User login

We offer our registered users tailored information, free online courses and exclusive content.

You have an old EXCEMED account ...

Our platform has been renewed. All users registered at any of the old websites are kindly requested to reset their password. Why is this?

... or you lost your password?

This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Recommended reading – key published papers from 2018 so far

Recommended reading – key published papers from 2018 so far
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

Resource type



Recommended references
metabotropic glutamate receptors



The PKU literature has seen the publication of 2 key trial papers in the first half of 2018 – the PRISM-1 and PRISM-2 clinical trials of Palynziq (pegvaliase-pqpz), coinciding with the FDA decision to license this novel enzyme substitution therapy for adults with PKU.

Other papers of note include a retrospective review of the long-term use of protein substitute for weaning, a study suggesting those on a protein-restricted diet do still grow to normal height, a novel therapy for PKU showing potential in mice, and several papers exploring the psychological impact on parents of having a child diagnosed with PKU.

These papers are in no particular order


Thomas JLevy HAmato SVockley JZori RDimmock DHarding COBilder DAWeng HHOlbertz JMerilainen MJiang JLarimore KGupta SGu ZNorthrup HPRISM investigators. Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM). Mol Genet Metab. 2018 May;124(1):27-38.

This Phase 3 clinical trial studied 261 pegvaliase-naïve patients with blood Phe >600 μmol/L who were randomized to receive either 20 or 40 mg/day pegvaliase. Most PKU patients in the Palynziq trials were on an unrestricted diet prior to and during the trials. Within 24 months, just over half the participants achieved blood Phe ≤120 μmol/L – that is, below the upper limit of normal in the unaffected population. Adverse events were mostly mild or moderate in intensity and resolved without needing to interrupt or reduce treatment. Acute systemic hypersensitivity was observed in 12 participants, of which 6 remained on therapy. These cases occurred most frequently during upward titration of the dose within the first year of treatment, and prompted a Boxed Warning from the FDA labelling (FDA approval information available from:

Article available from:


Harding COAmato RSStuy MLongo NBurton BKPosner JWeng HHMerilainen MGu ZJiang JVockley JPRISM-2 Investigators. Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial. Mol Genet Metab. 2018 May;124(1):20-26.

Results of the second Phase 3 trial for pegvaliase (PRISM-2) – a randomized discontinuation trial designed to evaluate the effects of treatment on blood phenylalanine levels and neuropsychiatric outcomes in adults with PKU are described in this paper. This trial took 66 patients who had completed either a prior Phase 2 or 3 trial with pegvaliase and who had achieved at least a 20% blood Phe reduction from their pre-pegvaliase baseline. Participants then received pegvaliase 20 or 40 mg/day or placebo for 8 weeks. The study found that the mean blood Phe reduction seen in the Phase 2 or 3 trial previously was sustained in the pegvaliase group, while the placebo group had mean blood Phe concentration increases toward pre-treatment baseline levels. The safety profile for most patients was manageable, with adverse events arthralgia and anxiety more common in those on active treatment than in those randomized to placebo.

Article available from:


Evans SDaly AMacDonald JPinto AMacDonald A. Fifteen years of using a second stage protein substitute for weaning in phenylketonuria: a retrospective study. J Hum Nutr Diet. 2018 Jun;31(3):349-356.

This retrospective analysis paper evaluated the long-term (>15 years) efficacy of a second stage, semi-solid, phe-free protein substitution to help meet non-Phe protein requirements during weaning of 31 children with PKU. Teething and illness adversely affected the administration of weaning protein substitute and the acceptance of solid foods.

Article available from:


Matic JZeltner NAHäberle J. Normal growth in PKU patients under low-protein diet in a single-center cross-sectional study. JIMD Rep. 2018 Feb 25.

This single-centre, cross-sectional study looked at growth in pediatric PKU patients (n=51) treated with a low protein diet and compared patient height with the height of healthy siblings and target height based on parents’ height. Results suggested that prepubertal patients were shorter that expected, but made up their growth after puberty, so that older patients were within their expected target height. This reassures parents and healthcare professionals that a low-protein diet in those with PKU allows for normal growth.

Article available from:


Liu XZhang CLiu KWang HLu CLi HHua KZhu JHui WCui YZhang X. Multiple SNPs detection based on lateral flow assay for phenylketonuria diagnostic. Anal Chem 2018 Mar  6;90(5):3430-3436.

This paper highlights a sensitive, low cost and easy-to-use point-of-care testing system formed by combining amplification refractory mutation system (ARMS) polymerase chain reaction with gold magnetic nanoparticles (GMNPs) and lateral flow assay (LFA) - the ARMS-LFA system – allowing the use of uniform conditions for multiple SNPs detection simultaneously. The high sensitivity and specificity of this testing system were demonstrated through genotyping seven pathogenic SNPs in the phenylalanine hydroxylase gene in 23 families. The ARMS-LFA concordance rate of the genotyping results with DNA sequencing results was up to 97.8%.

Abstract available from:


Pascucci TRossi LColamartino MGabucci CCarducci CValzania ASasso VBigini NPierigè FViscomi MTVentura RCabib SMagnani MPuglisi-Allegra SLeuzzi V. A new therapy prevents intellectual disability in mouse with phenylketonuria. Mol Genet Metab. 2018 May;124(1):39-49.

Mice modified to represent a murine model of PKU were treated from days 15 to 64 post-natal with weekly infusions of erythrocytes loaded with recombinant Anabaena variabilis Phe Ammonia Lyase (rAvPAL). Therapy with rAvPAL normalized blood and brain Phe, prevented cognitive developmental failure, brain depletion of serotonin, dendritic spine abnormalities and myelin basic protein reduction, compared with placebo. No adverse events or inactivating immune reactions were observed.

Abstract available from:


Nardecchia FOrlando RIacovelli LColamartino MFiori ELeuzzi VPiccinin SNistico RPuglisi-Allegra SDi Menna LBattaglia GNicoletti FPascucci T.

Targeting mGlu5 metabotropic glutamate receptors in the treatment of cognitive dysfunction in a mouse model of phenylketonuria. Front Neurosci. 2018 Mar 16;12:154.

Group-I metabotropic glutamate (mGlu) receptors were studied in Pahenu2 (ENU2) mice, which mimic the genetics and neurobiology of human PKU. Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions. In extended analyses, expression of the long isoforms of Homer (proteins that link mGlu receptors) was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. In behaviour analyses, mGlu5 receptors were blocked, which improved the behavioural abnormalities in ENU2 mice, and offers a further route for therapy.

Article available from:


Kölker S. Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases. J Inherit Metab Dis. 2018 Jun 4. [Epub ahead of print]

As amino acids can act as neurotransmitters and are involved in various metabolic pathways, their synthesis and recycling as well as the composition and function of their receptors are often compromised in inherited metabolic diseases. This paper reviews some of these diseases, describing some of the elucidated synaptic dysfunctions.

Abstract available from:


Ambler OMedford EHare DJ. Parenting a child with phenylketonuria: An investigation into the factors that contribute to parental distress. JIMD Rep. 2018 Apr 20. [Epub ahead of print]

This cross-sectional study identified factors contributing to distress in parents who care for a child/adolescent with PKU and manage their low-protein diet, distinct from parents in the general population. Questionnaires measured parental psychological resilience, child behaviour problems, perceived social support and distress. Parents of children with PKU also completed measures of their child's care dependency and behaviour related to developmental and intellectual disabilities. The findings revealed no statistically significant differences in distress between the groups, but parents of children with PKU reported more child behaviour problems, particularly anxiety. From this work, interventions in clinical settings can be developed tailored to reducing parents' distress by enhancing their psychological resilience and supporting them to manage child behaviour difficulties, particularly anxious behaviour.

Abstract available from:


Verduci EMoretti FBassanini GBanderali GRovelli VCasiraghi MCMorace GBorgo FBorghi E. Phenylketonuric diet negatively impacts on butyrate production. Nutr Metab Cardiovasc Dis. 2018 Apr;28(4):385-392.

The effects of a phenylalanine (Phe) restricted diet combined with Phe-free l-amino acid supplementation on dietary intake and gut microbiota biodiversity was compared in children with PKU with those with mild hyperphenylalaninemia (MHP), on an unrestricted diet. Compared with MHP children, those on a PKU diet had increased carbohydrate (% of total energy), fiber and vegetable intakes (g/day), but a lower microbial diversity and a decrease in fecal butyrate content.

Abstract available from:


Carpenter KWittkowski AHare DJMedford ERust SJones SASmith DM. Parenting a child with phenylketonuria (PKU): an interpretative phenomenological analysis (IPA) of the experience of parents. J Genet Couns. 2018 Feb 21. doi: 10.1007/s10897-018-0227-7. [Epub ahead of print]

When a child is diagnosed with PKU, parents must assume immediate responsibility for the management of PKU and prevention of neurological damage. This study interviewed the parents of children under the age of two with PKU to explore how they experienced the psychosocial stressors associated with the PKU diagnosis in their child. Three main themes were identified: control, striving for normality and acceptance of PKU as a continuum – with the acceptance of PKU central to the parent's experiences.

Abstract available from:

Terms of use

This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.