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5th European Phenylketonuria Group Symposium 'Advances and Challenges in PKU'

5th European Phenylketonuria Group Symposium 'Advances and Challenges in PKU'
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

Resource type



Nenad Blau (Switzerland/Germany), Symposium President, welcomed over 200 participants coming mostly from Europe, eastern and middle-east countries, with around  half being physicians and the other half dietitians, nutritionists and psychologists. Mübeccel Demirkol (Turkey) welcomed all the delegates and gave an overview of the improvements the Turkish health care system is making in PKU management, patient care and support.

Ehud Gazit (Israel) presented his studies on the possible amyloid-like fibrils deposits in the PKU brain of animals and patients that 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 cell/tissue that can be specifically recognized and neutralized by antibodies, thus opening a new perspective for immunotherapy.

Niels Gregersen (Denmark) gave an overview on other inherited metabolic diseases involving the mitochondria that could represent a model for pathophysiology and interventions in PKU. Fatty acid oxidation diseases cause excessive intracellular oxidative stress leading to misfolding proteins, altered metabolism, and gene modifications with cytotoxicity. Targeting oxidative stress reactions, such as by antioxidants and folding enhancing chemicals, could help manage specific PKU alterations.

Interallelic complementation in PKU appears to be an important phenomenon, said Ania Muntau (Germany), involving the disease’s phenotype and ultimately therapeutic approach. In compound heterozygote patients, PAH mixed protein might exhibit more or less activity depending on the interaction of the subunits coded by different mutated alleles. This was confirmed by in vitro cellular studies and support from the genotype-phenotype prediction model when facing PKU patients.

Several oral presentations were made with the lecture of Marta Danecka (Germany) receiving the SSIF award for best oral presentation in PKU, on biochemical studies clarifying the structural-function relationship of the pharmacological chaperone BH4 with mutated PAH in PKU. Two parts of BH4 molecule can stabilize PAH making it functional, but other proteins may not interact, so requiring a different chaperone. Another lecture receiving great interest was that of Chiara Cazzorla (Italy), who reported achieving  good levels of quality of life (QoL) in PKU patients having long-term treatment with BH4, both adult and pediatric ones, the latter underlying the importance of emotional aspects. Also, the perspective of parents was examined, with their perception of a good QoL in their child being satisfying. Of great interest was the presentation of Rianne Jahia (The Netherlands) showing that PKU adults under a relaxed diet express behavioral problems, while having relatively good executive functions. Probably the cause of such alterations is the loss of the brain protective effect from a strict diet made till adolescence, justifying the monitoring of cognitive functions in adults.

Cary Harding (USA) gave an update on the phase I-II clinical studies performed with rAV-PEG-PAL, enzyme substitution therapy for PKU. Its weekly subcutaneous injection seemed highly efficient in reducing phe blood levels (mean 60-70%) in almost all patients, with transient and treatable mild to moderate side effects, mostly skin rush and flu-like symptoms, with drug’s dose and duration of effects depending on individual immune response and residual PAH activity.

Non-physiologic amino acids could be an interesting therapeutic perspective in PKU, said Kenneth Michael Gibson (USA), who tested different compounds of this class capable of selectively competing with phe on the LAT-1 transporter in entering the brain, thus avoiding neurological toxicity. MAIB showed the best results in animals but a secondary reduction of other amino acids in the brain, e.g. Tyr, and renal nitrogen overload were observed, thus requiring other molecules to be tested.

Josef Weglage (Germany) presented a 5-year follow up study of early treated PKU adults in relaxed diet from adolescence onwards. No declining in neuropsychological aspects was seen but some cognitive functions were lower than younger patients and healthy controls, and MRI evidenced abnormalities correlated with phe levels in early ages. These results suggest a neurological impact of high phe from childhood that cannot be recovered and needs to be restricted in adulthood.

In PKU, the long-term restricted diet is accompanied by a reduced intake of fatty acids, especially LCPUFA, and some consequences may arise, said Uta Ceglarek (Germany). A small number of young PKU patients were studied in specific lipids level and parameters of their metabolism, with some differences compared to controls, such as increased levels of α- and γ-linolenic acids and lower lipid β-oxidation. These facts reveal both altered lipid mitochondrial oxidation and energy production.

Finally, Priscila Mazzola (Brazil), winner of the 2012 PKU Academy fellowship, showed the preliminary results of the funded project ‘Effects of acute physical exercise’ on metabolism and hormones in PKU patients in respect to healthy controls. Basal metabolism seems increased in PKU, and after exercise phe levels remain stable while Tyr and Trp seem to get up to normal levels. Further analysis and confirmations from more patients, and also from animal studies, are going to be made next.

Four workshops took place discussing the main aspects of PKU and related disorders management. Francjan van Spronsen (The Netherlands) and Francois Maillot (France) stressed the need for guidelines for PKU management, summarizing the results achieved up to today by the five working groups set by the E.S. PKU. Uniform, optimal and accessible care for all PKU patients should be the main goal. Jaime Campistol Plana (Spain) and Stephan Huijbregts (The Netherlands) described the several tests available to evaluate executive function in PKU patients that should be routinely used in the clinical setting. Poor adherence to diet and follow-up visits are still main reasons for neurocognitive impairment. Anita MacDonald (UK)Friedrich K. Trefz (Germany) and Julio Cesar Rocha (Portugal) all highlighted the evidences and causes for the increased frequency of overweight seen in PKU patients across all ages. Preventive dietary strategies should be implemented in clinical practice to avoid metabolic consequences. Nenad Blau (Switzerland/Germany) and Alberto Burlina (Italy) described respectively the varied diagnostic testing and the different therapeutic strategies to be set in BH4 deficiencies according to their causes and effects. Standardized management’s protocols have been defined to avoid pitfalls in patients’ care.

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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