Zagreb, Republic of Croatia, 24-25 October 2014
Eric Lange, president of the E.S.PKU, Prof Francjan van Spronsen, chair of the scientific advisory board of E.S.PKU, and Dr Sanja Peric, president of the Croatian PKU Society, welcomed an audience composed of professionals, patients and caregivers.
Prof Baric then spoke on “Care in PKU in Croatia”. He explained that the screening program for PKU started in 1978 funded by the state. The program reached 100% of newborns around 1993. The incidence of PKU in Croatia is 1:8592, but it differs from region to region. All patients are followed up in one centre, which has four physicians, two psychologists, metabolic nurses and dieticians who use a range of procedures depending on the age of patients. The Croatian PKU Society, founded in 1990 promotes improved Quality of Life for 181 PKU patients and family members. The Society promotes different activities including continuing education, cooking lessons, creative and sport activities, camps and more.
Tobias Hagedorn spoke on “Towards optimal PKU care in Europe: patients’ perspectives”. To challenge the gap in PKU care in Europe E.S.PKU members wrote a consensus paper published on the Orphanet Journal of Rare Diseases in December 2013. European patients called for:
A new standard of best practise guaranteeing equal access to screening, treatment and monitoring throughout Europe;
Mr Hagedorn underlined the success of the paper among scientists and the general population because for the first time ever, European patients have documented what they need as a minimum standard of care.
Annemiek van Wegberg announced the results of the survey conducted at the last E.S.PKU conference about the development of the guidelines for PKU. She emphasised how important it was to have a patient review of the guidelines. The survey results provide some broad conclusions:
• patients want transition to an adult care team, but this team needs to meet certain requirements;
• education needs to be repeated and different methods can be effective in patients at various phases of their lives;
• self-monitoring can have an additional value in compliance, but cannot replace the contact with the healthcare centre.
Prof van Spronsen presented the latest update in guidelines two years on from the first meeting held in Liverpool in 2012. The long journey to develop guidelines began because of large differences between countries and centres in treatment issues. The E.S.PKU asked the chair of their Scientific Advisory Board to build a team of experts and asked various pharmaceutical and nutritional companies to financially support the process. After the last meeting of experts there are now 40 finalised statements. Prof van Spronsen gave some examples for PKU targets:
He explained what still needed to be done: five more statements to be finalised; the full report to be written; inviting “reading professionals” to “judge” the statements; inviting patients to look at the results. After that the guidelines must be disseminated; we need to make sure the guidelines are used in practice; formulating a research agenda for the next years; and work on international guidelines for Europe and USA.
Mr Dalibor Dujmic introduced a video about the PKU Cup 2014, which was held in Croatia and included the Croatian and the Slovenian PKU Societies. He explained that the project PKU Cup is an initiative to connect European youth affected by phenylketonuria (PKU) in the form of an amateur sports competition. The project included 24 participants and was a bilateral youth exchange project with two themes: health and open air sport activities.
Specific goals were:
In the PKU Cup 2014 the winner was Slovenia 8:2. The winner of the PKU Cup 2014 becomes the host of the next PKU Cup amateur sports competition. Youths are competing in football, basketball, badminton, ping pong, diving, swimming, rope pulling, volleyball, handball, hide and seek.
Assistant Prof Zlatko Giljevic showed how the international education and rehabilitation centre University Hospital Centre Zagreb operates.
The purpose of the centre is:
The education programme of the centre includes the promotion of a multidisciplinary approach for chronically ill people through lectures, seminars and workshops and the education of teachers.
Associate Prof Laurie Bernstein presented “Nutrition Education Tools used in PKU”, based on experiences at her clinic. She started with some definitions. Patient education is the process by which health professionals and others impart information to patients that will alter their health behaviours or improve their health status. She underlined the individual differences in learning leading to health literacy - the capacity to obtain, process, and understand basic information and services when making decisions on their health. She surveyed patients and caregivers and gained 719 responses. Patients think that nutrition education is really important for dietary compliance and overall health. Handouts are the least effective in educating patients and caregivers, both clinicians and patients agree on that, even though clinicians utilise handouts nearly as often as one-on-one counselling.
She gave a quick overview on the project Radical Health that sees the patient as part of the educational process, with the concept of “compliance with treatment” becoming “a sustainable treatment”. She pointed out that usually appointments with physicians are quite short and most of the time the health care professional (HCP) is talking, determining that 50% of patients walk out of the appointment not knowing what they were told or what they are supposed to do. She gave some example of the materials she uses, starting from handouts to be used in teaching in groups or one-on-one situations. Better if these materials are not only printed out but are also interactive on the computer. She showed one of the tools she uses with children, “Energy Source Matching”, where you have to draw a line to connect the energy source to its user. She asked the audience to perform the exercise: if a rabbit needs the carrots, a mouse the cheese, a car the fuel, a PKU child needs its formula as an energy source. She let the audience do the “PKU Word Find”, words which are the mainstay of the disease and its treatment, i.e. energy, food, formula, phenylalanine (Phe), lowpro, vegetables and so on. Children will learn and reflect on words important to understand and learn how to manage their own disease. She showed in practice also another tool like the bingo made of food. The exercise for children is asking them to pick food from a box and asking them the content of Phe of that food (high or low), a yes or no food for a PKU patient. Finally she showed the Jeopardy game, with children achieving points for right or wrong answers to questions. . The most important goal of all these games are establishing and maintaining a shared perspective on the sustainability of chronic disease management. She said they are also working on computer-based simulations for the same purpose.
Prof Anita MacDonald illustrated her work on the development of taste in PKU patients, giving some background on the development of taste in the general population, starting with the early taste and experience of food flavours in amniotic fluid. Her aim was to determine the flavour preferences of children with PKU compared to age matched controls, to examine food and general neophobia and to consider dietary patterns. The conclusion of the study are that the PKU and control groups like sugar containing foods; the PKU group preferred sweet but not bitter vegetables, as expected from the early exposure to Phe-free amino-acids; and they have more food and general neophobia.
Annemiek van Wegberg conducted a survey with the audience on the patients perspective. First she asked some general questions like where patients are followed up, which health care professionals are seen during the regular check-ups at the clinic, which HCPs are available at the clinic and which are the ones patients would like to see and how often. Other questions were about Quality of Life, neurocognitive assessments, and the length of follow-up.
Dr Annet Bosch spoke on “Quality of life in PKU” with special focus on the PKU specific questionnaire she developed. She showed the validation study of the PKU-QoL questionnaire. A generic Health Related QoL (HRQoL) was insensitive to PKU-specific issues, that is why her working group developed and validated the first specific QoL questionnaire for PKU patients and their parents. The observational study aimed at validating the questionnaire was conducted in seven European Countries. The PKU-QoL questionnaire demonstrated satisfactory measurement properties for use in clinical research while its use in management in clinical practice is still being defined. They also tried to compare QoL in patients with and without BH4 treatment. What came out is that adolescents on BH4 treatment feel less sadness, while adults with BH4 feel less aggressiveness, less slow thinking. Nevertheless patients that are BH4 responsive have mild PKU, so future research is needed to address this issue.
Assoc. Prof. Bozena Mikoluc spoke about “The role of vitamin E in PKU”. She described vitamin E whose best-established biochemical function is its action as lipid antioxidant, even though it has also a nonantioxidant function like in cellular signalling. Her working group conducted a study in children with PKU detected on newborn screening and measured vitamin E, retinol and coenzyme Q10 with HPLC system. PKU patients showed significantly lower levels of vitamin E. This work, Prof Mikoluc said, opens new challenges about the need for routinely measured vitamin E in PKU patients and supplementing this when low. Symptoms of vitamin E deficiency are muscle weakness, loss of muscle mass, abnormal eye movements, vision problems, unsteady walking.
Dr Skadi Beblo shared her “Experiences with Sapropterin in Leipzig”, the centre where she works. With the introduction of BH4 usually there can be changes in metabolic control, in Phe-intake, in nutritional habits, in micronutrient supply and in QoL. Dr Belbo and colleagues assessed patients after 6 and 96 weeks from the start of BH4 treatment with regard to food habits, micro and macronutrients concentrations and QoL. The conclusion of the study is that in patients treated with BH4 there is a gain in QoL, patients show distinct nutritional differences in comparison with the healthy population: they adopt some “bad” nutritional habits of their healthy peers, they do not receive enough supply of iodine, calcium and vitamin D compared to the current recommendations. Thus patients under BH4 need nutritional education and control of micronutrient plasma concentrations.
Prof Jaume Campistol shared some data about “Target Phe levels: Is there evidence for 240 µmol/L?”. There are questions about the best target Phe levels raised by reports of suboptimal neurocognitive outcome in Early Treated PKU patients: those patients present mild neurological disturbances and impaired cognitive functions with differences in IQ, motor skills, visuo-spatial and executive functions. The primary goal of treatment for PKU patients is to achieve an outcome as normal as possible with regard to neurocognitive and psychosocial functioning. With time and research there has been some evidence of safe target levels developing normal intelligence but still subtle deficits especially in EF were detectable. Actual upper target Phe level is < 360 µM at least for the first six years of life but recent work raised the question about the 240 µM as upper limit to achieve no differences in performances with a control group. This subject needs further research on the problems of such a restricted diet for patients, family management and risk of nutritional deficits.
Prof Nenad Blau gave an overview about “Genotype-phenotype prediction in PKU”. He gave background information about the genetics of PKU: autosomal recessive inheritance; genotype determines the residual PAH activity; residual PAH activity determines the phenotype; compound heterozygosity occur in about 80% patients; genotype-phenotype correlation is partial (about 70%); importance of interallelic complementation. Using some bioinformatic tool such as FoldX and SNP3D for the protein stability and PoluPhen-2 and SIFT for the damaging effect of the mutations, his working group could improve the prediction of the phenotype and the BH4 responsiveness from the genotype. It is possible to predict phenotype for any genotype, but the quality depends on genotype class and information available; the best predictors are residual enzyme activity and the allelic phenotype; it is possible to also predict a BH4 responsiveness with the same limits.
Dr Stephan Huijbregts gave an introduction about “Neurocognitive measures: Differences between IQ and EF measures”. He started with a definition of IQ which is a score derived from one of the several standardized tests designed to assess human intelligence. The most used instruments to measure it are the Wechsler Intelligence Scales, different according to age range. Executive function (EF) instead refers to regulatory higher order cognitive abilities allowing integration and processing of information across a range of cognitive domains, sensory modalities, and response modalities. There are several instruments to measure it: paper and pencil tasks, computerized test batteries and questionnaires. IQ and EF are not unitary but EF is a little more unitary than IQ. Both have been found to be impaired in PKU and the impairment was found to be Phe-related. EF impairment appeared to be a little more evident and has been shown over an above IQ-impairment and irrespective of IQ. EF impairment has been linked to neuroanatomical abnormalities and also appears to be more directly linked to the dopamine pathogenic hypothesis. Nevertheless it is very difficult to find pure EF-tasks. Differences between PKU and controls seem to be a bit more convincing for EF than for IQ, EF is a clearer construct to try and improve in PKU than IQ.
Dr S. Demirdas showed the results about “Bone health in PKU: systematic review and meta-analysis”. Bone mineral density (BMD) is reported to be decreased in PKU patients. Results from the meta-analysis demonstrated that BMD in PKU patients is on the relatively lower side of the reference range for healthy individuals and prevalence of low BMD and osteoporosis seem to be higher in patients with PKU. Results from studies evaluating bone turnover markers (BTM) are inconclusive. Phe concentrations, vitamin D, PTH and other indicators do not seem to affect BMD or BTM.
Mrs Danique van Vilet presented a study entitled “BH4 treatment in BH4-responsive PKU patients: blood prolactin concentrations suggest increased cerebral dopamine concentrations”. The aim was to investigate whether BH4 may directly improve cerebral dopamine concentrations measured by mean of blood prolactin concentrations. Results are that high blood Phe in BH4-responsive PKU patients is associated with increased blood prolactin concentrations, suggesting reduced cerebral dopamine availability. With BH4 treatment blood prolactin are significantly lower, which cannot be explained by blood Phe levels. The issue to be addressed further is whether BH4 treatment may directly improve cerebral dopamine concentrations in PKU beyond its effect through lowering blood Phe concentrations.
Mrs van Vilet showed also the results of a study about “Large neutral amino acid supplementation improves cerebral neurotransmitter synthesis in adult PKU mice”. They tested the effect of LNAA supplementation on cerebral neurotransmitter synthesis. In PKU mice on LNAA supplemented diet, brain serotonin and norepinephrine concentrations were significantly higher compared to control diets, whereas dopamine concentrations did not significantly differ even in the presence of high brain Phe concentrations. Her working group thus suggest that LNAA supplementation might be a promising alternative treatment strategy for adult PKU patients who want to discontinue their dietary treatment.
Dr Hülya Gökmen Özel showed her work aimed at answering “Does diet liberalization have an impact anthropometric measure in PKU patients on relatively long-term BH4 treatment?”. 55 PKU patients on BH4 treatment for more than one year were recruited and data on height for age (HAZ) and body mass index (BMIZ) z scores were collected. In patients who could liberalize diet with the introduction of BH4 there was a significantly increase of HAZ while BMIZ did not change. In patients that were still on a diet together with BH4 treatment anthropometric measurements did not differ.
Dr Javier Sancho gave an update on the “Discovery and development of novel chaperones for PKU”. BH4, the natural cofactor of the Phenylalanine Hydroxylase (PAH) enzyme, exerts its chaperone effect on the mutated enzyme increasing its residual activity but it works only on some patients with mild PKU. His working group screened a chemical library of diverse compounds in search of novel PKU chaperones unrelated to BH4. Two novel compounds have been identified from the stabilization effect exerted on the WT enzyme, determined by means of thermal unfolding experiments. With the X-ray method the structure of the complex between PAH and one of the chaperones was solved. Now those compounds require to be tested on animal models and with different variants of PAH.
Mr Frederik Dagnaes-Hansen presented some data about “Breeding a PKU-mouse model on Phe-free diet, is it possible?”. The Pahenu2 mouse model on BTBR strain is available since 1990 and the mutation was then transferred to the inbred C57BL/6 mouse strain. His working group recently tried to breed homozygous animals on a Phe-free diet in order to reduce the number of surplus animals bred by heterozygous mothers. Results show that it is possible to breed the PKU mouse model homozygous animals on diet; that the offspring is viable and can be used for research; and that the colony efficiency is comparable to breeding heterozygous animals on normal chow.