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From basic knowledge to daily management

From basic knowledge to daily management
  • Endocrinology and metabolism
  • Phenylketonuria (PKU)

Resource type


What do mouse models tell us?

what do mouse models

Mouse models have been and continue to be vital in the development of our understanding of PKU and the development of diet-, cell- and gene-based therapies, Prof Beat Thöny 1 explained.

There are three distinct mouse models in use: PAH-enu1, PAH-enu2 and PAH-enu3. These strains were all created using random chemical mutagenesis. PAH-enu1 is a model for mild PKU/hyperphenylalanemia (HPA), the other two are models for classical PKU. PAH-enu2, the most widely used model, carries a missense mutation that completely inactivates the PAH.

Recently, heterozygous PAH-enu2/wt mice have been employed as a sensitive assay system to test antisense oligonucleotides for splice suppression therapy in the liver.

Oxidative stress in PKU

oxidative stress in pku

Oxidative stress caused by high Phe concentrations may be involved in the pathophysiology of the brain dysfunction, said Dr Priscila Mazzola 2. In vitro, high Phe concentrations (similar to those found in patients) lead to oxidative stress in neurons, although the mechanisms are not fully understood. In animal models of PKU there is oxidative stress in the brain, due to both increased production of reactive species and decreased antioxidant capacity. Given the degree to which the brain is affected in PKU, the possibility that oxidative stress may play a part is worthy of investigation. Studies in PKU patients have found increased damage to biomolecules and lower antioxidant defenses in plasma.

A number of studies on antioxidants (or redox active substances) have been conducted, showing that these substances can prevent oxidative stress in PKU. The PKU dietary formulas supply micronutrients, many of which are antioxidants. New antioxidant therapies are constantly being studied in order to prevent oxidative stress in PKU.

Oxidative stress is characterized by an imbalance in the production and removal of reactive chemical species and free radicals. These harmful substances are normally formed during cellular respiration and easily react with biomolecules. Cellular damage is prevented by the antioxidant system, a combination of enzymatic and non-enzymatic defenses which convert reactive species of oxygen into non-toxic compounds.


A question of taste

a question of taste

Children with PKU, aged four years and over, when given the choice, prefer sweet foods over savory foods. This, explained Prof Anita MacDonald 3, contradicts the long-held theory that early introduction of bitter-tasting Phe-free L-amino acids altered food preferences in children with PKU.

Prof MacDonald shared the results of an observational, controlled, prospective study recently completed by her team. The study compared the taste preferences of 35 children with PKU and 35 age/gender matched (control) children aged 4—13 years.

In a blind taste test, the children tasted 10 puree foods in random order, rating them using a 7-point pictorial hedonic scale (super yummy to super yucky) and then ranked them in preferential order. Carers completed a neophobia and food frequency questionnaire.

Both PKU and control groups rated sugar containing foods highly. Generally children with PKU ranked vegetables higher than controls and the controls ranked fruit higher than children with PKU. Children with PKU had more overall neophobia (uncomfortable in unfamiliar environments) and were untrusting/fearful of new foods. Compared with control children, those with PKU consumed 50—100% more high energy foods including: sugar containing drinks, sweets, chips, sweet biscuits and crisps.

Is early aging and cognitive loss a risk in PKU?

is early aging and cognitive

A link between high Phe levels and neurodegenerative disorders has been suggested, Dr Andrea Pilotto 4 told delegates. If this proves to be the case, it could have a bearing on the current recommended ‘safe’ Phe levels for adults and be a concern for adult patients wishing to liberalize their diet.

Early treated PKU (ETPKU) patients could have an increased risk of neurodegenerative disorders because of the complex pathophysiology of the disease. Dysmetabolic abnormalities, oxidative stress and amyloid pathology may increase the risk of incident neurodegenerative disorders such as Alzheimer’s (AD) or Parkinson’s (PD) diseases in ETPKU subjects entering their middle age.

Most ETPKU patients present in early adulthood with subtle neurological symptoms, especially in behavioral, executive, visual-spatial and motor functions. The damage to the central nervous system has been explained by several mechanisms including vitamin or neurotransmitter deficits, increased oxidative stress and white matter abnormalities.

Recently an atypical amyloid pathology probably secondary to Phe aggregation has been reported in PKU brains. A pilot study to assess the risk of early neurodegeneration (EN-ETPKU Study) will evaluate the presence of neurodegenerative biomarkers in ETPKU patients entering middle-age.

European guidelines statements: have your say

european guidelines

 'I am not here so much to talk as to listen!' announced Ms Annemiek van Wegberg 5.  As we progress towards the formulation of EU guidelines we are finding that in some areas there are sufficient data for the working groups to reach consensus relatively easily. However, in other areas the evidence-base is weak or contradictory. Consensus is much harder to reach when this is the case. The unpublished experience-base of the wider PKU community can be vital here. Ms van Wegberg asked delegates for their views and encouraged them to be part of the process.

  1. Prof Beat Thöny (Division of Metabolism, Department of Paediatrics, University of Zürich, Zürich, Switzerland)
  2. Dr Priscila Mazzola (Department of Molecular Neurobiology, Beatrix Children's Hospital, University of Groningen, The Netherlands)
  3. Prof Anita MacDonald (Dietetic Department, The Children's Hospital, Birmingham, UK)
  4. Dr Andrea Pilotto (Neurology Department, Prof. Daniela Berg Research Group, Hertie-Institut for Clinical Brain Research and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany)
  5. Ms Annemiek van Wegberg (University Medical Centre Groningen, Groningen, The Netherlands and Radboud University Medical Centre, Nijmegen, The Netherlands)

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Target audience
Paediatricians, Dietitians, nutritionists, Scientists, Healthcare professionals
by Excemed
Endocrinology and metabolism