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. 2025 Jul 2;17(1):37.
doi: 10.1186/s11689-025-09622-8.

Diffusivity alterations related to cognitive performance and phenylalanine levels in early-treated adults with phenylketonuria

Jèssica Pardo #  1   2 , Clara Capdevila-Lacasa #  1 , Bàrbara Segura  3   4   5 , Adriana Pané  6   7 , Pedro J Moreno  8 , Glòria Garrabou  8   9   10 , Josep M Grau-Junyent  2   8   9   10 , Carme Junqué  1   2   11 ; Consortium PKU.cat
Collaborators, Affiliations

Diffusivity alterations related to cognitive performance and phenylalanine levels in early-treated adults with phenylketonuria

Jèssica Pardo et al. J Neurodev Disord. .

Abstract

Background: Altered white matter (WM) is consistently reported in patients with phenylketonuria (PKU). However, the knowledge about WM microstructural integrity in early-treated adults with classical PKU and its relationship with cognition and metabolic parameters is inconclusive. This study aims to explore the cerebral WM microstructural alterations in adult patients with early-treated classical PKU and their association with blood phenylalanine (Phe) levels and neuropsychological performance using whole-brain diffusion tensor imaging (DTI).

Methods: Twenty-nine patients with early-treated classical PKU (mean age = 30.86, SD = 7.74) and 31 healthy controls (mean age = 32.45, SD = 9.40) underwent neuropsychological assessment and MRI. Phe dry blood spot (DBS-Phe) samples, along with venous Phe levels, were collected from the PKU sample to calculate the index of dietary control (IDC). Tract-based spatial statistics (TBSS) of the mean diffusivity (MD), and fractional anisotropy (FA), were carried out with FSL v6.0.4 to assess between-group differences and to explore associations with both cognitive and clinical data.

Results: Patients exhibited a widespread white matter tract involvement, with lower MD and higher FA values compared to controls. The most affected tracts were the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus for MD, and the anterior corona radiata, uncinate fasciculus and forceps minor for FA. MD negatively correlated with IDC and venous Phe levels, whereas FA negatively correlated with full-scale intelligence quotient (FSIQ) (p-value ≤0.05 FWE-corrected).

Conclusions: Microstructural WM alterations were present in adults with early-treated classical PKU, and these abnormalities were related to global intelligence and metabolic control markers. Although our results suggest the importance of proper disease management, further studies are needed to determine its long-term relevance.

Keywords: Cerebral white matter; Dietary control; Diffusion tensor imaging; Neuropsychological performance; Phenylketonuria.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Bioethics Committee of the University of Barcelona (IRB00003099) and Hospital Clínic of Barcelona (HCB/2020/0552) and was conducted in accordance with the basic principles of the Declaration of Helsinki. This study was conducted following the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. All the participants of this study provided signed written informed consent, after a complete explanation of the procedures involved, and are available from the corresponding author upon reasonable request. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Graphic shows mean scaled scores of the subtests and indices of the WAIS-IV, per group. A Neuropsychological performance based on the subtests of the WAIS-IV, per group. B Neuropsychological performance based on the indices of the WAIS-IV, per group. Abbreviations: FSIQ, Full Scale Intelligence Quotient; HC, healthy controls; PKU, patients with phenylketonuria; PRI, Perceptual Reasoning Index; PSI, Processing Speed Index; VCI, Verbal Comprehension Index; WMI, Working Memory Index. *highlights significative results (p<0.05, FDR-corrected). Specific data regarding means and SD can be found in Table 2
Fig. 2
Fig. 2
Group differences in whole-brain MD and FA. A Lower MD values at whole-brain in the PKU group vs the HC group with age as a covariate. B Higher FA values at whole-brain in the PKU group vs the HC group with age as a covariate. Differences between groups are calculated through tract-based spatial statistics (TBSS). Results are overlaid on the WM skeleton (green) and displayed over the sagittal and axial sections of the MNI 152 standard brain, at p<0.001 TFCE-corrected. Specific data regarding highest statistically significant voxel, clusters and tracts can be found in Table 3, and other MD and FA significant tracts in Supplementary Table 2 and Supplementary Table 3, respectively. Abbreviations: A, anterior; L, left; P, posterior; PKU, patients with phenylketonuria; R, right
Fig. 3
Fig. 3
Whole-brain tract-based correlation between FA and FSIQ, in the PKU group. The image shows a negative correlation between whole-brain FA and the PKU group’s FSIQ performance with age as a covariate. Results are overlaid in white matter skeleton tracts (green), through tract-based spatial statistics (TBSS) and displayed over the axial, coronal, and sagittal sections of the MNI 152 standard brain (p<0.05, TFCE-corrected). Significant negative correlations are marked in cold colours. Specific data is detailed in Table 4. Abbreviations: A, anterior; FA, fractional anisotropy; FSIQ, Full Scale IQ; L, left; P, posterior; PKU, patients with phenylketonuria; R, right
Fig. 4
Fig. 4
Correlations between MD and Phe levels in the PKU group. A Significant negative correlation between MD and IDC Phe levels in PKU with age as a covariate. B Significant negative correlation between MD and venous Phe levels in PKU with age as a covariate. Results are overlaid in white matter skeleton tracts (green), through tract-based spatial statistics (TBSS), and displayed over the sagittal, coronal, and axial sections of the MNI 152 standard brain (p<0.05, TFCE-corrected). Significant negative correlations are marked in cold colours. Abbreviations: A, anterior; IDC, index dietary control; L, left; MD, mean diffusivity; P, posterior; Phe, Phenylalanine; PKU, patients with phenylketonuria; R, right. Specific data is detailed in Table 5
See this image and copyright information in PMC

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