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5th European Phenylketonuria Group Symposium

5th European Phenylketonuria Group Symposium
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

Resource type



The symposium ‘Advances and Challenges in PKU’ took place in Istanbul (Turkey) on March 14th and 15th 2013. The two-day program gave an international audience of over 200 physicians and researchers the opportunity to attend a variety of presentations and workshops.

The themes explored included:

  • new therapy options for PKU
  • genetic modifiers and metabolomics in PKU
  • management of BH4 deficiencies
  • neuropsychological and executive function assessment in PKU
  • development of EU guidelines for PKU management.


prof nenad blau welcomes

Prof Nenad Blau1 opened the symposium and welcomed over 200 participants. Half of the delegates were physicians and the other half comprised dietitians, nutritionists and psychologists. Prof Mϋbeccel Demirkol2 then gave an overview of the status of PKU in Turkey, providing an overview of the improvements the Turkish health care system is making in PKU management, patient care and support.

The final program, abstracts, a selection of presentations and videos recorded during the Symposium are available on the Serono Symposia International (SSIF) website.


Advances in PKU research

Possible mechanism for Phe toxicity

Possible mechanism for Phe toxicity

Could immunotherapy be an option for PKU? Dr Ehud Gazit3 reported that Phe forms amyloid-like fibrils in the PKU brain of animals and patients. These could, in part, be responsible for the neurological consequences of the disease. Transmission and scanning electron microscopy has revealed such deposits in the parietal cortex of PKU patients, where they show toxicity to the cells, that can be specifically recognized and neutralized by antibodies.

Linking genotype to phenotype

linking genotype

In vitro studies of PAH structure might lead to better understanding of the link between genotype and phenotype, according to Prof Ania Muntau4. Because phenylalanine hydroxylase (PAH) is a homotetramer, a dimer of dimers, it is possible that in complex heterozygote patients (more than 80% of PKU patients) the PAH protein is composed of hetero-oligomers derived from both mutated alleles with interallelic complementation (interaction between the two protein species.) This was, said Prof Muntau, confirmed by in vitro studies and may influence the therapeutic approach to PKU patients.


Advances in PKU management

PEG-PAL on trial

PEG-PAL on trial

Prof Cary Harding5 gave an update on the phase I-II clinical studies performed with recombinant Anabaena variabilis pegylated phenylalanine ammonia lyase (rAV-PEG-PAL), enzyme substitution therapy for PKU. Weekly subcutaneous injection seemed highly efficient in reducing blood-Phe levels (mean 60-70%) in almost all patients, with transient and treatable mild-to-moderate side effects, mostly skin rash and flu-like symptoms. These effects varied with drug dose and their duration depended on immune response and residual PAH activity of the patient. Phase III studies will start soon.

Competition might provide the answer

Competition might provide the answer

The possibility that managing Phe might become less important was raised by Prof Michael Gibson6. Instead of reducing    blood-Phe levels, Prof Gibson suggested that non-physiologic amino acids could be used to selectively out-compete Phe at the extended blood-brain barrier (BBB), thus preventing neurological toxicity. Prof Gibson’s group reported on their work with a variety of compounds that are capable of selectively competing with Phe on the LAT-1 transporter at that level. Methylaminoisobutyrate showed the best results in animals but was found to cause reduction of other amino acids in the brain (eg Tyr) and renal nitrogen overload was observed. The search for other suitable molecules continues.

Assessing diet for life

Assessing diet for life

Although the neurological impact of high Phe levels in childhood cannot be undone, a low-Phe diet can still be of benefit to adults, said Dr Josef Weglage7, presenting results of a 5-year follow up study of early treated PKU adults in relaxed diet from adolescence onwards. No decline in neuropsychological aspects was seen but some cognitive functions were lower than in younger patients and healthy controls and MRI evidenced abnormalities correlated with Phe levels in early age.

Fatty-acid restriction has lifelong effects

Fatty-acid restriction has lifelong effects

In PKU, the long-term restricted diet is accompanied by a reduced intake of fatty acids, especially long chain polyunsaturated fatty acids, said Dr Uta Ceglarek8. This can result in both altered lipid mitochondrial oxidation and energy production. Dr Ceglarek reported this following a study involving a small number of young PKU patients where their levels of specific amino acids were studied along with a broad selection of other metabolic markers. The results were compared with controls.


Oral presentations

dr. marta danecka receives award

Dr Marta Danecka9 received the SSIF award as the meeting's best oral presentation in basic research with her presentation. She reported that both parts of the BH4 molecule can stabilize PAH making it functional, but other proteins may not interact. A different chaperone, she said, is required to achieve this. A prize of €4000 was presented to Dr Danecka in order to fund her attendance at continuing medical education courses and congresses.

long-term treatment

Long-term treatment with BH4 has positive benefits on the quality of life (QoL) of both adult and pediatric patients reported Dr Chiara Cazzorla10. In a study of 22 BH4 responsive patients who had received BH4 for more than 12 months. QoL was assessed using scales appropriate for the age of the patients. The parents of pediatric patients were also asked to complete questionnaires.

oral presentations 4

Although the executive function of adult PKU patients with relaxed diet appears not to be affected, they still risk behavioural problems, reported Dr Rianne Jahja11. This is possibly caused by the loss of the brain protective effect provided by the strict diet made till adolescence, and is a strong justification for continued monitoring of cognitive function in adults concluded Dr Jahja.


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

2 - Prof Mϋbeccel Demirkol (Children’s Hospital, Division Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey)

3 - Dr Ehud Gazit (Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel)

4 - Prof Ania C. Muntau (Departments of Inborn Errors of Metabolism and Molecular Pediatrics, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany)

5 - Prof Cary O. Harding (Oregon Health and Science University, Molecular and Medical Genetics, Portland, OR, USA)

6 - Prof K Michael Gibson (Clinical Pharmacology, College of Pharmacy, Washington State University, Pullman, USA)

7 - Josef Weglage (Josef Weglage, Department of Pediatrics, University of Münster, Münster, Germany)

8 - Dr Uta Ceglarek (University Hospital Leipzig, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany)

9 - Dr Marta Danecka (Department of Molecular Pediatrics, Children’s Research Center, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany)

10 - Dr Chiara Cazzorla (Division of Inherited Metabolic Diseases, Department of Pediatrics, University-Hospital Padova, Italy)

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

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Target audience
Specialists in pediatric, Dietitians, nutritionists, clinical biochemists, genetists, basic scientists, psychologists, Nurses, Healthcare professionals
by Excemed
Endocrinology and metabolism