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4th European Phenylketonuria Group (EPG) Symposium

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

Resource type


van spronsen

Marcello Giovannini (Italy) reported the long Italian experience of  PKU and presented data from the national registry showing an incidence of 1 in 3500 newborns, mainly Caucasian, with mild forms, and not linked to specific genotypes. He underlined the neuroprotective effects of omega-3 addition to diet early in life and in pregnant PKU women.

 Nenad Blau (Switzerland) explained that BH4 can show other beneficial effects beyond Phe level reduction, favoring an ncrease in neurotransmitters with positive neurological effects. BH4 crosses the blood-brain barrier and seems to improve endothelial function, thus possibly reducing oxidative stress in the brain as well as in the cardiovascular system.

Bioinformatics in PKU was discussed by Søren W. Gersting (Germany) who explained that PAH gene mutations induce misfolding proteins, whose function is repaired by drugs, such as sapropterin. Analysis of enzyme kinetics and molecular structure can help in correlating genotypes with phenotypes, allowing for tailored diagnosis and therapies.

A retrospective study on sapropterin use below 4yrs in mild BH4-responsive PKU was presented by François Labarthe (France). Subjects received up to 20mg/kg/day to achieve age-target Phe levels, and diet was simplified accordingly. After two years, Phe normalized and stabilized, with satisfying neurological outcomes; no side effects were seen.

Berthold V. Koletzko (Germany) discussed overweight in childhood and obesity in adult PKU patients as a result of the higher glycemic and protein load since early-life diet, with increased GH and insulin response predisposing to metabolic syndrome, and also because of poor physical activity. Breastfeeding and infant formulations can be protective.

Harvey L. Levy (USA) reported the highlights of the NIH PKU conference: Phe levels should be targeted lifelong, better defining age cut off; management in pregnancy and in early life should be stricter, with sapropterin use more definite; diet and formulations should be more suitable and easy to get; analyzing genotype and phenotype is key.

 Anita MacDonald (UK) and Margreet van Rijn (The Netherlands) discussed amino acid supplementation in PKU mainly GMP and LNAAs. GMP decreases Phe levels more than conventional formulas but can lead to weight gain and tastes no better. LNAAs content is variable but sufficient in conventional formulas. Tyrosine may be given, mainly in pregnancy.

Alberto Burlina (Italy) and Friedrich K. Trefz (Germany) discussed BH4 deficiencies, having high Phe levels and the deficit of many neurotransmitters, with severe neurological signs. Diagnosis is made by BH4 loading test, and by measuring pterins, biogenic amines and specific cell-enzyme activities. Therapy requires diet, sapropterin, neurotransmitters precursors, and folates.

Adherence to diet is a major problem in PKU, Francjan J. van Spronsen (The Netherlands) and Laurie Bernstein (USA) reminded participants. It can arise from parents not respecting diet principles or having guilty or rejection feelings, as well as from patients themselves, as a reaction to feeling different, and, especially in adolescence, from lack of willpower and poor self-care skill. Poor adherence can also be significant in girls at risk of unplanned pregnancy. 

Communicating a PKU diagnosis to parents can be a difficult task for health care professionals, said François Feillet (France) and Ania C. Muntau (Germany). The physician’s role is key to not alarming parents while giving clear information and optimism for solutions. A day-hospital is necessary to explain PKU to parents and give dietary notions, and also for offering psychology support and planning follow-up.

 Karen Anjema (The Netherlands) presented a study showing that the 48hr BH4 loading test is a valid way to predict long-term BH4 responsiveness in PKU patients, with good reliability. The test is cheap, when compared to genotyping which is more accurate but very expensive and not inclusive of all mutations. False negative deserve re-testing or genotyping.

Caroline Heintz (Switzerland) discussed assessing BH4-responsiveness by molecular characterization of PAH gene mutations causing alternative splicing with misfolding proteins. Mutations often affect PAH catalytic domain with dysfunctional enzyme activity, and they can be correlated with clinical phenotypes responsive to sapropterin at loading test and therapy.

The influence of individual PAH mutations on BH4 responsiveness in PKU patients was discussed by Frank Rutsch (Germany) who explained that some peculiar mutations are often associated with good a response and with the degree of it (e.g. L48S), while others with non-response. Most patients needed 20mg/kg/day of sapropterin for Phe reduction.

Treatment of PKU with minicircle-based naked-DNA blood injections to the liver of a mouse model was tested by Hiu Man Viecelli (Switzerland). The transfer of PAH gene occurred in liver cells, its expression being dependent on the given dose and was also persistent and consistent, lowering Phe levels, with improved behaviour of the treated animals.

Rianne Jahja (The Netherlands) 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 already altered in children with the accepted Phe levels below 360 and above 240umol/l when compared to those with Phe below 240 or to controls. She then additionally presented a study on the capacity of the Phe:Tyr ratios to predict motor-cognitive abilities of PKU children when compared to Phe levels alone. Phe:Tyr ratios were better predictors of cognitive functions, concurrent of cognitive flexibility and lifetime of inhibition, while lifetime Phe levels were better for the motor control.

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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