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2014 Annual Multidisciplinary European Phenylketonuria Symposium: PKU a lifetime of challenges

2014 Annual Multidisciplinary European Phenylketonuria Symposium: PKU a lifetime of challenges
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

Resource type


Anita MacDonald, Birmingham Children’s Hospital, UK

For my dietetic colleagues, the meeting in Zagreb, Croatia was full of charm and expectation, with plenty of hidden nutritional gems included within many plenary lectures and workshops. Before the meeting, we knew little about PKU management in south eastern Europe (Balkan Peninsula) and to hear about the daily struggles that some of these countries experience was very sad. In total their population was 52.5 million people, but unfortunately, there were still 4 of 11 countries surveyed that were without newborn screening and only 4 of 11 countries had a dietitian working within their clinics.

With the development of the European PKU guidelines featuring heavily within the meeting, optimal blood phenylalanine levels in relation to neurocognitive outcome was widely debated for all age groups. The latest evidence from Rianne Jahja suggested that on assessment of neurocognitive testing, children aged between 6 to 15 years of age with a lifetime mean blood phenylalanine below 240 µmol/l out performed children with lifetime phenylalanine levels of 240 to 360 µmol/l. These findings have considerable implications for future PKU guidelines and day to day dietary management of PKU.

Preliminary results from the American and Turkish experience with sapropterin with children under 4 years of age were reassuring. Forty four patients under the age of 4 years were treated with sapropterin from Ankara in Turkey. Information from 30 subjects suggested that phenylalanine increased by a median of 2.26 fold and they were tolerating a final phenylalanine intake of 114 mg/kg/day which equates to over 2g/kg/day of natural protein.  They concluded that sapropterin was safe and efficacious. The USA experience was similar to the Turkish group.

Skadi Beblo from Leipzig in Germany described her team’s detailed work on dietary experiences with sapropterin. Fourteen patients with PKU (aged 4 to 18 years) were able to increase their phenylalanine intake from 629 mg/day to 2131 mg/day whilst maintaining good metabolic control. The children increased their intake of higher protein foods such as processed meats, milk and dairy products but decreased their intake of fruit and ate less low protein special products. Although natural protein increased, intake of nutrients such as iron, calcium and zinc decreased suggesting their may be need for micronutrient supplementation. L-amino acid supplements decreased by at least 50%. 

In the workshop on maternal PKU, the proposed PKU guidelines were extensively discussed.  This included: the desired time that optimal phenylalanine concentrations should be maintained prior to conception, the importance of avoiding weight loss in maternal PKU and attaining appropriate weight gain throughout pregnancy, avoiding over restriction of dietary phenylalanine (particularly in the second and third pregnancy trimesters), the lack of evidence to support the need for additional tyrosine supplementation during maternal PKU, potential need for folic acid supplementation and that breastfeeding should not be contraindicated with maternal PKU.

Other fascinating topics included oxidative stress, taste studies in PKU, and diet and exercise outcomes. All in all, this was a wonderful and vibrant meeting which provided a great opportunity to meet up with so many friends and colleagues working in PKU.


Nenad Blau, University Childrens' Hospitals, Heidelberg Germany and Zurich, Switzerland

Scientific highlights of the 2014 Annual Multidisciplinary European Phenylketonuria Symposium - PKU: a lifetime of challenges in Zagreb, Croatia included research reports on development of new therapies for PKU, use of animal models for the elucidation of pathophysiological mechanisms of PKU and application of bioinformatics and patients’ database for the phenotype-genotype correlation. In the field of new drug development for PKU two main streams are followed; the enzyme replacement therapy and small molecule pharma-chaperons.

Professor Nicola Longo from the Medical Genetics and Pediatrics at the University of Utah in Salt Lake City, USA presented the latest evidence about the use of PEG-PAL in PKU patients. PEG-PAL (pegylated phenylalanine ammonia lyase) is a bacterial enzyme degrading phenylalanine to the low toxic compound cinnamic acid and ammonia. Subcutaneous administration of PAL-PEG during the Phase I Study in a single dose of up to 0,1 mg/kg was found to be fairly safe and well tolerated in adult patients with PKU. At the highest dose tested, PAL-PEG reduced blood phenylalanine concentrations significantly. Professor Longo concluded that in view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing (daily). Early Phase II data shows that PEG-PAL has a safety profile with most reactions being mild to moderate hypersensitivity-type reactions.

Professor Aurora Martinez from the Department of Biomedicine, University of Bergen, Norway presented two promising compounds that have good potential as pharmacological chaperones for (PAH). Pharmacological chaperones are compounds of low molecular weight that promote folding by selectively stabilizing the native state of target proteins, allowing them to pass through the cell’s quality-control system and become correctly routed. Sapropterin (BH4), which is already on the market, acts as pharmacological chaperone that stabilizes folding the phenylalanine hydroxylase (PAH), but unfortunately not every patient is BH4-responsiv. After the primary screening two new compounds showed to increase the amount of PAH protein and activity in animal models and cell systems and will undergo further investigations.  The way to the clinical application with PKU patients is, however, long.

Professor Beat Thöny from the Children’s Hospital in Zürich, Switzerland presented the importance of PKU mouse models in the development of dietary and cell and gene-based therapies for PKU. Three distinct mouse models were generated as product of a random chemical mutagenesis: PAHenu1 (a model for mild PKU/HPA), and PAHenu2 and PAHenu3 (models for classical PKU). PAHenu2 mouse carries a missense mutation that completely inactivates the PAH enzyme and is the most widely used. Mouse models are useful for the study of etiology and pathophysiology of PKU and to test therapeutic option, including gene therapy.

Sarah Wettstein a medical student at the Children’s Hospital in Zürich, Switzerland presented her MD thesis on prediction of phenotypes and BH4-responsiveness by linking data available from PAH locus-specific and genotypes databases.  Amongst the 4181 patients (15,1% HPA, 24,4% mild PKU, 41,3% classic PKU, 19,2% no information) she observed 463 different mutations. BH4-responsiveness data were available from 2128 patients (44,4% responders). She showed that using genotype scoring both the phenotype and BH4-responsiveness could be estimated, thus offering a robust method for patients’ characterization and management. Sara Wettstein was awarded by EXCEMED for the best oral presentation.

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Target audience
Paediatricians, Dietitians, nutritionists, Scientists, Healthcare professionals
by Excemed
Endocrinology and metabolism