Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study

Nardecchia, Francesca; Manti, Filippo; Chiarotti, Flavia; Carducci, Claudia; Carducci, Carla

doi:10.1016/j.ymgme.2015.04.003

Cited by 61 publications

(70 citation statements)

References 36 publications

(37 reference statements)

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“…On this issue, statistical analysis showed that all the disease-associated determinants we included in the statistical model leave unexplicated about 30 % of variability of WMSS. The apparent lack of a consistent link between white matter abnormality variations and variations of IQ (as in the present paper) and other cognitive domains such as executive functions [12] suggests that white matter alterations could not reflect the neuropathological background of the neuropsychological impairment. The fact that the exposure to phenylalanine may affect both mental functioning [30] and white matter integrity [18,19,29] but that these two effects are non reciprocally related might indicate that the pathogenic effect of phenylalanine affects independently different brain structures/functions with a different timing, perhaps according to their critical developmental stage [14].…”

Section: Discussioncontrasting

confidence: 62%

“…Despite the numerous studies focusing on this topic, several aspects of the white matter alterations in PKU remain to be elucidated: a) the outcome of white matter alterations; b) the weak link between neuroimaging alterations and neurological/neuropsychological impairment [1,11,12] even when more sophisticated MRI DTI-based microstructural examination were performed [19,28,29] c) the factors causing the wide interindividual variability in white matter alterations [10]; d) the neuropathological background of white matter abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…Thus it is possible that MRI variations had occurred and progressed before the ages considered in the presented series. In younger patients who were Cognitive test 26 22 F 12,0 0 441 610,5 NA NA 16,5 7 970 789 NA NA 20,5 2 1471,68 1003,75 88 WAIS-R 27 26 F 10,5 0 364 583 100 WISC III 16,0 0 799 623,5 NA NA 19,8 3 920 743 NA followed for a longer period, lasting about 14 years, we recently showed non-coincidental variations of white matter alterations and neuropsychological performances [12].…”

Section: Introductionmentioning

confidence: 85%

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The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

Mastrangelo

Chiarotti

Berillo

et al. 2015

Molecular Genetics and Metabolism

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

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The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

Mastrangelo

Chiarotti

Berillo

et al. 2015

Molecular Genetics and Metabolism

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“…Seven publications compared effects of high versus low Phe levels [33, 34, 40, 46–49]. However, all of these studies used different cut-off Phe levels for their high and low Phe groups: Bik-Multanowski et al [34] compared cognitive performance of ET AwPKU with concurrent levels of ≤720 μmol/L and > 720 μmol/L; Brumm et al [33] used cut-off Phe levels of < 1000 μmol/L and > 1000 μmol/L at the time of testing; Jahja et al [40] compared effects of concurrent, childhood, adolescent and lifetime Phe by comparing low and high Phe groups according to the most frequently used upper target treatment level during childhood, 360 μmol/L (low: < 360 μmol/L, high: ≥360 μmol/L); Bartus et al [48], de Felice et al [47] and Nardecchia et al [49] compared cognitive functioning of patients with Phe levels below and above 600 μmol/L, a frequently used upper target treatment level during adolescence and adulthood [50]; additionally, Bartus et al [48] compared cognitive task performance of ET AwPKU with average childhood (0–12 years) Phe below and above 360μmo/L; and, finally, Romani et al [46] divided their sample into two equally large subgroups based on their adulthood Phe levels (low: < 650 μmol/L, high: > 950 μmol/L), noting that their ET AwPKU group with good metabolic control (low Phe group) had adulthood Phe levels close to current treatment guidelines in the UK (< 700 μmol/L [51]).…”

Section: Resultsmentioning

confidence: 99%

“…Finally, three studies reported on a longer-term follow-up study of ET AwPKU [42, 49, 52]. Two of these compared cognitive outcomes during childhood with cognitive outcomes in the same sample in adulthood [42, 49].…”

Section: Resultsmentioning

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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The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

Burlina

Lachmann

Manara

et al. 2019

J of Inher Metab Disea

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Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long‐term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine‐restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early‐treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early‐treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU‐specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.

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Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study

Cited by 61 publications

References 36 publications

The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

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

The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

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