The impact of metabolic control on cognition, neurophysiology, and well-being in PKU: A systematic review and meta-analysis of the within-participant literature

Abstract

Phenylketonuria (PKU) is a metabolic disease where Phenylalanine (Phe) rises much above normal levels. Cross-sectional and correlational studies provide valuable information on the importance of maintaining low blood-Phe to achieve good outcomes, but they may be confounded, at least partially, by differences in participant demographics. Moreover, the effect of Phe at older ages is difficult to ascertain because of strong associations between Phe levels across ages. Within-participant studies avoid confounding issues. We have reviewed these studies. We followed PRISMA guidelines to search the literature for studies reporting the impact of Phe changes within participants. Phe was either increased or decreased through diet relaxation/resumption or through pharmacological interventions. Forty-six separate articles reported, singly or in combination, results on cognition (N = 37), well-being (N = 22) and neurophysiological health (N = 14). For all studies, we established, in a binary way, whether a benefit of lower Phe was or was not demonstrated and compared numbers showing benefit versus a null or negative outcome. We then analyzed whether critical parameters (e.g., length of the study/condition for the change, size of Phe change achieved) influenced presence or absence of benefit. For a subset of studies that reported quantitative cognitive outcomes, we carried out a meta-analysis to estimate the size of change in cognitive performance associated with a change in Phe and its significance. There were significantly more studies with benefits than no benefits, both for cognitive and well-being outcomes, and a trend in this direction for neurophysiological outcomes. The meta-analysis showed a highly significant effect size both overall (0.55) and when studies with adults/adolescents were considered separately (0.57). There was some indication that benefits were easier to demonstrate when differences in Phe were larger and achieved across a longer period, but these effects were not always consistent. These results reinforce results from the literature by demonstrating the importance of lower Phe in children as well as in adolescents and adults, even when confounding factors in group composition are eliminated. The field would benefit from further studies where Phe levels are contrasted within-participants to ascertain how much Phe needs to be changed and for how long to see a difference and which measures demonstrate a difference (e.g., which cognitive tasks).

Publication DOI: https://doi.org/10.1016/j.ymgme.2022.106969
Divisions: College of Health & Life Sciences > School of Psychology
College of Health & Life Sciences > Clinical and Systems Neuroscience
College of Health & Life Sciences > School of Optometry > Vision, Hearing and Language
College of Health & Life Sciences
Additional Information: Copyright © 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
Uncontrolled Keywords: PKU,Metabolic control,Within-participant studies,Outcomes,Treatment studies,Phenylketonuria
Publication ISSN: 1096-7206
Last Modified: 07 Oct 2024 07:42
Date Deposited: 18 Jan 2023 15:15
Full Text Link:
Related URLs: https://www.sci ... 096719222004474 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Review article
Published Date: 2023-01
Published Online Date: 2022-12-13
Accepted Date: 2022-12-10
Authors: Thomas, Lucie
Olson, Andrew
Romani, Cristina (ORCID Profile 0000-0002-5693-4131)

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