Tract‐based evaluation of white matter damage in individuals with early‐treated phenylketonuria

Abstract

Previous research has documented white matter abnormalities in the brains of individuals with early-treated phenylketonuria (ETPKU). The majority of these past studies have relied on a region-based approach which focused on a limited number of spatially-defined regions within the brain. In the present study, we used diffusion tensor imaging (DTI) in conjunction with tract-based spatial statistics (TBSS) to perform an extensive examination of white matter tracts in the brains of ten individuals with ETPKU (mean age = 23.2 years) and 12 healthy non-PKU individuals (mean age = 23.5 years). Consistent with past research, we found that mean diffusivity (MD) was significantly restricted in the ETPKU group, and fractional anisotropy (FA) was comparable between the ETPKU and non-PKU groups. Moreover, we found restricted axial diffusivity (AD) and radial diffusivity (RD) in our ETPKU in numerous white matter tracts, suggesting widespread white matter compromise in ETPKU. In addition, this white matter pathology was more evident in older ETPKU participants with higher blood phenylalanine (phe) levels as compared to younger participants with lower phe levels.

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

“…In the lack of neuropathological data from early treated PKU patients, the information on the brains of these patients comes from MRI studies performed in the last 20 years [1], which showed that white matter changes: a) usually appear during the second decade of life in virtually all PKU patients [11]; b) are related to the increase of blood phenylalanine, as supported by the fact that they recede 3 to 6 months after the restoration of a strict metabolic control [18,19]; c) are not found in subjects with blood phenylalanine level lower than 500-600 μmol/l. [20][21][22][23][24]; c) are affected by the levels of blood phenylalanine and the duration of the exposure to high phenylalanine levels [10,[25][26][27][28][29].…”

“…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.…”

Brain White Matter Integrity Mediates the Relationship Between Phenylalanine Control and Executive Abilities in Children with Phenylketonuria

“…Our knowledge of relationships between DTI findings and cognition is quite limited, but the three relevant studies to date point to associations between MD across a range of brain regions and IQ (Peng et al 2004(Peng et al , 2013Antenor-Dorsey et al 2013). There is, however, no research in which the interplay among white matter integrity, cognition, and Phe control has been modeled within a single study.…”

Linking genotypes database with locus-specific database and genotype–phenotype correlation in phenylketonuria

“…The SNPs3D (http:// www.snps3d.org) module assesses the effect of non-synonymous SNPs on protein stability and function based on sequence analysis, structural analysis (using wild-type protein structures as reference) and a Support Vector Machine (SVM). 16 A negative SVM Score classifies the substitution as destabilizing to the folded state, while positive scores indicate non-deleterious substitutions.…”

“…Various algorithms analyzing mutant PAH protein folding, stability and function have been developed to predict metabolic and clinical phenotype. We tested FoldX, 13 PolyPhen-2, 14 SIFT Blink 15 and SNPs3D 16 algorithms as well as residual PAH activity (%PAH) for each variant as instruments for phenotype prediction.…”