A systematic review of cognitive functioning in early treated adults with phenylketonuria

Abstract

BackgroundEven though early dietary management of phenylketonuria (PKU) successfully prevents severe neurological impairments, deficits in cognitive functioning are still observed. These deficits are believed to be the result of elevated levels of phenylalanine throughout life. Research on cognitive functioning in adults with PKU (AwPKU) often focuses on domains shown to be compromised in children with PKU, such as attention and executive functions, whereas other cognitive domains have received less attention. This systematic review aimed to provide an overview of cognitive functioning across domains examined in early treated (ET) AwPKU.MethodsA systematic search was performed in Ovid MEDLINE(R), PsycINFO, Web of Science, Cochrane, Scopus, Embase, ScienceDirect, and PubMed for observational studies on cognitive performance in ET AwPKU.ResultsTwenty-two peer-reviewed publications, reporting on outcomes from 16 studies were reviewed. Collectively, the results most consistently showed deficits in vigilance, working memory and motor skills. Deficits in other cognitive domains were less consistently observed or were understudied. Furthermore, despite reports of several associations between cognitive performance and phenylalanine (Phe) levels throughout life the relationship remains unclear. Inconsistencies in findings across studies could be explained by the highly heterogeneous nature of study samples, resulting in large inter- and intra-variability in Phe levels, as well as the use of a variety of tests across cognitive domains, which differ in sensitivity. The long-term cognitive outcomes of early and continuous management of PKU remain unclear.ConclusionsTo better understand the development of cognitive deficits in ET AwPKU, future research would benefit from 1) (inter)national multicentre-studies; 2) more homogeneous study samples; 3) the inclusion of other nutritional measures that might influence cognitive functioning (e.g. Phe fluctuations, Phe:Tyrosine ratio and micronutrients such as vitamin B12); and 4) careful selection of appropriate cognitive tests.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0893-4) contains supplementary material, which is available to authorized users.

Phenylketonuria, co‐morbidity, and ageing: A review

“…Despite treatment, subtle cognitive deficits are still observed in ETAwPKU. [28][29][30] Underlying mechanisms are still under debate, and there is wide inter-individual variability, but such deficits have been associated with observed disruptions in brain pathophysiology (eg, demyelination and disturbed neurotransmitter synthesis). Some observed disruptions are similar to those seen in healthy ageing, but occur at a younger age in ETAwPKU (see Box 2).…”

Generic preference‐based health‐related quality of life in children with neurodevelopmental disorders: a scoping review

“…12,29,33,[49][50][51] The quality of identified studies was assessed by a single author (RL) using the Quality Assessment Tool for Studies with Diverse Design. Further goals were to collect evidence on psychometric properties of these instruments in the identified studies, to explore how the authors justify instrument selection for a particular NDD and the respective group(s) of respondents, and to explore authors' concerns regarding the use of instruments and the respondent type.…”

Examining the blood amino acid status in pretherapeutic patients with hyperphenylalaninemia

“…They are transported to the brain by the same amino acid transporter in the blood–brain barrier. In PKU, elevated plasma Phe levels impair the transport of other LNAAs, resulting in cerebral depletion of LNAA and hence decreased biosynthesis of protein and impaired brain function . Increased cerebral Phe competes with Gly and Glu for their receptors, changing the levels of receptor expression and thus influencing the synaptic function .…”

“…In PKU, elevated plasma Phe levels impair the transport of other LNAAs, resulting in cerebral depletion of LNAA and hence decreased biosynthesis of protein and impaired brain function. 8,15 Increased cerebral Phe competes with Gly and Glu for their receptors, changing the levels of receptor expression and thus influencing the synaptic function. 16 A previous study reported that the glutamatergic synaptic transmission in the brain is impaired in patients with PKU.…”