PKU is an autosomal recessive genetic disorder characterized by a deficiency in the phenylalanine hydroxylase (PAH) enzyme. The latter is an enzyme which catalyses the addition of a hydroxyl group to the end of the 6-carbon aromatic ring of phenylalanine, such that it becomes tyrosine. When there is PAH deficiency, phenylalanine is accumulated and converted into phenylpyruvate, also known as phenylketone, which is detected in the urine. A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the tetrahydrobiopterin cofactor in the patient. This cofactor is needed for proper activity of the PAH enzyme. Other, non-PAH involving mutations can also cause PKU. The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. The disease can arise unexpectedly when two people who conceive a child are both silent carriers of the gene. When two carriers conceive a child, there is a 25% probability for each pregnancy that the baby will have PKU.
The incidence of carriers in the general population is approximately one out fifty people, but the chance that two carriers will mate is only one out 2500. The incidence of PKU in USA is about 1 to every 10,000 to 20,000 Caucasian or Oriental births and far less in African Americans. Studies performed in Western Europe showed an incidence of 1:8000. These disorders are equally frequent in males and females and there are approximately 50,000 diagnosed patients in the developed world.
Since phenylalanine cannot be metabolized normally, it builds up in the blood and tissues and prevents the brain from developing properly therefore early diagnosis is essential because symptoms are not obvious in a newborn infant. Mental retardation may develop gradually and may not be evident for a few months since infants with PKU appear normal at birth. Many have blue eyes, fairer hair and skin than other family members. About 50% of untreated infants have early symptoms, such as vomiting, irritability, an eczema-like rash, and a mousy odor in the urine. Some may also have subtle signs of nervous system function problems, such as increased muscle tone, and more active muscle tendon reflexes. Later, severe brain problems occur with mental retardation and seizures. Other commonly noted features, in untreated children, include microcephaly, prominent cheek and upper jaw bones with widely spaced teeth, poor development of tooth enamel and decreased body growth.
The screening of the blood phenylalanine level of all newborns is carried out in each country at least 12 hours and generally 24-28 hours after birth. If the screening test is abnormal, other tests are needed to confirm or exclude PKU. Newborn screening allows early identification and early implementation of treatment. When treatment is not started within the first few weeks of life, mental retardation occurs, but if treatment is begun early and well-maintained, affected PKU children can expect normal development and a normal life span.
The aim of the treatment of PKU is to maintain the blood level of phenylalanine between 2 and 10 mg/dl through the elimination of amounts of phenylalanine higher than those occurring in normal diet. High protein foods, such as meat, fish, poultry, eggs, cheese, milk, breast milk, dried beans and peas must be avoided. Instead, measured amounts of cereals, starches, fruits and vegetables, along with a milk substitute, are usually recommended. Dietary foods and dietary soft drinks containing aspartame must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid. Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a protein free diet. For women affected by PKU, it is essential, for the health of their child, to maintain low phenylalanine levels before and during pregnancy, because, if they are not on diet, the child may develop congenital heart disease, growth retardation, microcephaly and mental retardation.
The oral administration of tetrahydrobiopterin or BH4, a cofactor in the oxidation of phenylalanine, reduces blood levels of the amino acid especially in patients with mild mutations and significant residual enzyme activity. It is being introduced in the US for treatment of the disease. A synthetic BH4 has been recently obtained a marketing authorization by the European Commission. Such drug had previously received Orphan Medicinal Product designation from the EMEA as the first orphan drug for the treatment of HPA.
It is not possible to know in advance whether an individual with PKU will be responsive to the drug, so it must be tried for a certain length of time to determine its effectiveness. If it is effective, then a dosage requirement needs to be determined by the doctor. Patients treated with the drug have been able to discontinue the diet entirely; in other cases a combination of BH4 treatment and diet is required.
Future therapy may consist in the implementation of new techniques of nutrigenomics that investigate the interaction between nutrition and the genome, thereby combining nutritional research with functional genomics. Nutrigenomics could be able to clarify the relationships between bioactive molecules, genetic polymorphisms and biological system thus improving the prevention of nutrition-related diseases, by establishing customized nutritional recommendations.
Francesca Romana Antonetti
Tommaso Sacco
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The topics covered started from the epidemiological approach to the disease, immunopathogenesis, pathophysiology, MS diagnosis and monitoring to end up with treatments and future approach to the disease management.
Prof Kock-Henriksen and Prof Cree presented data on the role of genetics and epidemiology in defining the etiology of the Multiple Sclerosis and these two presentations there were three keynote lectures held by Professors Hartung, Antel and Weiner that gave outstanding overviews on immunopathogenesis, biological basis of the recovery and phatophysiology of Multiple Sclerosis. Despite of the complexity of the above topics, the speakers were able to involve the audience and give them a good understanding of the subject. The morning ended with three more presentations on MS diagnosis, clinical courses and the application of Neurophysiology to monitor MS.
Other very interesting topics that developed a high level of scientific discussion were the differentiated treatment of the disease and disease management. Prof Edan showed an interesting clinical case on treatment strategy in aggressive remitting relapsing in a young woman with two different possible approaches “Induction versus escalating therapy”. Prof Freedman gave an excellent talk on the treatment approach by presenting diverse clinical cases and how to face them. Also mentioned were timing for therapy as a key to prevent disability, how to optimize treatment by modifying treatment regimens, and finally the balance between benefit and risk.
Prof. Comi concluded this excellent edition of MS Academia by giving a complete overview of the future treatment in MS and by inviting all the speakers to repeat this success next year in Düsseldorf, Germany.
Monica Lispi
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This international meeting brought together more than 250 participants from all over the world, and it also gave the opportunity to young scientists to present a talk on the topics covered by the symposium. The best presentation was awarded.
The two days were scheduled into seven sections. The first was focused on gametes and embryo evaluation. This topic is becoming more and more important especially considering the influence that legal as well as ethical issues are having in various countries on the supernumerary embryos produced in ART and how to store and use them. The lecture presented by Dr Paffoni on the Parthenogenetic activation in mammals was particularly challenging. This model was proposed as an alternative tool to investigate embryo development which may solve ethical concerns.
The second topic was concentrated on the complex interactions between the embryo and the endometrium during implantation. Dr. Garlanda gave an interesting talk on the role of molecular dialogues that take place between the maternal endometrium, the conceptus and placenta. These dialogues involve several molecules such as hormones, growth factors, cytokines, chemokines, and adhesion molecules. This maternal-fetal interaction creates an inflammatory response and a state of system inflammation; she explained how this scenario modulates the embryo implantation and the first phases of fetus development.
The relationships between ART, pregnancy rate and risk factors were covered in the third session. Prof. Devroey showed, by using available tools such as Single Embryo transfer and GnRH antagonist protocol, how it is possible to avoid multiple pregnancy and OHSS. Fertility preservation and cancer in fertility are the most novel topics in reproductive medicine and this was extensively covered in sessions four and five by Italian and International specialists.
In session six the speakers provided an overview on pregnancy and heart diseases as well as in patients with autoimmune diseases. For the first topic Prof. Presbiterio argued the need to establish a solid network between gynecologists and cardiologists to facilitate successful pregnancies in patients with heart diseases. Dr Bellver from Valencia gave an intriguing presentation on how to manage ART in patients with SLE, which are the risks, and he highlighted when we should avoid ART in such patients.
Monica Lispi
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Tommaso Sacco
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Session I was dedicated to stem cells. Carlos Simon showed the lastest achievements in understanding the role of endometrial stem cells, Ana Marqués delivered a speech on the use of stem cells as source of gametes and Roberto Ensenat reviewed the methods aimed at reprograming somatic stem cells and mature differentiated stem cells, such as nuclear transfer or cellular fusion. Session II was designed based on the COGI format where two speakers offered different points of view in order to stimulate the discussion. The topics covered were: in vitro maturation (IVM) in clinical practice, the choice of better preparation for IVM and the role of IVM in fertility preservation. In particular, Seang Lin Tan delivered a comprehensive lecture on the methods used for fertility preservation in cancer and autoimmune patients.
This was not the only part of the Symposium dedicated to fertility preservation. Sessions III and IV saw some lectures focused on methodologies proposed or implemented for fertility preservation. This has been another step in SSIF mission in spreading the knowledge on this topic and the next one will be the Symposium that SSIF will organize in Brussels, in December 2009, together with the International Society of Fertility Preservation. The speakers that animated the next Sessions offered a comprehensive review of methods aimed at the cryopreservation of gametes, embryos, whole ovaries and stem cells. Alan Handyside closed the meeting with an interesting lecture on perspectives of reproductive medicine in the era of personal genome.
Tommaso Sacco
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The success of the meeting was thanks to the absolute excellence of the faculty and the enthusiasm that animated discussions. The first session was dedicated to the methodological aspects with Stephen Sawcer and Jorge Oksenberg delivering two exhaustive speeches that were the right introduction to the subsequent talks. Daniel Cohen’s lecture was both informative and provocative concluding that “many methodological improvements are required to better exploit modern genetic tools and this demands behavioural changes: unique thinking, reductionism, gene by gene approach”. The next two sessions offered a comprehensive review of linkage and genome wide study outcomes in four main autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic lupus erithematosus and Crohn’s disease. The speakers, all deeply involved in researches in these fields, reported both personal data as well as literature overviews and compared experiences. Session four was focused on multiple sclerosis and showed how fast are researches on genetic factors influencing response to MS pharmacological treatments proceeding and that, in the near future, genetic based personalized medicine will be implemented in MS, like now in oncology for same cancers.
In the following session Federica Di Nicolantonio, in her interesting lecture, offered some examples of optimization of oncological therapies based on genetic and molecular traits of both patients and tumours. Fabio Macciardi, in the last session, reviewed the statistical issues related to pharmacogenetic studies and Giancarlo Comi, summing up the main contents of the Symposium, provided many stimulating take home messages.
Tommaso Sacco
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New Frontiers in Fertility; February 13-14, 2009; Lisbon, Portugal
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NEW ONLINE COURSE IN REPRODUCTIVE HEALTH
New trends: IVF in a globalised world is now available on the Serono Symposia International Foundation website |
The objective of this course is to provide participants with the most updated knowledge on IVF procedures and with skills useful in IVF practice using an interactive format with a strong emphasis on discussions between the faculty and the participants.
Recent findings have provided new insights on the pathophysiology of Multiple Sclerosis and on the role of the immune system in this disease. The aim of this annual edition of the Serono Symposia International Foundation conference in MS is to provide an update on these topics and to review the effects of available as well as future therapies on these mechanisms which offer the opportunity to individualize treatment. An overview on the neuroprotection approach will also be covered.
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NEW ONLINE COURSE IN NEUROLOGY
Improving current MS therapy is now available on the Serono Symposia International Foundation website |
The increasing knowledge on the pathogenesis and genetics of neurodegenerative disorders are showing that despite the categorization into a general definition, the disease patterns are very different one from another. In some case, the differences are so marked that it can support the hypothesis that each neurodegenerative disorder includes a cluster of disease. The aim of the symposium is to summarize evidences this approach is based on and stimulate the discussion.
This is an educational programme created to encourage the dissemination of scientific knowledge in the field of MS. It will stress the benefits of new diagnostic tools for defining the natural history of MS and disease activity monitoring. Current diagnostic criteria for MS will also be reviewed in the light of new medical evidence. A review of recent clinical trials and treatment optimisation guidelines will also be presented.
This is an educational program created to encourage the dissemination of scientific knowledge among nurses from all over the world in the field of MS.
The aim of the Symposium is to create an interdisciplinary forum for discussing present and future developments in the field of phenylketonuria (PKU). PKU was formerly one of the most frequent definable causes of mental retardation. Thanks to newborn screening and early dietary therapy, mental retardation is now rarely seen in PKU. As a consequence of this remarkable and dramatic development, PKU has become the flagship for treatable genetic disease. Despite this wonderful advance, however, there remains a number of very troubling problems in long term outcome. Included among these is disagreement on how long the diet should be continued. Thus, new approaches such as enzyme replacement therapy, gene therapy, large neutral amino acids (LNAA), and tetrahydrobiopterin are of interest.