Increased blood–brain barrier permeability with thymidine phosphorylase deficiency

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive multisystemic disorder caused by thymidine phosphorylase deficiency. Whereas the pathomechanism of the secondary mitochondrial dysfunction has been extensively studied, that of the leukoencephalopathy has not been elucidated. We hypothesized that the white matter hyperintensities on T2-weighted magnetic resonance images reflect disturbance of blood-brain barrier function. Albumin immunohistochemistry disclosed quantitative (p < 0.01) and qualitative differences between the mitochondrial neurogastrointestinal encephalomyopathy and control brains, indicating that loss of thymidine phosphorylase function impairs the integrity of the blood-brain barrier.

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

“…The observation of a marked mtDNA depletion in small vessel wall supports the hypothesis that the edematous features shown at cerebral magnetic resonance imaging in MNGIE patients could be due to breakdown of the blood-brain barrier. 22 Regarding the other types of mtDNA abnormalities described in MNGIE (ie, mtDNA deletion and point mutations), our results confirm the finding of very low levels of site-specific mtDNA point mutations in the different tissues of the GI wall. In addition, we show that mtDNA deletions are limited to the skeletal muscle component of the upper esophagus, in combination with partial mtDNA depletion, which is virtually complete in the COX-negative fibers as demonstrated in our single-fiber analysis.…”

The Role of Brain MRI in Mitochondrial Neurogastrointestinal Encephalomyopathy

“…The phenomenon is known as T2 washout 41,42 and is determined by annulment of DWI hypointensity because of T2 hyperintensity, as seen in posterior reversible encephalopathy syndrome 43 . This finding could indicate vasogenic interstitial oedema and correlate with the results of pathological studies 39 . severity of the disease did not significantly correlate with the extension and distribution of the white matter abnormalities.…”

“…In one report, all three studied patients had increased water content, reduced NAA, Cho and Cr and no lactate peaks in the areas of white matter T2-hyperintensity 35 , whereas in another study no abnormalities of the main metabolites were detected 36 . Divergent results were also obtained in pathological studies of brain autopsies in which loss of myelin and reduction of the number of myelinated fibres without gliosis were found in one patient 37 , while in two other studies no demyelination, gliosis, or spongy degeneration were detected 38,39 . On the other hand, a MNGIE mouse model showed increased T2 signal in the cerebral white matter on MRI and, at pathological evaluation, multiple vacuoles in subcortical, periventricular, internal capsule and cerebellar white matter without signs of focal demyelination 40 .…”

Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy

“…29 Similarly, in patients with relapsing-remitting multiple sclerosis, tract-specific DTI analysis of the optic radiations showed selective increases in RD only within the T2 lesions and, therefore, related to local myelin disruption. 30 The absence of demyelination at postmortem examination in one of our patients with MNGIE as well as in the other 2 previously reported cases 14 points to increased intramyelin water content as the most likely explanation for prominent or selective radial diffusivity found in brain white matter structures in our patients. A negative correlation between N-acetylaspartate concentration and mean diffusivity values within the same white matter volume was demonstrated, supporting the hypothesis of a dilution effect as the basis of the metabolite concentration reduction, possibly affecting neuronal cells, because no correlation was observed between any other metabolite concentration expressed in either neural or glial cells and any DTI metrics.…”

“…12 The neuropathologic study of 2 patients with genetically confirmed MNGIE did not show neuronal loss, demyelination, or glial proliferation, despite a striking loss of thymidine phosphorylase expression in capillaries of the white matter and an increased intracellular albumin staining, consistent with altered blood-brain barrier permeability. 14 The purpose of this study was to elucidate the mechanisms underlying brain leukoencephalopathy in patients with MNGIE using a multimodal neuroradiologic and pathologic approach.…”