UCL Great Ormond Street Institute of Child Health


Great Ormond Street Institute of Child Health


Does early biochemical metabolic control of Phenylalanine predict neurocognitive outcomes in childre

Supervisors: Professor Michelle de Haan, Imogen Newsom-Davis

Does early biochemical metabolic control of Phenylalanine predict neurocognitive outcomes in children with Phenylketonuria (PKU)?

Phenylketonuria (PKU) is a rare autosomal inborn error of metabolism, affecting approximately 1 in 10,000 UK births, with worldwide variation and, if untreated, results in global intellectual disability (1). Early infancy (0-2 years) is a critical time period for brain development and disruptions during this time can have long lasting detrimental effects on cognition (2). Newborn screening (NBS) means that PKU is now identified early, usually by five days of age, with treatment involving a low protein diet and dietary supplements starting soon after this. The aim of treatment is to reduce and stabilise Phenylalanine (Phe), an amino acid, within recommended levels as this is known to significantly improve cognitive outcomes (3,4). European guidelines (5) suggest that treatment should start by day ten but there is no evidence to support this treatment start time. In our tertiary PKU clinic at Great Ormond Street Hospital (GOSH), we have found that even with early initiation of treatment it can take on average 56 days (range 9-192 days) to stabilise Phe treatment commencement. The potential effect of very early Phe levels (and time to stability) on infant brain development, and its longer-term neurocognitive consequences, has not been explored. The NBS Programme and European guidelines also remain unable to give advice on exactly when stable Phe levels within range should be reached. We plan to conduct neurocognitive and electroencephalogram (EEG) assessments of a cohort of children with PKU (8-16 years) already known to the service, to provide further confirmation of the impact of very early stabilisation on cognitive outcome.

Aims /Objectives:

To determine: i) if the timing of treatment commencement and time to stabilisation of Phe in the neonatal period predicts neurocognitive functioning in childhood; ii) conduct cognitive and EEG assessments of children (ages 8-16 years) to define a childhood phenotype so that we are informed about which neurocognitive functions should be tracked in infancy in future studies.

This study will involve recruitment and assessment of the neurodevelopment and brain activity of children with PKU, a rare and unique cohort from GOSH.


80 children in the age range 8-16 with PKU known to GOSH who have been treated early and continuously with diet since the newborn period. To assess current cognition and brain activity during theory-driven tasks, along with concurrent and early Phe levels. In addition, standardized questionnaires will be used to evaluate any social, behavioural or emotional difficulties. Routine clinical blood samples will provide information on Phe levels.

Timeline (if applicable):
Fall 2023: Training on assessments and finalising ethics approval; literature review and library skills sessions
Jan 2024: Start of Data collection; start of systematic review on the topic
Jan 2025: Submit systematic review for publication
Jan 2026: Complete data collection and finalise analysis; write up of thesis; identify examiners.
Fall 2026 Submit completed thesis


1. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417-27.
2. Andersen SL. Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev. 2003;27(1-2):3-18.
3. Hood A, Grange DK, Christ SE, Steiner R, White DA. Variability in phenylalanine control predicts IQ and executive abilities in children with phenylketonuria. Mol Genet Metab. 2014;111(4):445-51.
4. Vilaseca MA, Lambruschini N, Gomez-Lopez L, Gutierrez A, Fuste E, Gassio R, et al. Quality of dietary control in phenylketonuric patients and its relationship with general intelligence. Nutr Hosp. 2010;25(1):60-6.
5. van Wegberg AMJ, MacDonald A, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162