The relationship between metabolic control and basal ganglia morphometry and function in individuals with early-treated phenylketonuria

Brown, Alexander A.; Clocksin, Hayley E.; Abbene, Emily E.; Ursery, Mikayla; Christ, Shawn E.

doi:10.1016/j.ymgme.2022.09.006

Cited by 7 publications

(6 citation statements)

References 72 publications

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“…In a small sample of 13 participants with PKU, mixing children, adolescents, and adults and performing manual volumetry of basal ganglia, Bodner et al [ 27 ] reported increased volumes of putamen and a significant positive correlation between current Phe levels and putamen volume. A similar positive correlation was reported by Brown et al [ 28 ] using automatic volumetry. To summarize, these discrepant results may be explained by methodological differences and/or the inclusion of dissimilar study groups, sometimes including patients with immature brains.…”

Section: Introductionsupporting

confidence: 89%

Volumetric brain reductions in adult patients with phenylketonuria and their relationship with blood phenylalanine levels

Pardo,

Capdevila-Lacasa,

Segura

et al. 2024

J Neurodevelop Disord

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Background Continued dietary treatment since early diagnosis through newborn screening programs usually prevents brain-related complications in phenylketonuria (PKU). However, subtle neurocognitive and brain alterations may be observed in some adult patients despite early treatment. Nevertheless, neuropsychological and neuroimaging studies in the field remain scarce. Objectives This work aimed to determine possible neuropsychological and structural brain alterations in treated adult patients with PKU. Methods Thirty-five patients with PKU and 22 healthy controls (HC) underwent neuropsychological assessment and T1-weighted magnetic resonance imaging on a 3 T scanner. FreeSurfer (v.7.1) was used to obtain volumetric measures and SPSS (v27.0.1.0) was used to analyze sociodemographic, neuropsychological, volumetric, and clinical data (p < 0.05). Results Adult patients with PKU showed significantly lower performance than HC in Full Scale IQ (t = 2.67; p = .010) from the WAIS-IV. The PKU group also showed significantly lower volumes than HC in the pallidum (U = 224.000; p = .008), hippocampus (U = 243.000; p = .020), amygdala (U = 200.000; p = .002), and brainstem (t = 3.17; p = .006) as well as in total cerebral white matter volume (U = 175.000; p = .001). Blood phenylalanine (Phe) levels in PKU patients were negatively correlated with the pallidum (r = -0.417; p = .013) and brainstem (r = -0.455, p = .006) volumes. Conclusions Adult patients with early-treated PKU showed significantly lower global intelligence than HC. Moreover, these patients showed reduced global white matter volume as well as reductions in the volume of several subcortical grey matter structures, which might be related to the existence of underlying neurodevelopmental alterations. Higher blood Phe levels were also negatively correlated with pallidum and brainstem, suggesting a higher vulnerability of these structures to Phe toxicity.

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Section: Introductionsupporting

confidence: 89%

Volumetric brain reductions in adult patients with phenylketonuria and their relationship with blood phenylalanine levels

Pardo,

Capdevila-Lacasa,

Segura

et al. 2024

J Neurodevelop Disord

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“…Mean Phe level for the year preceding study participation was calculated. As described previously by Christ et al [ 41 ] and Brown et al [ 42 ], an index of dietary control (IDC) was computed as the mean of all half-year median Phe concentrations for early childhood (0–5 years), middle childhood (6–11 years), adolescence (12–17 years), adulthood (18 + years), and across the lifetime (0-present). In the case of small gaps (eg, 1–2 years) in records, values were extrapolated using linear regression and Phe levels of adjacent years for purposes of IDC calculation.…”

Section: Methodsmentioning

confidence: 99%

Total choline intake and working memory performance in adults with phenylketonuria

Schoen

Boland

Christ

et al. 2023

Orphanet J Rare Dis

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Background Despite early diagnosis and compliance with phenylalanine (Phe)-restricted diets, many individuals with phenylketonuria (PKU) still exhibit neurological changes and experience deficits in working memory and other executive functions. Suboptimal choline intake may contribute to these impairments, but this relationship has not been previously investigated in PKU. The objective of this study was to determine if choline intake is correlated with working memory performance, and if this relationship is modified by diagnosis and metabolic control. Methods This was a cross-sectional study that included 40 adults with PKU and 40 demographically matched healthy adults. Web-based neurocognitive tests were used to assess working memory performance and 3-day dietary records were collected to evaluate nutrient intake. Recent and historical blood Phe concentrations were collected as measures of metabolic control. Results Working memory performance was 0.32 z-scores (95% CI 0.06, 0.58) lower, on average, in participants with PKU compared to participants without PKU, and this difference was not modified by total choline intake (F[1,75] = 0.85, p = 0.36). However, in a subgroup with complete historical blood Phe data, increased total choline intake was related to improved working memory outcomes among participants with well controlled PKU (Phe = 360 µmol/L) after adjusting for intellectual ability and mid-childhood Phe concentrations (average change in working memory per 100 mg change in choline = 0.11; 95% CI 0.02, 0.20; p = 0.02). There also was a trend, albeit nonsignificant (p = 0.10), for this association to be attenuated with increased Phe concentrations. Conclusions Clinical monitoring of choline intake is essential for all individuals with PKU but may have important implications for working memory functioning among patients with good metabolic control. Results from this study should be confirmed in a larger controlled trial in people living with PKU.

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“…Even with early and continuous treatment, individuals with PKU remain at risk for significant neurologic disruption affecting both white matter (e.g., Christ, Huijbregts, et al, 2010; Peng et al, 2014; Vermathen et al, 2007) and gray matter structures of the brain (e.g., Aldridge et al, 2020; A. A.…”

Section: The Present Studymentioning

confidence: 99%

The relationship between working memory and anxiety in individuals with early treated phenylketonuria (PKU).

Boland,

Schoen,

Singh

et al. 2024

Neuropsychology

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Objective: Although early diagnosis and treatment prevent the severe impairments associated with untreated phenylketonuria (PKU), individuals with early treated PKU (ETPKU) nonetheless experience significant neurocognitive and psychological sequelae, including difficulties in working memory (WM) and increased risk of anxiety. The primary objective of the present study was to examine the extent to which anxiety may moderate the relationship between ETPKU and WM performance. Method: A sample of 40 adults with ETPKU and a demographically comparable sample of 40 healthy adults without PKU completed a comprehensive assessment of WM performance and anxiety symptomatology. Data were collected using a variety of remote assessment methods (e.g., web-based neurocognitive tests, semistructured interview, report-based measures). Results: The ETPKU group demonstrated significantly poorer WM performance as compared to the non-PKU group. The groups did not differ significantly in anxiety; however, high anxiety was more common in the ETPKU group (53% of sample) than the non-PKU group (33%). A significant interaction between anxiety, metabolic control (as reflected by Phe levels), and WM performance was observed for the ETPKU group. Individuals with high anxiety and/or high Phe levels (>360 μmol/L) performed poorer than the non-PKU group. Individuals with low anxiety and relatively low Phe levels (<360 μmol/L) performed comparably to the non-PKU group. Conclusions: Anxiety was found to moderate the relationship between Phe levels and WM performance in individuals with ETPKU. This finding underscores the importance of accounting for anxiety when evaluating neurocognitive performance in individuals with ETPKU whether for research or clinical purposes.

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The relationship between metabolic control and basal ganglia morphometry and function in individuals with early-treated phenylketonuria

Cited by 7 publications

References 72 publications

Volumetric brain reductions in adult patients with phenylketonuria and their relationship with blood phenylalanine levels

Volumetric brain reductions in adult patients with phenylketonuria and their relationship with blood phenylalanine levels

Total choline intake and working memory performance in adults with phenylketonuria

The relationship between working memory and anxiety in individuals with early treated phenylketonuria (PKU).

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