Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria

Bilder, Deborah A.; Noel, J. Kay; Baker, Erin Ruth; Irish, William; Chen, Yinpu; Meriläinen, Markus; Prasad, Suyash; Winslow, Barbara

doi:10.1080/87565641.2016.1243109

Cited by 111 publications

(119 citation statements)

References 81 publications

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“…However, Barkley () pointed out that although ADHD has been viewed as a disorder of primarily inattention and hyperactive–impulsive behavior, newer theories characterized deficits in executive functioning as essential to the disorder. Executive function problems are found to be associated with high levels of phenylalanine (Bilder et al, ). Because of the possible shared cognitive/behavioral phenotypes in PKU and ADHD, executive functioning is therefore also of particular interest when investigating HT‐1.…”

Section: Introductionmentioning

confidence: 99%

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

Barone

Bliksrud

Elgen

et al. 2019

American J of Med Genetics Pt B

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Hereditary tyrosinemia Type 1 (HT-1) is a rare metabolic disease where the enzyme catalyzing the final step of tyrosine breakdown is defect, leading to accumulation of toxic metabolites. Nitisinone inhibits the degradation of tyrosine and thereby the production of harmful metabolites, however, the concentration of tyrosine also increases. We investigated the relationship between plasma tyrosine concentrations and cognitive functions and how tyrosine levels affected enzyme activities of human tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2). Eight Norwegian children between 6 and 18 years with HT-1 were assessed using questionnaires measuring Attention Deficit Hyperactivity Disorder (ADHD)-symptoms and executive functioning. Recent and past levels of tyrosine were measured and the enzyme activities of TH and TPH2 were studied at conditions replicating normal and pathological tyrosine concentrations. We observed a significant positive correlation between mean tyrosine levels and inattention symptoms. While TH exhibited prominent substrate inhibition kinetics, TPH2 activity also decreased at elevated tyrosine levels.Inhibition of both enzymes may impair syntheses of dopamine, noradrenaline, and serotonin in brain tissue. Inattention in treated HT-1 patients may be related to decreased production of these monoamines. Our results support recommendations of strict guidelines on plasma tyrosine levels in HT-1. ADHD-related deficits, particularly inattention, should be monitored in HT-1 patients to determine whether intervention is necessary. K E Y W O R D SADHD, dopamine, hereditary tyrosinemia Type 1, inattention, serotonin

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Section: Introductionmentioning

confidence: 99%

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

Barone

Bliksrud

Elgen

et al. 2019

American J of Med Genetics Pt B

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“…In childhood, deficits are mainly observed in executive functions (EF), such as working memory (WM) and reasoning/planning, attention, and processing speed [8, 9]. In adults, similar deficits have been reported [10]. However, the majority of research has focussed on these specific cognitive domains, whereas other cognitive functions have received less attention.…”

Section: Introductionmentioning

confidence: 99%

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

Hofman

Champ

Lawton

et al. 2018

Orphanet J Rare Dis

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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.

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“…An estimated 88% of adults with PKU are unable to adhere to Phe-restriction long term, and even in those reporting adherence, blood Phe concentrations above recommended ranges commonly occur [4,[10][11][12][13]. Sapropterin is currently the only pharmacologic agent approved to treat adults with PKU, though it is only effective in patients with residual PAH activity; in clinical trials, only 20%-56% of patients with PKU responded to sapropterin, as measured by a reduction in blood Phe concentration [2,6,14,15].…”

Section: Introductionmentioning

confidence: 99%

Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial

Harding

Amato

Stuy

et al. 2018

Molecular Genetics and Metabolism

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Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria

Cited by 111 publications

References 81 publications

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

Tyrosinemia Type 1 and symptoms of ADHD: Biochemical mechanisms and implications for treatment and prognosis

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

Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial

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