User login

We offer our registered users tailored information, free online courses and exclusive content.

You have an old EXCEMED account ...

Our platform has been renewed. All users registered at any of the old websites are kindly requested to reset their password. Why is this?

... or you lost your password?

4th European Phenylketonuria Group Symposium

4th European Phenylketonuria Group Symposium
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

Resource type


4th epg symposium

The symposium ‘Advances and Challenges in PKU’ took place in Rome (Italy) on March 23rd and 24th 2012. The 2 day programme gave an international audience of physicians and researchers the opportunity to attend a wide range of presentations and workshops.

Download the final programme and abstracts from the symposium.

The themes explored included:

  • strategies for providing essential amino acids in the diet of PKU patients, comparing and contrasting glycomacropeptide and large neutral amino acids as supplements
  • diagnosis and treatment of BH4 deficiencies
  • strategies for improving adherence to PKU treatment
  • the importance of effective and reassuring communication between physicians and parents at diagnosis.


The event culminated in the Asbjørn Følling lecture, given this year by Prof Harvey Levy1.

Download a range of presentations from the symposium.


The Italian problem

Prof Marcello Giovannini2 gave the opening presentation, providing the delegates with an overview of PKU in Italy. Neonatal screening for hyperphenylalaninemia (HPA) has been compulsory in Italy since 1992 but has been a common practice in some areas for longer than this; in the Lombardy region of Northern Italy, screening began in 1977. Since 2010 there has been a National Registry for PKU patients.

The incidence of all types of HPA in Italy is 1 in 3,494 live births with 1:8,681 babies affected by forms of HPA that require treatment. The incidence of Type I HPA (classical PKU) is 1:17,905. Similar numbers of newborns, 1:17,362 are diagnosed with Type II (mild PKU) and 1:5,907 with Type III (mild HPA).

The Clinical Department of Pediatrics, San Paolo Hospital, University of Milan, is Lombardy’s Regional Reference Centre for the diagnosis and treatment of PKU patients. There are 660,550 patients currently being followed by the centre (200 of whom have been followed for over 18 years). The ages of the patients range from newborn to 50 years of age, with a mean age of 14.5 years. The majority of the patients are ethnic Europeans (93.8%).

BH4 beyond blood Phe

4th epg symposium 3

The ability of BH4 to reduce blood Phe levels in some PKU patients, the so-called BH4-responders, is changing the way the disease is being treated across the world. Prof Nenad Blau2 discussed other potentially beneficial effects of BH4 that are attracting research interest:

  • the effect of BH4 in non-responder PKU patients, particularly those with neuropsychiatric symptoms including Attention Deficit Hyperactivity Disorder, anxiety and depression
  • the role of BH4 on endothelial function in cardiovascular disorders, including diabetes linked to the effects of BH4 on nitric oxide synthesis
  • the potential role of BH4 to reduce oxidative stress in the brain due to its ability to cross the blood–brain barrier and its involvement with the synthesis and catabolism of catecholamines and serotonin
  • the possibility that BH4 pharmacotherapy could have the potential to target other diseases.


Watch Prof Nenad Blau’s lecture – ‘Mode of action of BH4 beyond blood Phe control’


Exploring complexity through bioinformatics

4th epg symposium 4

PKU is a complex trait, acknowledged Dr Søren Gersting3. Although it is caused in 98% of cases by a mutation in the phenylalanine hydroxylase (PAH) gene, there are more than 600 mutations characterised to date. In addition, the clinical phenotype is affected by other factors: the amount of dietary Phe, the degree to which ingested Phe is absorbed, the metabolic state of the patient and the degree to which Phe in the blood passes across the blood–brain barrier.

Dr Gersting described how bioinformatics can be used to help correlate genotype with phenotype through the analysis of enzyme kinetics and molecular structure. This could allow tailored diagnosis and therapies to be developed and may help:

  • understand the molecular mechanisms behind loss of function
  • define sub-groups of patients with respect to treatment
  • identify novel biomarkers that could be useful in the development of the next generation of drugs to assist PKU management.


BH4 for under 4?

pku newsletter 03

BH4 therapy is efficient and has been demonstrated to be safe for children aged under 4 years according to Dr François Labarthe4. In Europe, BH4 has been available since 2009 for patients over 4 years of age but not for younger patients. In France, however, its use has been allowed in certain circumstances. Using retrospective data from 15 children under 4 years old who had received BH4 in this way, Dr Labarthe argued that BH4 is both safe and effective in the treatment of mild PKU in BH4-responsive patients under 4 years old. Studied subjects had received a BH4 dose of up to 20 mg/kg/day to achieve age-target Phe levels with a simplified diet. After 2 years, blood Phe levels had normalised and stabilised with satisfactory neurological outcomes. No side effects were seen.

Worth the weight?

4th epg symposium 6

Physicians treating PKU patients need to consider developing strategies for encouraging sustainable enhanced physical activity levels in their patients, said Prof Berthold Koletzko5. Patients with PKU have a high risk of being overweight or obese due, in no small part, to the PKU diet. Prof Koletzko detailed a study of 33 early-treated PKU patients aged 25 years or over. The Body Mass Index (BMI) and energy expenditure of the PKU patients were compared with controls, matched for age with similar levels of formal education. The PKU patients had higher BMIs and lower activity levels. Although it is impossible to attribute which is the cause and which the effect, there is certainly a real need to intervene to prevent the cycle of weight gain and decreasing activity.


'State of Science'

4th epg symposium 7

What is best for PKU patients now and tomorrow? To answer this question, in 2000, the US National Institutes of Health (NIH) published a Consensus Development Conference Statement for screening and management of PKU to provide guidelines for clinicians. Since then, new therapies have emerged and new strategies for PKU treatment have been developed. To revise the guidelines, the NIH organised a ‘PKU Scientific Review Conference: State of the Science and Future Research Needs’ in February 2012. Prof Harvey Levy1 reported the highlights of the conference:

  • blood Phe levels should be monitored and controlled for the entire life of the patient
  • management in pregnancy and in early life should be stricter, with targeted use of sapropterin
  • diet and formulations should be improved and more readily available
  • analysing genotype and phenotype is key to future treatment success.



4th European Phenylketonuria Group Symposium Oral Presentation Highlights

48 hour BH4 loading test is cost-effective and reliable Dr Karen Anjema7

Dr Anjema presented a study showing that the 48 hour BH4 loading test is a valid way to predict long-term BH4-responsiveness in PKU patients. The test is not as accurate as genotyping, but is significantly cheaper.


The value of molecular characterisation, Dr Caroline Heintz8

Dr Heintz discussed assessing BH4-responsiveness by molecular characterisation of the phenylalanine hydroxylase (PAH) gene mutations which cause misfolding. Where these mutations affect the PAH catalytic domain to cause dysfunctional enzyme activity, this can be correlated with clinical phenotypes that are responsive to sapropterin.


Understanding the role of PAH mutations, Dr Frank Rutsch9

The influence of individual PAH mutations on BH4-responsiveness was further discussed by Dr Rutsch, who identified mutations that can be used to predict the degree of response (e.g. L48S).

A step towards gene therapy, Dr Hiu Man Viecelli10

4th epg symposium 9

Dr Viecelli reported lowered Phe levels with improved behaviour in PKU mice following treatment with minicircle-based naked-DNA blood injections to the liver. PAH gene transfer occurred in liver cells, its expression was dependent on the dose given and the effects were persistent and consistent.

Dr Hiu Man Viecelli won the Serono Symposia Foundation (SSIF) award for best oral presentation on basic research at the EPG Symposium.


Strict diet vital, Dr Rianne Jahja11

4th epg symposium 8

Dr Jahja stressed the importance of a stricter Phe blood level control in the first 12 years of life to achieve normal neurological outcomes in PKU. Some aspects of executive functions are altered even when Phe levels are kept within currently accepted levels between 240 µmol/l and 360 µmol/l when compared with controls and individuals with Phe below 240 µmol/l.

Dr Jahja won the SSIF award for best oral presentation on clinical practice at the EPG Symposium.


1  Prof Harvey Levy (Medicine/Genetics, Harvard Medical School, Children’s Hospital Boston, USA)

2  Prof Marcello Giovanni (Department of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy)

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

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

5  Dr François Labarthe (Médecine Pédiatrique & INSERM U921, CHRU de Tours, Université François Rabelais, Tours, France, & Réseau Maladies Métaboliques Hôpitaux Universitaires du Grand Ouest, France)

6  Prof Berthold V Koletzko (Division of Metabolic and Nutritional Medicine, Dr von Hauner Children’s Hospital, Munich, Germany)

7  Dr Karen Anjema (Beatrix Children’s Hospital, University Medical Center of Groningen, Groningen, Netherlands)

8  Dr Caroline Heintz (Department of Pediatrics, University Children’s Hospital, University of Zürich, Zürich, Switzerland). Ms Heintz obtained her PhD on 22/06/2012. Congratulations Dr Heintz!

9  Dr Frank Rutsch (Klinik und Poliklinik für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Münster, Münster, Germany)

10 Dr Hiu Man Viecelli (Department of Pediatrics, University Children’s Hospital, University of Zürich, Zürich, Switzerland)

11 Dr Rianne Jahja (Beatrix Children’s Hospital, University Medical Center of Groningen, Groningen, Netherlands)

Terms of use

This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.

Rome, Italy
Mar 23 - 24, 2012
Target audience
Specialists in pediatric, Dietitians, nutritionists, clinical biochemists, experts in genetics, basic scientists
by Excemed
Endocrinology and metabolism