LAUNCH ISSUE SUMMER 2011 Advances and challenges in PKU

Transcription

1 PKU ACADEMY NEWSLETTER ADVANCES & CHALLENGES IN PKU Meeting report from the 3rd European Phenylketonuria Group Symposium & Dietitians Workshop, Lisbon, Portugal, March LAUNCH ISSUE SUMMER 2011 Advances and challenges in PKU 300 delegates from across Europe met in Lisbon, Portugal, to discuss strategies to improve the lives of people with PKU. Welcome to the first issue of the PKU Academy Newsletter. In this edition, we focus on reports from the 3rd European Phenylketonuria Group Symposium & Dietitians Workshop held in Lisbon, Portugal, March We hope you will find the content of Main symposium During the main lectures, the delegates reviewed and discussed the pathophysiology of phenylketonuria, the role of vitamin B 12 deficiency and its impact on brain function in PKU patients, oxidative stress in patients with PKU, updates in phenylalanine hydroxylase (PAH) and chaperone research, and ongoing trials for new treatment options in phenylketonuria. this first newsletter interesting and welcome your feedback or requests for topics in our subsequent issues. Please contact us with your thoughts and requests at: info@pkuacademy.org Worldwide PKU website Specialist websites and social networks are being effectively used by patients and parents. Medical professionals can also now access specialist resources that support continuous medical education. See the PKU academy website for courses and up-to-date information about the latest developments in PKU: The symposium Advances and chal lenges in PKU was organised by the Scientific Advisory Board on Phenylketonuria, chaired by Professor Nenad Blau, in cooperation with Serono Symposia International Foundation (SSIF). The symposium, and dietitians workshop, brought together a multinational, multidisciplinary audience to focus on identifying the practical problems faced by those treating and developing treatments for PKU patients. Contents Main symposium 1 Worldwide PKU website 1 Advances and challenges in PKU 1 Challenges of dietary treatment are worthwhile 2 Dietitians Workshop 2 With sapropterin can we forget diet? 3 PKU pathophysiology 3 B 12 deficiency may harm brain 3 Adjuvant antioxidants 4 BH4 a chaperone? 4 Dr Rani H. Singh 4 Dr Anita MacDonald 6 Professor Nenad Blau 7

2 Challenges of dietary treatment are worthwhile There is tremendous variation internationally regarding recommended blood-phe levels, Dr van Rijn commented. The tremendous success of dietary treatment for PKU was emphasized by Dr Margreet van Rijn, in her opening lecture at the Dietitians Workshop. International inconsistency There are marked differences in recommended maximum blood Phe levels, dosages of protein substitutes, systems for allocating daily phenylalanine allowance, foods that can be eaten without restriction (so called free foods ) and the encouragement of breastfeeding. Across Europe the training, roles and responsibilities of dietitians and nutritionists vary widely. Next steps In the discussions that followed Dr van Rijn s lecture, the group agreed that many aspects influence dietary compliance and only a multidisciplinary approach can improve adherence to therapy. The group felt that improvements were needed in our understanding of the cognitive effects of PKU and diagnostic tools to measure executive function/prodromal symptoms for all ages. There was consensus regarding the urgency of follow-up of adolescents and adults with PKU, and of women, in particular, in order to prevent maternal PKU syndrome and fetal effects. It was agreed that during pregnancy (and before conception), strict blood Phe control within low target ranges is essential. The group acknowledged the crucial role of drug therapy in attaining treatment goals. Margreet van Rijn: Beatrix Children s Hospital section Metabolic Diseases, University Medical Hospital Groningen, Groningen, Netherlands. Dr van Rijn reminded everyone how far the treatment of PKU had come, but she also illustrated the scale of some of the challenges still to be overcome. Gaps in the evidence base Key studies in the literature that shape our understanding of the effects of PKU are based on very young patients and are not recent. There is no consensus on issues such as the energy requirements for PKU patients and the incidence of obesity compared with the reference population. Dietary side effects PKU treatment with diet has some related health problems. It can affect bone density and essential fatty acid status, and can cause vitamin and mineral deficiencies especially vitamins B 12 and B 6, folic acid, iron, calcium and selenium. Patients need support Patients, when choosing their own optimal treatment often miscalculate their phenylalanine intake. Dietitians Workshop The audience of dietitians, nutritionists and physicians discussed the management of different patient types and were able to contribute their local country experiences in a series of workshops covering subjects including: PKU management in 2011: a review of what we know and don t know and what needs to be done Life with diet and PKU? How do we measure it? Sharing best practice in PKU Individual workshops addressed provision of care for diverse ethnic populations/groups, the challenges of maintaining dietary control in older patients, exploring nutritional complications and how we can use modern technology to enhance patient care. 02 PKU Newsletter

3 With sapropterin can we forget diet? Not according to Dr Amaya Bélanger- Quintana in her presentation, Diet and Sapropterin. Sapropterin does not remove the need for regular PKU supervision, dietary education or nutritional re-evaluations. Dosage and diet may need to be reconsidered as conditions change and therefore continued monitoring is essential. There may also be allied benefits or side effects that need to be monitored. The diagnosis that a patient is BH4 responsive heralds the start of a juggling act said Dr Bélanger- Quintana. The four balls are: natural proteins special Phe-free formulas low-phe foods BH 4 dose PKU pathophysiology Kurt Ullrich discussed his research to elucidate the mechanisms by which Phe causes the neurodegeneration associated with PKU. Only by appropriately managing these variables can a dietitian juggle these requirements effectively. Dr Bélanger-Quintana stressed the importance of working with patients to ensure they were adhering to their new treatment regimes and to check for misunderstandings. The treatment effects of sapropterin can vary markedly between phenotypes. For example, Dr Bélanger-Quintana commented that with milder mutations the reduction of Phe levels can be very pronounced allowing a normal diet or x3 Phe tolerance. With more severe mutations, the rise in Phe tolerance is in the range x Amaya Bélanger Quintana: Unidad de Enfermedades Metabólicas, Servicio de Pediatría, Hospital Ramón y Cajal, Madrid, Spain. Patients following a PKU diet are required to avoid the foods wich would normally provide vitamin B12. B12 deficiency may harm brain Dr John Walter reported that B12 deficiency may be a cofactor in the development of severe neurological disease reported in a small number of adults with PKU. Phe, he demonstrated, affects neurite outgrowth induced by the cell adhesion molecule L1-CAM. He noted that Phe could interfere with other intracellular signalling processes. Dr Ullrich also reviewed the cellular effects of Phe and its in ter ference with the dopamine and serotonin systems: how Phe interacts with the PPARγ receptor system how Phe inhibits the proliferation of human neuroblastome cell lines how maturation expression of PPARγ may explain agedependent differences in Phe toxicity Dr Ullrich concluded therefore that microcephalia in untreated patients with PKU and maternal PKU may be explained by Pheinduced alterations of the extracellular matrix and receptors influencing cell differentiation and proliferation. Kurt Ullrich: Zentrum für Geburtshilfe, Kinder und Jugendmedzin, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany. A number of studies have demonstrated low B12 levels and/or functional deficiency in individuals with PKU, explained the consultant paediatrician. Vitamin B 12 deficiency can cause a wide range of clinical problems, but patients following a PKU diet are required to avoid the foods which would normally provide the vitamin. Dr Walter recommended that all individuals with PKU are routinely monitored for evidence of B 12 deficiency and treated with additional B 12 if required. Dr John Walter: Department of Genetics Medicine, Willink Biochemical Genetics Unit, Manchester, UK. 03

4 Adjuvant antioxidants Antioxidants may be considered as an adjuvant tool to be used in association with the present mainstay therapy: restriction of phenylalanine with amino acid supplements or BH 4 treatment. So said Dr Carmen Regla Vargas, who went on to discuss the in vitro and in vivo findings that phenylalanine and its metabolites induce reactive species generation in the rat brain. Dr Vargas went on to discuss the implications that oxidative stress is found both at diagnosis and also in treated PKU patients (both where compliance is good and where it is not): oxidative damage occurs despite dietary treatment dietary restrictions can contribute to depleted anti oxidant status phenylalanine is not the only metabolite involved with oxidative events If these findings occur generally in clinical practice it may, she said, be presumed that oxidative stress is involved in the pathophysiology of the neurological damage typical of PKU. Carmen Regla Vargas: Analises, Universidade Federal do Rio Grande do Sul, Porto Alegre RS, Brazil. BH 4 a chaperone? BH4 appears to exert a chaperone effect that protects phenylalanine hydroxylase (PAH) mutants against degradation and inactivation, explained Dr Aurora Martinez. When used therapeutically, BH4 rescues the misfolded PAH by stimulating its correct folding in vivo and/or the stabilisation of native-like conformations. Dr Rani H. Singh It s an exciting time to be involved in PKU, says Dr Rani Singh. Rani H. Singh is Associate Professor of Human Genetics and Paediatrics and Director of the Genetic Metabolic Nutrition Program at Emory University in Atlanta, Georgia, USA. Dr Singh gave a presentation at the 3rd European Phenylketonuria Group Symposium in Lisbon, Portugal (March 2011) focused on the work she and her research group are currently undertaking to evaluate the emerging alternative and adjunct therapies for patients with PKU. Afterwards, she spoke to us about her current research interests looking at the effects of BH 4; neuromarkers; developing a classification for BH 4 responders and validating a home Phe monitoring system that is being developed. BH 4 responders cannot always increase phenylalanine intake Dr Singh described that it is now known that some of the patients Therefore, supplementation with BH4 stimulates PAH activity, raising the concentration of the cofactor to supra-physiological levels. This suggests that pharmacological chaperones are a promising approach for the treatment of PKU and of other inborn errors of metabolism associated with misfolding. Aurora Martinez: Department of Biomedicine, University of Bergen, Bergen, Norway. whose plasma phenylalanine (Phe) concentrations originally drop are not necessarily able to increase their phenylalanine intake or decrease their medical food intake; which is what the family expect they will be able to do if they respond to BH4. The classification that she is now using aims to detect other positive outcomes from the lowering of the blood Phe concentrations (apart from enabling the increase in the amount of phenylalanine in the diet). The classification, based on the Phe tolerance, first identifies Preliminary Responders. These are patients who, one month after the initiation of BH4 therapy, show a 15% reduction of blood Phe concentration. We then go on to a further assessment which determines whether the patient is a Definitive Responder, capable of increasing their dietary Phe intake by at least 300 mg and decreasing their medical food need by at least 25% a day Dr Singh said. If the patient responds to BH 4 but cannot increase their dietary Phe or reduce their medical food intake by this amount they are classified as Provisional Responders. Artefact or way forward? It is possible that the Provisional Responders are the result of an ar- 04 PKU Newsletter

5 tefact in the testing protocol Dr Singh explained. We ve got to figure this out because we need to know whether BH4 can do more than increasing dietary Phe tolerance: improving neurocognitive functions for example. This group may also provide additional genotype phenotype associations and could support work to compare blood Phe maintenance on BH4 versus diet therapy alone she added. BH 4 benefits The effects of BH4 on neurocognitive function are being investigated in the PKU ASCEND study, Dr Singh said. In this double-blind, placebocontrolled, randomised study we have been looking at the therapeutic effects of BH4, focusing on symptoms of ADHD and the global functioning of patients who have a reduction of 20% in their blood Phe concentration after their first four weeks of treatment Dr Singh explained. Alternatives to BH 4 Patients who do not respond to BH4 may now have something to look forward to as there is a potential new drug currently in Phase II clinical trials, an enzyme substitution therapy, Dr Singh explained. PEG-PAL The investigational drug, a pegylated recombinant phenylalanine ammonia lyase (PEG-PAL), is a bacterial enzyme that breaks down phenylalanine, catabolising it to ammonia and trans-cinnamic acid. Dr Singh is hopeful that it will provide an option to all patients who do not respond to BH 4. PEG-PAL may even benefit patients who respond to BH 4, she added, because it may have a potential to lower the Phe to near normal range and give an alternative choice to families by potentially allowing complete diet liberalisation. Dr Singh said that Phase III Home blood Phe monitoring will particularly benefit pregnant PKU women. trials are planned for the first half of Home monitoring The blood Phe monitor (BPM) is another potential new tool which may revolutionise patient treatment. This is a simple, easy-touse, portable, handheld device, said Dr Singh. Currently investigational, it is expected soon to be available to clinicians and consumers. Home monitoring means that the model for PKU treatment will become more parallel to that of diabetic patients. Patients will be able to check their blood Phe concentrations at home, multiple times a day if necessary. This will be particularly beneficial for pregnant PKU women who currently have to wait for days before receiving results from their clinic. Through more frequent monitoring, patients will be able to take more control of their healthcare. Exciting times ahead Considering developments in research, Dr Singh said I think it s an exciting time for PKU, not only for clinicians but also for families because of the diverse treatments that are becoming available. These different ways of treating patients, beyond just dietary management, will revolutionise how we achieve an outcome for our patients and our patients quality of life. 05

6 Dr Anita MacDonald Dr Anita MacDonald provides ageappropriate education to PKU patients as young as 3 years old. Anita MacDonald, Consultant Dietitian in Inherited Metabolic Disorders at Birmingham Children s Hospital, was scientific organiser of the Dietitians Workshop, belongs to the European Phenylketonuria Group organising committee and is an Editorial Board Member of the PKU Academy. A passion for PKU Although she had always planned to be a children s dietitian, Dr MacDonald s decision to devote her attention to PKU was made while still an undergraduate when she visited a children s hospital and saw the difference that diet makes to outcome for a PKU child. After university, she started working with PKU patients and has been working in this field ever since. We asked her how the management of PKU has changed over the course of her career to date, about new treatment strategies and about the challenges of encouraging adherence to diet by patients. Big changes in the management of PKU When I first started practising in the late 1970s, we first stopped treatment for PKU at the age of 8 years, then 10 years, later 17 years, until we recommended treatment for life. Dr MacDonald also described major change in the way health professionals approach care. Today we are much more organised and expect higher standards from our families. When I first started work, the approach to treatment was more relaxed; target blood phenylalanine concentrations were higher and blood test monitoring less rigorous. The third big change in PKU management said Dr MacDonald has been the introduction of alternative therapies. Sapropterin has been a huge advance in the care of PKU and has been eagerly awaited by patients and their families she said, adding We have always made the very best of diet therapy but sapropterin allows patients to have an easier treatment. Improved adherence Dr MacDonald observes that dietary adherence is better today. This, she says, is partly due to the wider range of dietary products that are available; in the past there was only a very limited range of products and they were either unpalatable or difficult to use. Patient empowerment Patient education is fundamental to improvements in patient care. The more patients are involved in their own treatment; the more they take charge of their treatment, and making their own decisions can facilitate better control of their blood Phe concentrations Dr MacDonald said. Early years education In Dr MacDonald s experience, starting young is the best route to enabling patient engagement with looking after their health. We believe in introducing education to children at the very beginning. We run special schools for children from the age of 3 years. We encourage parents to talk to their children about PKU, encouraging them to use technical words like phenylalanine, and we support the parents. We have a Buddy Support Worker a health professional who has actually had personal experience of caring for a child with a metabolic problem. She visits the patients homes, she shows them how to prepare lowprotein meals, answers their questions and helps the parents find practical solutions to their problems Dr MacDonald described. Supporting parents Although a family with a newly diagnosed baby with PKU is devastated by the diagnosis, infant feeding through a combination of breast feeding and phenylalaninefree protein substitutes is relatively straightforward says Dr MacDonald. It is more challenging when we start to wean the baby and give more variety in the diet. Babies soon learn to say no to food and, when they do this, parents may become very anxious. Feeding problems may be the consequence, so it is important that we do everything we can to ensure the feeding process in PKU is as close to normal as possible. Sometimes, it s just important for parents to know that there are other people who understand what is happening to them Dr MacDonald observed. Putting children and young people in charge Through PKU schools Dr MacDonald s team teach children how to cook with low-protein food, prepare their own snacks and help them become independent. From the age of 9 10 years, we take children on holidays where they are expected to take responsibility for their diet, with support from our staff. This training then enables them to go away with their own schools on residential holidays with confidence that they can care for their own PKU care. By the age of years, many children with PKU are responsible for their own diet and are very 06 PKU Newsletter

7 independent Dr MacDonald said, commenting further that some young people know more about their treatment than their parents. Education from a young age is central to enabling PKU patients to take ownership of their care. Managing elderly late-treated patients Thinking about PKU and the elderly, Dr MacDonald described the effect of treatment In our clinic we have older people with PKU, born before neonatal screening was introduced, who started dietary treatment only after the age of 1 year. These people have been severely affected by PKU and have learning disabilities. But we are finding that, if these patients start on a low-phenylalanine diet, it can help them and give them a much better quality of life Dr MacDonald said. Current interests At the moment, Dr MacDonald is particularly interested in research looking at feeding development in children less than 2 years of age. I m looking at how many of the problems we see may be due to carer anxiety and how many are due to the special diet. Dietitians have to better understand the families they work with, in order to help patients and the carers of young children adhere to diet Dr MacDonald said. Another piece of work Dr MacDonald is involved in is trying to define the omega-3 fatty acid (docosahaexaenoic acid) requirements of children with PKU. This is the subject of an ongoing international trial that is expected to report findings in early A question of taste Dr MacDonald described her interest in studying the development of taste in children and how it affects the acceptance of the food products. Many of the low-protein products currently available are very sweet, yet we have observed that PKU children appear to prefer savoury foods, particularly those with strong flavours. Children often ignore sweet treats when offered. I think the protein substitutes we use at an early age are often very bitter tasting and this may have an effect on the development of taste preferences in PKU children Dr MacDonald commented. A need for more evidence There are many hot topics in dietetics and PKU, said Dr MacDonald, observing that there are several areas where a more evidence-based approach to healthcare is needed to support decision making. We know we have to obtain more evidence on the dosage of pro - tein substitute, the phenylalanine tolerance of different groups of patients with PKU, and energy requirements and the true impact this has on blood Phe control. These are basic things but we are still lacking data to support clinical decisions Dr MacDonald said. Much more to learn We also still have to settle the debate about whether patients face treatment for life. Certainly, in my mind, there s absolutely no doubt that we need treatment for life Dr MacDonald commented, adding that right now is certainly an exciting time to be working in PKU. There are many things that I want to do before I finally retire, there is always something new to look at and there is always something that needs to be researched. Professor Nenad Blau Professor Nenad Blau looks forward to the creation of uniform guidelines in Europe for the treatment of PKU. At the 3rd European Phenylketonuria Group symposium Professor Blau delivered the keynote Asbjörn Fölling Lecture and used the opportunity to review how far we have come in our understanding of PKU and related metabolic disorders to date. He also charted the history of BH 4 from its initial discovery and purification to the latest models of BH 4 metabolic pathways. Looking to the future, he was in no doubt that these are exciting times for PKU, with new treatments and greater flexibility for patients just a few years away. How, we asked, would he describe the current state of PKU management, where is research taking us and what are his hopes for the future for the diagnosis and treatment of PKU? The need for guidelines The current management of PKU today is not perfect, but it is good, said Professor Blau. Guidelines matter because they affect not only the treatment, but the patient s quality of life. If a patient moves from a country where the treatment is more liber- 07

8 What will the future hold for patients diagnosed today with PKU? al to a country where the treatment is more strict they need to adapt to a new regime Professor Blau observed. Creating uniform guidelines will be more of a problem to organise in Europe than in the United States of America, but this is something we are working on today at the symposium and I think we could have something agreed in 1 2 years he added. Liberalising diet and liberating patients Professor Blau said that these are exciting times in PKU research, both for researchers and for the patients because there are new alternative treatment options coming. Ten years ago there was diet; today we have pharmacological treatments. The pharmacological treatments don t just aim to lower the blood phenylalanine levels but also to increase the tolerance of phenylalanine so that patients can follow a normal diet and eat whatever they want. Some patients can completely replace diet with BH 4 while some patients need a combination of both. I think we should think now about treatment for life instead of just diet for life Professor Blau proposed. We still don t know everything Professor Blau s current research interest is with BH4-responsive PKU. He is looking to answer the questions: How can we use the genotype? How can genotype predict the responsiveness? His team is currently trying to express all these different mutations in the cell system. Next, they plan to coexpress different mutations in different combinations and run the protein kinetics. If we then put everything in a database together with the patient s data, we could potentially develop an algorithm which can help to define the phenotype, genotype and responsiveness of each individual patient Professor Blau said. My wish Thinking about the future, Professor Blau said that his wish is for all patients with PKU across the world to receive consistent management with international agreement over definition of phenotype, treatment protocols and harmonised care pathways in order to achieve optimal, standardised patient care. Winter issue In our next issue, we feature an interview with PKU Academy Editorial Board Member Professor Francjan van Spronsen, the role of patient networks such as E.S.PKU, a special article on utilising social media to enhance patient compliance, plus updates and information about new e- courses. Your continuing medical education partner Editors: Alison Eden, Flaminia Masprone, Michael Withers Contributors: Alison Eden, Massimo Mammucari Representative Office Serono Symposia International Foundation Salita di San Nicola da Tolentino 1/b Rome, Italy T F Headquarters Serono Symposia International Foundation 14, Rue du Rhone 1204 Geneva, Switzerland Copyright Serono Symposia International Foundation, All rights reserved.