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ADVANCES & CHALLENGES IN PKUWINTER 2012/2013

Comment from key opinion leaders in the PKU field. Reports from the SSIEM Annual Symposium 2012 and the 26th ESPKU conference.

PKU ACADEMY NEWSLETTER

Welcome to Issue Four of the PKU Academy NewsletterThis edition of the PKU Academy Newsletter features reports from the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium 2012 and the 26th Conference of the European Society for Phenylketonuria and Allied Disorders (ESPKU).

Both these meetings took place in the UK in a Diamond Jubilee year, the 60th anniversary of Sheila Jones, patient of Dr Horst Bickel, becoming the first person to be treated for PKU with a phenylalanine (Phe)-restricted diet at the Birmingham Children’s Hospital.

We celebrate another jubilee in this issue with a profile of Eleanor Weetch1, who has retired after 25 years as the dietitian for the UK National Society for Phenylketonuria (NSPKU).

Continuing our series of ‘Perspectives’ interviews, we focus on the views of three more people behind the presentations and papers.

Prof Ania Muntau2 talks about communicating with parents after a diagnosis of PKU.

Prof Laurie Bernstein3 discusses the need for better education to improve adherence to PKU treatment.

Dr Søren Gersting4 shares his views on how bioinformatics is impacting on PKU research.

In this issue, we also look at the life of the artist Bryan Pearce from Cornwall (UK), who was born with PKU, was untreated and today is recognised internationally for his paintings.

ISSUE 4 WINTER 2012/2013

ContentsSSIEM Symposium 2012 ....... 2

European guidelines by 2014 ............................. 3

26th ESPKU conference ....... 4

Feature interview with Prof Ania Muntau .............. 5

Feature interview with Prof Laurie Bernstein ......... 6

Feature interview with Dr Søren Gersting ............. 8

Eleanor Weetch profile ....... 9

The life of Bryan Pearce ....11

Read and share the online version of the newsletter − http://bit.ly/pkunews04

2 | PKU Newsletter Issue 4 Winter 2012/2013

The promise of GMPProf Denise Ney5 reported that preliminary studies in animals and humans on the use of glycomacropeptide (GMP) as a supplement in protein-restricted diets were encouraging. GMP, a natural whey protein extracted from milk and a by-product of cheese-making, has no, or a very low, Phe content. It appears to offer a number of advantages over an amino acids (AA)-deprived diet as it provides: a better range of AAs in the blood, less protein degradation, positive effects on bone health and immunity, promotion of satiety, lower fat mass, better adherence to diet and no side effects. Phase II clinical trials are ongoing and will provide a clearer picture of the advantages and any drawbacks.

The problems of non-essentialsIn AA disorders, non-essential AAs become ‘essential’, said Prof van Spronsen6. In addition to the AA which cannot be metabolised effectively, the levels of other AAs may be affected. In PKU for example, levels of tyrosine (Tyr), normally produced as a breakdown product of Phe metabolism, may be reduced.

Deficiency of a required AA may cause skin and growth problems. It can also result in non-optimal neurological development. The levels of these collateral AAs may need to be raised through the provision of dietary supplements. Detection of an AA deficit such as this may require both fasting and non-fasting blood samples.

Giving large doses of LNAA may become a therapeutic option but such an approach is a long way from becoming part of normal care and would require further research.

Urine test for a healthy brainIt has been observed that treated PKU patients often have lower executive function and a higher prevalence of depressive and anxiety disorders, possibly due to deficiencies of neurotransmitters including serotonin and dopamine.

Prof Shoji Yano7 discussed the potential of using easily measurable urinary metabolites of melatonin as biomarkers for serotonin and dopamine deficiency in PKU patients’ brains. In a recent study, patients and controls were, following washout, given LNAA tablets or placebo. It was seen that levels of such metabolites fell in PKU patients on placebo but increased significantly in those that received LNAAs.

SSIEM Annual Symposium 2012

GMP is extracted from milk and is a by-product of cheese-making

Birmingham (UK), famous for its canal network

The SSIEM Symposium 2012 took place in Birmingham (UK), 4−7 September. More than 1500 participants convened to address the theme of phenotypic diversity of inherited metabolic diseases (IMD). There were a number of paper and poster presentations of interest to PKU Academy members and we bring you a selection here.

Full abstracts of the symposium are available online − http://bit.ly/pku0402

Tyrosine

Urine samples could reveal neurotransmitter deficiencies

www.pkuacademy.org | 3

Getting the message acrossPatients with IMD and their families need more support to correctly follow their diet away from the clinic. Prof Anita MacDonald8 recommended that patients need accurate equipment and refresher training courses with dedicated time on food preparation. Prof MacDonald presented the results of two clinical studies that evaluated the ability of IMD parents at home to prepare special formulae. The study particularly looked at parents’ accuracy in:

�� measuring the correct amount of ingredients using a range of different methods

�� mixing more than one feed ingredient (modular feeds) compared with single ingredients.

In both studies, patients and parents were capable of preparing feeds in the clinic and after training from the dietitian. However, once at home, they were unable to achieve similar good results.

Evaluating NPAAsNon-physiological amino acids (NPAAs), such as methyl-aminoisobutyrate (MAIB), can competitively inhibit Phe transport across the blood−brain barrier, reported Prof Michael Gibson9. Studies using a mouse model showed a significant reduction in Phe levels with no side effects. However, further studies are required to investigate whether there are collateral consequences such as a decrease of other LNAAs.

Important first steps were taken towards the development of European guidelines on the diagnosis and disease management of PKU at the ESPKU conference in October 2012. This was the beginning of a process that aims to present agreed guidelines at the ESPKU conference in 2014.

The executive board of the ESPKU asked the chair of the ESPKU scientific committee, Prof Francjan van Spronsen6 to start the process.

Prof van Spronsen told us that ‘All but one of the invited experts accepted their invitations to take part in the development of the guidelines. The initial meeting brought together a biochemist, nutritionists/dietitians, psychologists, as well as paediatricians and physicians taking care of adult patients who can be seen as real experts on PKU. During the ESPKU conference, five working groups started their journey focusing on different aspects of PKU management.’

�� Neurocognitive outcomes including neurological imaging.

�� Psychosocial outcomes and adherence to treatment.

�� Nutritional treatment and biochemical/nutritional follow up.

�� Adult and maternal PKU and late-treated PKU patients.

�� Diagnosis of PKU and drugs in PKU.

The initial proposals from the working groups will be released for comment in Spring 2013.

Currently, there are no universally agreed guidelines and professional views on the correct way to manage patients, particularly adults, vary across Europe and in some cases within countries. These differences can have a big impact on patients. For example, someone who is considered to have acceptably controlled blood Phe in one part of Europe can be classified as poorly controlled in another.

Prof van Spronsen detailed the scale of the task ahead. ‘Apart from the blood Phe target concentrations, the guidelines have to take into account other issues of follow up, such as the levels of other amino acids (AA), the measurement of neurocognitive outcome, nutritional issues, evaluation of bone density and differences between “standard” care and research-based investigations.’

To be part of the process, visit www.espku.org

Parents and patients need accurate equipment and refresher training to correctly prepare formulae

European Guidelines by 2014

1 Mrs Eleanor Weetch (Formerly of the National Society for Phenylketonuria, UK)

2 Prof Ania Muntau (Departments of IEM and of Molecular Pediatrics, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany)

3 Prof Laurie E Bernstein (Department of Pediatrics/ Director of IMD Nutrition Department, Department of Pediatrics, University of Colorado School of Medicine, The Children’s Hospital, Aurora, Colorado, USA)

4 Dr Søren W Gersting (Department of Molecular Pediatrics, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany)

5 Prof Denise Ney (University of Wisconsin-Madison, Madison, USA)

6 Prof Francjan van Spronsen (Beatrix Children’s Hospital, University Medical Center of Groningen, University of Groningen, Netherlands)

7 Prof Shoji Yano (Genetics, Pediatrics, University of Southern California, Los Angeles, USA)

8 Prof Anita MacDonald (Dietetic Department, The Children’s Hospital, Birmingham, UK)

9 Prof K Michael Gibson (College of Pharmacy, Washington State University, Washington, USA)


26th ESPKU Conference

Lactobacillius sp. a possible new treatment option

The 26th annual ESPKU conference took place in Liverpool (UK), 18−21 October 2012. The meeting, hosted by the NSPKU, attracted over 400 participants from across Europe and the world. The delegates were scientists, healthcare professionals, representatives of patient groups, patients and their families. The wide mix of expertise from the scientific to the personal has always been a strength of the ESPKU conference and this year’s event was no exception. Here we bring you a selection from the presentations and workshops.

Phase III for PEG-rPAL

Prof Cary Harding10 announced that Phase III clinical studies using PEGylated recombinant phenylalanine ammonia lyase (PEG-rPAL) would be going ahead in the USA in 2013. PEG-rPAL is an enzyme substitution therapy, administered by injection. Prof Harding provided an update on the results of the Phase I and II studies which indicate that PEG-rPAL seems capable of significantly reducing blood Phe without major side effects.

Variety is the keyProf Anita MacDonald8 challenged current formulations of Phe-free protein substitutes in the dietary treatment of PKU.

In order to reduce blood Phe levels efficiently and stably, protein substitutes should include a wide range of natural nutrients and novel protein sources.

Prof MacDonald suggested:

�� protein supplements with selected di- or tri-peptides

�� a wider integration of LNAAs

�� more ‘natural’ components such as GMP

�� omega-3 fatty acids and vitamin D3.

Added fibre, probiotics and prebiotics were important as they can serve to reduce any gastrointestinal discomfort associated with protein substitutes.

Friendly bacteriaCould a probiotic drink be a cheap, safe and effective PKU treatment? Possibly, according to Ms Katherine Deming11,

who showed the results of laboratory studies using genetically modified Lactobacillus sp. The bacteria had been altered to express phenylalanine ammonia lyase and were shown to be capable in vitro of degrading Phe in conditions that simulated the intestine of a host animal. The next step, reports Ms Deming, will be for the bacteria to be tested in a mouse model.

The Liver Building, Liverpool (UK)

A liberalised diet remains a goal for developing PKU therapies


Workshop − introducing sapropterin therapyThe complexities associated with introducing sapropterin with diet in PKU patients were discussed in this workshop. After appropriate testing for true long-term BH4−responsiveness by different methods, Phe tolerance has to be assessed and the amount of natural proteins balanced with AA supplementation to determine the right dose of sapropterin for each patient. Side effects, poor adherence and bad adaptation to the new therapeutic regimen have to be considered.

Workshop − effective communicationIf healthcare professionals want to influence patients’ behaviour, they have to think carefully about how they communicate. This workshop looked at tools that can help a PKU patient engage with their treatment and improve adherence to diet. An empathetic attitude is vital. Techniques such as ‘telling a story’ about the patient’s life and the problems they have encountered in dealing with the disease can help establish trust. Even in difficult situations, such techniques

can enable a discussion to take place that focuses on the critical issues that lie beneath.

Prof Ania Muntau2 heads the departments of Inborn Errors of Metabolism (IEM) and of Molecular Paediatrics at the Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich (Germany).

For many in PKU research and treatment there is a divide between the work that goes on with the whole patient and the work ‘within’ the patient, to better understand the disease at the molecular level. The European Phenylketonuria Group (EPG) Symposium in Rome (23−24 March 2012), as an event, provided opportunities for expertise to be shared at both ends of this scale. Prof Muntau works across the entire spectrum, from patients to basic research. When we spoke to her at the EPG Symposium, we were keen to find out what this broad range of interest gives a clinician and a researcher.

Prof Muntau has been looking after children with IEM since she qualified as a doctor, but she met her first PKU patients while still a student.

‘During my final years of medical school, while studying and working in hospital, I spent some of that time in paediatrics’ she told us. ‘There I got to know my first two newborn PKU patients. I met one of these patients last week and she is now a beautiful young lady of 23, who works as a paediatric nurse.’

First impressions countThese PKU infants clearly made an impression on the young Ania Muntau, but how important, we asked, are the first impressions the doctor makes on the parents of a PKU child at the point of diagnosis.

‘Communicating the diagnosis is a crucial point in the long-term treatment

of PKU patients’ Prof Muntau said. ‘Every metabolic paediatrician needs to appreciate that the moment of diagnosis delivery has an enormous impact on the life of the parents but also on the life of the child affected with PKU. This is because the way the diagnosis is communicated, the setting in which the diagnosis is communicated, the key words that are used, will make the difference between a positive or a negative attitude of the parents towards the disease, the way they deal with it and the way they talk to the child about it. This impacts on the quality of treatment for this patient.

‘I really would like people to think about these points before they go into such a conversation.’

Dr Muntau said that the work Prof Feillet12 presented at the symposium on communicating diagnoses was really the first solid data they had. ‘And it is important that we continue to share best practice and systematically review what is working and what is not. We know from interviews with patients that, even 30 years after diagnosis, they will recall the time and date of the meeting, what the doctor was wearing and perhaps four or five points: it is not to be healed, lifelong treatment, heavy burden, neurologic symptoms…

Effective communication is essential for adherence

Perspectives

Ania Muntau

Ania Muntau talks about communicating with patients after a diagnosis

10 Prof Cary Harding (Oregon Health & Science University, Portland, Oregon, USA)

11 Ms Katherine Deming (University of North Texas, Denton, Texas, USA)

12 Prof François Feillet (Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital d’Enfants, CHU Brabois Vandoeuvre les Nancy, France)


‘But there is a lack of training for metabolic paediatricians in communication skills and, in particular, concerning delivery of the first diagnosis. The workshops at the EPG Symposium are the first instance where we have really addressed this topic and I am very happy that we got the chance to do so.

‘With my own students, in their last year, I run a training programme called “Breaking Bad News” where we use role play so the students can explore how it feels to give the diagnosis and try to understand better what it might feel like to receive it. We record these sessions on video so that we can then review and discuss them. Activities like this, integrated into training, are an important step forward where, in the past, workers in the field have all had to teach themselves.’

But metabolic paediatricians aren’t the only doctors who have to break bad news. Is there something to be learnt from other specialities, we asked.

Dr Muntau: ‘I think that in other areas the situation is a bit better, for example in oncology. This is where I see that they work much more on

this. This has to do with the nature of the diagnosis but also has to do with money. Every oncology department has several psychologists and they have the funds to organise specific training.’

Battling against obscurityWas the relative obscurity of IEM when compared with, say, childhood leukaemia a challenge, we asked the professor. ‘Certainly’ she replied. ‘Everyone knows what leukaemia is, but awareness of IEM is lacking in society and this leads to a lack of support. In Germany, we say that the patients with IEM have no “lobby”.

‘It is difficult to raise funds, and when you try to contact politicians and the media they often have difficulty appreciating the importance of the conditions and the work needed to treat them. These conditions are considered rare but in total, when seen together, PKU and the other “rare” IEM caused by missense mutations, affect 1 person in every 500 of the EU population.’

Look again at the unusualWe suggested that, despite the challenges that metabolic

paediatricians face, this is surely an exciting time to be working in this field?

Dr Muntau declared ‘When I started work in this field 22 years ago, my boss said “Don’t think about research in PKU because everything is known, there is nothing to do anymore.” Yet now, after 60 years of dietary treatment, we have identified a new mechanism of treatment.

‘If I had a room of already qualified metabolic paediatricians and I had to give them a single “take-home” message, I would remind them that they should look very closely at things that do not appear logical, to watch for things that don’t fit together. When we see these things we tend to put it away “It’s strange; it’s a bit different from that which I expected.”

‘But these are the things that, if you investigate and you go in depth, may result in the discovery of something new. Remember, this is how the potential of BH4 as a treatment was discovered in the first place.’

Perspectives

Laurie Bernstein

Laurie Bernstein talks about the need for better education to improve adherence

Laurie Bernstein3, Associate Professor in the Pediatrics Department and Director of the IMD Nutrition Department at the Children’s Hospital, Aurora, Colorado (USA)13, contributed to the Dietitians’ Workshop and EPG Symposium in Rome on 22 March 2012 with sessions on ‘Education and motivation of patients: what

works in PKU’ and ‘How to improve adherence to PKU treatment’.

While some have struggled to use the Internet and social media effectively in order to support patients, Prof Bernstein and the team at IMD in Colorado have not hesitated to exploit the opportunities these offer − as a quick search of the Internet will show,

with the many videos, webcasts or online presentations listed, in which she has appeared or helped create.

However, her work isn’t limited to the digital domain, and she remains passionate about the need to support patients face-to-face and enable them to participate in ‘live’ learning and networking events in the real world.

We talked to Prof Bernstein at the Dietitians’ Workshop and asked what the challenges are in educating PKU patients and their families.

‘There are many times when we, the professionals, only see the clinical perspective’ she said. ‘We know what we want the outcome to be and we have this idea of how it should work, so we make a recommendation and then we go back to our office and send the family home.

‘But we need to understand how our recommendations impact their lives.’

Watch the full interview with Prof Muntau, recorded at the 4th EPG Symposium in March 2012 − http://bit.ly/pkuvidmunt


Getting off to the right start‘For infants, you really need to get the family involved, you need to educate the parents but this is not easy. You come into their life, you tell them that their child has a metabolic disorder and that you, a complete stranger to them, are now going to be an important part of their life. I think for most families, they suddenly feel like they are in a fishbowl and all of a sudden everything they say and do is being monitored and judged.

‘We need to make sure we have a strong foundation and that people have what we call in the USA a “buy-in”, that they’re really on board because it really makes sense. I wouldn’t want to do anything in my life without understanding why I’m doing it, nor would I ask my patients to do that.’

Grandma knows best?Prof Bernstein added that in order to provide truly individualised care, the clinician must understand how a family is going to react to the advice. Cultural issues and traditions were important, particularly when these conflicted with clinical advice.

‘If we have a Hispanic family from Colorado and we advise them that during the first year of life the only fluid their baby should take in is the metabolic formula and we say “No water!” this can cause problems because it conflicts with their tradition. The parents may agree to follow our advice when they are in the clinic but, when they go home and tell their family “We’re not allowed to give our baby extra water”, Grandma says “What do you mean no extra water? That’s what we do. That’s what that baby needs.” The parents are unwilling or unable to tell us about the conflict that our guidance has caused so they keep it to themselves.

‘The parents may well follow the instructions, but Grandma is a different matter’ Prof Bernstein said. ‘If she’s sneaking water to the infant, it will affect the formula intake. If we see

inadequate weight gain or high Phe levels, and are assured by the parents that our instructions have been followed, we become concerned that there is something that we have missed.

‘In cases like this I think we have to be prepared to balance short-term compliance against the risk to long-term compliance posed by a breakdown in the relationship with the family.’

Throw out the guidance?‘I’m not saying we should throw out the guidance, but we have to remember that every family is different. Sometimes I think that in the USA we are too strict and I think that in some countries it goes too far the other way. International meetings like this one are valuable because they allow us to consider these questions and compare practice. These meetings teach us to step outside our comfort zones, to look at how other people do things.

‘There are many factors that play a vital part in long-term compliance. The transfer of responsibility for adherence to diet from parents to their children is crucial. This cannot be done in a single step, it’s a process that has to happen alongside the child’s development. In our clinic, children as young as 3 years old start to identify “Yes” and “No” foods.

‘I think it’s important to share the tools we create to help educate patients and their families. I’m always very grateful when I can incorporate somebody else’s expertise and make it specific for my families, and I encourage others to use what we have created.

‘Our teaching modules, games and an anticipatory guidance book called “Eat Right Stay Bright”13 can all be accessed or ordered online.’

Bringing in the professionalsProf Bernstein said ‘When we asked our patients what the biggest “roadblocks” to adherence were, we kept hearing “Difficulty in preparing meals”,

“There’s not enough variety” or “Low-protein foods are too expensive”. Our answer to this was to create a programme called Network PKU. Originally a video offering practical advice and featuring PKU patients and their families14, Network PKU grew into a conference run at a culinary school, featuring professional chefs. The first conference was held over a weekend in 2004 and was such a success that repeat events were organised in 2006, 2009 and 2011. The next one will be in 2013.

She told us ‘Families come to the conferences and they learn how to cook foods that are naturally low-Phe but not necessarily specially formulated low-protein foods. They learn from professional chefs how to create meals that are easy, fast and accessible.

‘All of a sudden our families are like “Okay, this is difficult, but maybe it’s manageable.” The events also allow patients and families from all over to meet each other. They can make new connections and by exchanging phone numbers and emails, they can stay connected.

13 Inherited Metabolic Diseases Nutrition Department @ucdenver.edu − http://bit.ly/pku0403

14 Watch the Network PKU video − http://bit.ly/pku0405

Watch the full interview with Prof Bernstein, recorded at the 4th EPG Symposium in March 2012 − http://bit.ly/pkuvidbern

Professional chefs can help families create more exciting and less expensive low-Phe meals


PerspectivesSøren Gersting

Søren Gersting talks about the impact of bioinformatics on PKU research

Dr Søren Gersting4 trained as an MD but changed direction into basic research. Following the award of his PhD in 2003 he joined the Molecular Paediatrics group at the Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich (Germany). Here, his initial research focus was the mechanism of BH4 interaction with the PAH protein. He has published a number of papers on the mechanisms of action of cofactors that ameliorate the effects of missense mutations. Who better then, to comment on the ‘Zeitgeist’, bioinformatics?

New tools for old dataDr Gersting told us ‘The potential in bioinformatics lies in the fact that it’s not so complicated to apply if you know what to do. Using these methods we can get more information out of the wealth of data that is already there.

'We have so many studies on basic research in PKU over the last 10 years. These studies provide data from both basic research on the protein itself and clinical research on blood Phe levels, neurocognitive function, etc. All this can be brought together.

‘There are so many intertwined factors that influence patient outcome. Using bioinformatics, you can investigate the interplay between a number of these different factors, such as stress, metabolic state and BH4 supply, in different patients with different genotypes and mutations. The true relationship between multiple interacting factors that influence

outcome can easily be obscured when only a single factor is studied.’

Blind dataset?Dr Gersting continued ‘Bioinformatics is a marvellous tool for finding potentially meaningful correlations in vast datasets but, in order to function, such analyses need a lot of data. These data need to be accurate and accessible.’

Given the need for data, is enough material being made available? ‘There are some databases already available’ Dr Gersting said. ‘There’s the PAH database15 founded by Dr Charles Scriver16, the BIOPKU17 database curated by Prof Nenad Blau18 and RAMEDIS19 by Prof Fritz Trefz20, just to mention three of them. Here we find data on mutations, on the clinical phenotypes, on the BH4 supply and so on.'

Towards individualised treatment‘What is lacking at the moment is a database that brings together the basic research information on the mutations, so when variant protein is expressed you can find out, is it more unstable? Is it aggregation-prone? What is the affinity to the substrate or to the cofactor? We have tried to bring this together in our current study but a larger database is not yet available. Creating such a database, that could allow these data to be combined with the clinical databases, would be a step forward for the future.’

How, we asked, do advances in bioinformatics impact on patient confidentiality. ‘It’s true that individualised medicine requires us to treat the whole patient rather than specific mutations. With many other factors to consider, it is not enough to just know about the genotype, which could be non-personalised. We need more personal information about the patients. Capturing these data, gathered through newborn screening programmes, for example, or adding in the available data on siblings or parents certainly raises issues about confidentiality. I think this is something the research community has to deal with because, although there is risk, there is so much we could potentially take out of it.’

Where next?How is the greater understanding of how BH4 works as a pharmacological chaperone influencing research and the development of potential medicines for other IEM?

Dr Gersting said ‘Treatment with exogenous BH4 is now, I would say, proven to stabilise the PAH protein. This binding-induced stabilisation has now been shown for other diseases. We have seen clearly that it is missense mutations that induce protein misfolding. If we keep in mind that about 60% of all mutations in IEM are missense, we can imagine how many patients could benefit from a pharmacological chaperone treatment. This clearly points the direction for further research.

‘One example would be the medium-chain acyl-Coenzyme A dehydrogenase (MCAD) deficiency, the deficiency in the metabolism of medium chain acyl-CoAs; another example is glutaryl-CoA dehydrogenase, which is related to the MCAD protein but behaves completely differently. In our group we are already looking at pharmacological chaperone therapy for glutaric aciduria type 1 patients.’

To what extent will bioinformatics play a role in the development of further treatments for PKU? ‘Historically, people tended to think of PKU as a simple


15 PAH Locus Knowledgebase (PAHdb) World Wide Web site − www.pahdb.mcgill.ca

16 Dr Charles R Scriver (Biochemical Genetics Unit, McGill University, Montreal, Canada)

17 BIOPKU: International Database of Patients and Mutations causing BH4-responsive HPA/PKU − http://www.biopku.org

18 Prof Nenad Blau (Division of Inborn Metabolic Diseases, University Children’s Hospital, Department of General Pediatrics, Heidelberg, Germany)

19 RAMEDIS: Rare Metabolic Diseases Database − www.ramedis.de

20 Prof Friedrich Trefz (Medical Centre Gammertingen, Kreiskliniken Reutlingen GmbH, Gammertingen, Germany)

Mendelian disorder but it is not’ said Dr Gersting. ‘It is a complex trait because every patient has his or her individual molecular phenotype. If you analyse a lot of parameters you will find that most mutations are unique in their behaviour. Bioinformatics approaches will allow us to find out where there are similarities and where there are differences.

‘This approach can show us how patients can be grouped, and based on new sub-groups we might identify new biomarkers. This is an

important step to creating the next generation of drugs beyond BH4.’

And what of the future?‘When we think about basic research in PKU concerning protein misfolding and pharmacological chaperone treatment, one could have the misunderstanding that we went very far and that we know everything’ said Dr Gersting.

‘But, to be precise, there are more than 600 mutations known and only maybe

30 have been analysed in depth − and to think that analysing less than 10% is enough to provide an understanding of the whole picture might be misleading. I hope that the research community in PKU will continue to do this work as they have been for the last decade. This will give us expanded datasets and allow better bioinformatics.’

Watch the full interview with Dr Gersting, recorded at the 4th EPG Symposium in March 2012 − http://bit.ly/pkuvidgerst

Many readers will know Eleanor Weetch1, from her work as Dietitian for the NSPKU. She retired in February 2013 after 25 years there and, to mark the occasion, we spoke to her about her work, the Society and the future of both.

She said she had come to focus on PKU more by chance than design, while working as a District Dietitian in Scunthorpe (UK). Although in this role she was looking after seven PKU children, she had no idea how important PKU was about to become in her life.

‘One day, quite unexpectedly, I received a phone call from a woman of about 20, with PKU, who had just got married and wanted to have a family. This woman was one of the first adults to have been early-treated and one of the first to want to have a family’ Mrs Weetch said.

‘Planning her diet through pregnancy was a real challenge that required a lot of research and careful consideration

of the best advice to give. The outcome was excellent, the lady had her baby and the baby was fine. Soon after, I was asked if I would give a talk to the Sheffield hospitals about the practical issues of looking after maternal PKU.

‘The talk was part of a study day which had been organised by NSPKU and it was there I met their Dietitian, my predecessor, Rachel Stockings. We got on really well and when, a few months later, she asked if I could help out by writing some articles and going to some meetings I agreed. When Rachel retired, I applied for the position, got it and have been with the NSPKU ever since.’

We need to get togetherMrs Weetch stressed the importance of making and keeping up with contacts through training days and seminars, even in the digital age. ‘Over the last 25 years the way people communicate and access information has changed. When I started, everything was done by letter and telephone; now we have email and the Internet. But we need to keep meeting face-to-face and talking on the telephone. You find out a lot more when you actually talk to people and meet them.

‘We are more likely to be able to reach consensus on issues like European guidelines for PKU treatment if we meet face-to-face’ she said. ‘The world is much smaller, and it is really helpful for us to be discussing what we’re doing. If we are going to effectively promote change in policy and procedures in those countries that

do not yet screen for and treat PKU effectively, they need to see clear guidance on the best way forward.’

Building bridgesAs Mrs Weetch had left the medical establishment to work for NSPKU we were interested to know why she thought it was important for support organisations to have dietitians and medical professionals on board. She explained ‘The medical profession has changed over the last few decades. It’s certainly true that at one time, professionals were wary of patient groups and not at all happy with the idea of patients getting together to discuss their PKU and their diets.

‘Patient focus is now understood to be key to better patient outcomes. The support and advocacy groups have helped build that understanding. By involving medical professionals, organisations like NSPKU gain credibility and are taken more seriously by the rest of the profession. This builds bridges and a bridge is built between the patients and the professionals.’

Mrs Eleanor Weetch

Profile


PKU Academy OnlineThe PKU Academy website provides opportunities to learn about PKU through a variety of educational resources and online programmes.

There are currently three courses available:

�� Pathophysiology and Diagnosis of Phenylketonuria

�� Optimising PKU Treatment by Assessment of Sapropterin (BH4) Responsiveness

�� Clinical Management of Phenylketonuria − European Accreditation Council for Continuing Medical Education (EACCME) accredited, 1 CME credit.

The PKU Academy in collaboration with Serono Symposia International Foundation (SSIF) awards a 24−month

research fellowship to support planned research and to broaden the experience of young graduates in medicine (specialised or specialising in metabolic medicine), scientists and dietitians who work in the field of PKU.

For further details and an application form go tohttp://bit.ly/PKUnews03-13

Taking timeIs the medical mainstream still something that patients need help to challenge, we wondered. Is there still a role for support and advocacy groups? ‘It’s not about taking sides, it’s really all about time’ Mrs Weetch said. ‘We can provide something outside of the hospital. We can organise events that take place at a hotel rather than a hospital for example.

‘This normalises things and gets away from the clinical feel. This is important because of what we are trying to achieve: helping people to follow the diet in a way that allows them to live as normal a life as possible.

‘There’s so much that societies like NSPKU can do: organising events, cookery demonstrations and activity weekends for children. We organise amino acids analysis for example and each year we get different foods analysed for Phe content so they can be assessed and included in the diet.’

Start them youngAnother big change that has occurred over the last 25 years has been the general acceptance of ‘diet for life’. This has had great benefits but what were the challenges? ‘Children were frequently taken off diet at 8−12 years of age’ Mrs Weetch replied. ‘Back then, children weren’t really involved in their diet; it was their parents who took responsibility because they thought the children wouldn’t need it when they were older. I hate the term ‘diet for life’ because it sounds like a prison sentence, but today we recognise how important it is for people to keep to the diet. We now work to get children involved in their treatment from the start. If the children know their diet then everyone is more confident and the children can go on sleepovers, they can go on school trips. I don’t think you can start too young, you can involve them from the very beginning. This has been a huge change in the way we treat.’

Getting better all the timeWhat impact have developments in protein supplements had? ‘There’s so much variety now in the supplements and they’re so much more convenient. Fourteen years ago, we started organising activity weekends for children. We’d have 20 children, all with PKU, who would come in from a hard day’s abseiling or whatever and they had to mix up a powdered protein substitute, getting the consistency right and ensuring it wasn’t lumpy, getting the temperature right. It was a lot of effort. Today they just grab a pouch of a ready-mixed substitute and drink it like a sports drink. It’s just so much easier. That might seem like a small thing but it’s a huge step forward.’

Looking to the futureAsked whether NSPKU would continue to employ a dietitian, Mrs Weetch said it was essential for a support group to have a dietitian’s expertise as well as support from medics. ‘Paula Hallam, who was previously with Guy’s

and St Thomas’ Hospitals in London (UK), will be taking over from me. Paula is highly regarded within the PKU community and will fit in well with the NSPKU medical advisers, management team and families.’

We were keen to know what Mrs Weetch had planned for her retirement. ‘Nothing yet. I expect I’ll have plenty to do, but right now I’m looking forward to paying a little more attention to my neglected garden!’

A parting word‘We keep saying “Keep positive” but we have to recognise that PKU is not going to go away anytime soon. So, you’ve got to embrace it. You mustn’t resent it because then everything is blamed on the PKU. You can’t say, “Because of your PKU you can’t do this and you can’t do that”. The diet can be difficult but there are far worse things than this and PKU is very successfully treated. There is no reason why you cannot make the most of every situation − life is for living!’

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Bryan Pearce was a painter from Cornwall (UK), a member of the famous artists’ colony of St Ives, whose work is highly regarded around the world.

He was a ‘primitive’ or self-taught artist who developed his own, unique, way of depicting the landscapes and townscapes of his beloved St Ives and its environs. His style, characterised by the depiction of surface design and full of vivid colour, is instantly recognisable and remains popular with collectors today. An original work sold recently at auction for nearly £50,000.

Born with PKU, at a time before diagnosis and treatment, he was learning disabled. Prof Anita MacDonald8 recalls a story she’d heard from a shopkeeper in St. Ives, ‘Bryan and his mother would come to town to see if any of his pictures in the gallery had sold. If they had, she would buy him a train and chocolate as a treat. Chocolate? I think that’s a sure sign that Bryan was not on diet.’

Prof MacDonald is enthusiastic about Bryan’s paintings, but also feels his life story offers us much. She told us ‘It is often the case that, when we remember the people who have played a part in the history of PKU, we focus on the scientists who have made discoveries and the parents who have fought for recognition of the condition and treatment. It is not often that we celebrate the patients themselves.’

Bryan Pearce’s talent for art was discovered when he was 24 years old by his mother, herself a talented painter. Desperate to find activities that would engage her son, she gave him a children’s colouring set. The combination of the bright watercolour paints and the strong lines of the pictures in the book set him on the path to becoming a professional painter. After completing the colouring tasks, he set to work creating his own paintings on blank paper.

Impressed by this initial work, Leonard Fuller accepted Bryan at the St Ives School of painting in 1953. The school was the perfect environment for him to develop as an artist. He produced a great many watercolours and developed the motifs of boats moored in the harbour and heavily outlined buildings which characterise his work. Influenced possibly by other artists in the school, Bryan moved more towards landscapes and still-life painting.

In 1957, Bryan started painting in oils and also began exhibiting his work at the Penwith Gallery in St Ives.

With support from the sculptor Denis Mitchell, he joined the Newlyn Society of Artists and had a solo show at Newlyn Gallery in 1959. This first show was followed over the next four decades with many more across the UK.

It is the oil paintings, unique and self-assured, that brought Bryan wider attention. His famous ‘all round’ works such as ‘St Ives Harbour (all round) No. 4’, featuring buildings flattened out around the calm of the harbour in the centre, are typical of the style. This bird's-eye view of the buildings rejects perspective and notions of there being a ‘right way up’.

Known for his slow, careful and consistent working practice, Bryan kept up a steady stream of new work throughout his life. He was working in his studio almost till the day he died in 2007, aged 77. He was never treated with diet.

Feature

The Life of Bryan Pearce

Top: Bryan Pearce at work in his studio. Photograph © Rosemary Hoskin. Reproduced with permission

Middle: St Ives Harbour by Bryan Pearce

Bottom: Tulips (1965) by Bryan Pearce

Bryan Pearce’s work is reproduced with permission of the Bryan Pearce Estate/Bridgeman Art Library 2013


Improving the patient’s life through medical education

Serono Symposia International [email protected]

Editorial Board MembersProf Nenad Blau18, Prof Anita MacDonald8, Prof Francjan van Spronsen6

EditorsAlison Eden, Flaminia Masprone, Dorina Monaco, Howie Watkins, Michael Withers

ContributorsDavide Mineo, Howie Watkins

Representative officeSerono Symposia International Foundation

Salita di San Nicola da Tolentino 1/B00187 Rome, Italy

T +39.06.420.413.206F +39.06.420.413.677

HeadquartersSerono Symposia International Foundation 14, Rue du Rhone 1204 Geneva, Switzerland

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Summer IssueIn our next issue, Summer 2013 − Advances and Challenges in PKU, we will be focusing on the 5th European Phenylketonuria Group (EPG) Symposium and 3rd Dietitians’ Workshop held in Istanbul, Turkey (14−16 March 2013).

We welcome your feedback or requests for topics in future issues. Please contact us at [email protected]

Copyright © Serono Symposia International Foundation, 2013. All rights reserved

Watch a slideshow of 37 paintings by Bryan Pearce − http://bit.ly/pku0404

St Ives Harbour (all round) by Bryan Pearce. Reproduced with permission of the Bryan Pearce Estate/Bridgeman Art Library 2013

Bryan’s working method was to start by ‘mapping out’ his subject from life with a line drawing in light pencil. He would then work over this drawing in his studio with a fine brush, often using yellow ochre. Finally he would add the rest of the colour, working on each painting for 4−5 weeks. He painted around 12 pictures a year, along with etchings and, later in his life, conté crayon sketches.

In his will, Bryan left a substantial body of work to the Institute of Cornwall. The bequest includes examples of his work

from beginning to end, starting with a selection of his early watercolours and including his last oil painting. In total, 9 watercolours, 27 oil paintings, 2 pen-and-ink drawings, 3 conté crayon sketches and 11 etchings.

Cover image: Detail from The Harbour and St Ia’s Church, St Ives (1967) by Bryan Pearce. Reproduced with permission of the Bryan Pearce Estate/ Bridgeman Art Library 2013

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