplements comes to fruition. Mrs Kirsten Ahring of the Kennedy Center (Glostrup, Denmark) presented the results of research on the determination of the effects of supplementation with large neural amino acids (LNAAs) on diet intake in PKU adults, considering their positive effect on mood and other symptoms while avoiding malnutrition due to a stricter low-protein diet. A study of four consecutive three-week phases was conducted to test two different brands of commercially available LNAAs given in different dosages and combinations, together with a semi-free Phe diet. Patients completed a three-day food record at the start and end of each study period. While protein content and energy intake varied slightly according to study phases and conditions, there was no correlation with the amount (high or low dose) and brand of LNAAs used, outlining their utility in giving patients sufficient protein and energy intake while allowing them to follow a less Phe-restricted diet.


Use of neonatal tests to predict disease status

Are neonatal tests for PKU a good predictor of disease status? Dr Karen Anjema of the Beatrix Children’s Hospital, University Medical Center (Groningen, the Netherlands) compared the older neonatal 8-24 hours BH4 loading test (BLT) with the current standard infantile 24-48 hours BLT to evaluate efficacy in identifying BH4 responsiveness (over 30% Phe-reduction) in PKU children over 4 years. The rationale for this investigation was the potential availability of sapropterin for newborns’ therapy and evidence that extending the BLT over 24 hours is risky in terms of postponing dietary treatment in those with PKU. Some discordance was found in tests at different time points, but positive results in both signified long-term sapropterin responsiveness. The neonatal tests when positive seem to be a good predictor of disease status, but when negative do not fully rule out BH4 responsiveness. A new strategy should be developed such as the neonatal BH4 withdrawal test (starting low Phe diet and sapropterin then withdrawing BH4 some weeks later).

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