Phenylketonuria Scientific Review Conference: State of the science and future research needs

Abstract

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Confe...

Key European guidelines for the diagnosis and management of patients with phenylketonuria

“…Средняя фенилкетонурия (900-1200 мкмоль/л); 5. Классическая фенилкетонурия (>1200 мкмоль/л) [10]. Вышеуказанные клинические классификации признаются условными, так как у новорожденного концентрация фенилаланина не всегда максималь-ная к моменту проведения анализа.…”

“…Так, несмотря на раннее начало лечения и соблюде-ние диеты, у больных могут наблюдаться когнитив-ные отклонения, характеризующиеся особенностями зрительных и исполнительских функций, снижением скорости обработки информации, низким уровнем концентрации внимания, нарушениями динамич-ности процесса запоминания, речи. Даже при нор-мальном уровне интеллектуального развития у 96% детей с фенилкетонурией определяются различные изменения в эмоциональной сфере, мешающие их полноценной социальной адаптации: снижение по-знавательных способностей, высокий уровень тре-вожности, эмоциональная неустойчивость, гиперак-тивность, агрессивность [4,10]. Т.В.…”

Phenylketonuria felnőttkorban

“…Mivel az első, már újszülöttkora óta kezelt populáció most éri el a negyvenes életkort, nincs sem hazai, sem nemzetközi számottevő tapasztalat vagy klinikai vizsgálat a kezelt PKU, az élethosszig tartó fehérje-szegény diéta vagy a mesterséges aminosavtápszer késői kihatásairól. Kevés az ebben a témában rendelkezésre álló irodalmi adat, a nemzetközi ajánlások gyenge bizonyítékokon alapulnak, nagyon sok esetben gyermekgyó-gyászati tapasztalatokat használtak fel [8].…”

“…Egy friss amerikai ajánlás ezt a csoportot továbbosztja mérsékelt és enyhe PKUcsoportra, ahol az előző csoport a 900-1200 µmol/l, míg az utóbbi a 600-900 µmol/l vérszinttel bírókat foglalja magában. Normális diéta melletti 360-600 µmol/l vér Phe-szint közötti értékek a hyperphenylalanaemia szürke zónáját jelentik, míg a 360 µmol/l alatti szintekkel bírók a nem kezelendő enyhe hyper phenylalaninaemia-csoportba sorolandóak [8]. A tömeg-szűrés hatékonyságának köszönhetően azonban napjainkban olyan gyorsan kiemelik az érintett újszülöttet, hogy a fehérjeszegény diéta előbb kerül bevezetésre, mint hogy a vér Phe-szintje elérné a maximális értéket.…”

Intervention in the Context of Development: Pathways Toward New Treatments

“…This not only makes the intervention worthwhile, but it makes it easy to study, not even requiring a placebo-controlled trial. Further, developmental delay in PKU is evident before 2 years of age, allowing a much shorter duration of study than for most behavioral or cognitive impairments (Camp et al, 2014).…”