The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study

TLDR: MRI abnormalities in phenylketonuria are the result of a distinctive alteration of white matter suggesting the intracellular accumulation of a hydrophilic metabolite, which leaves unaffected white matter architecture and structure.

Abstract: Objective: To gain insights into the nature and pathogenesis of white matter (WM) abnormalities in PKU Methods: Thirty-two patients with phenylalanine hydroxylase deficiency (21 with early and 11 with late diagnosis and treatment) and 30 healthy controls underwent an integrated clinical, neuroimaging (30 T MRI, diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI)) and neurochemical (1H MRS) investigation Results: All patients had white matter abnormalities on T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) scans; parietal white was consistently affected, followed by occipital, frontal and temporal white matter T1-weighted hypointense alterations were also found in 8 of 32 patients DWI hyperintense areas overlapped with those detected on T2W/FLAIR The apparent diffusion coefficient (ADC) was reduced and correlated inversely with severity of white matter involvement Fractional anisotropy index, eigenvalues λmin, λmiddle, λmax obtained from DTI data, and the principal brain metabolites assessed by 1H MRS (except brain phenylalanine (Phe)) were normal Brain Phe peak was detected in all but two subjects Brain and blood Phe were strictly associated Blood Phe at the diagnosis, patient’s age, and concurrent brain Phe independently influence white matter alteration (as expressed by conventional MRI or ADC values) Conclusions: (a) MRI abnormalities in phenylketonuria are the result of a distinctive alteration of white matter suggesting the intracellular accumulation of a hydrophilic metabolite, which leaves unaffected white matter architecture and structure (b) White matter abnormalities do not seem to reflect the mechanisms involved in the derangement of mental development in PKU (c) Our data do not support the usefulness of conventional brain MRI examination in the clinical monitoring of phenylketonuria patients