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Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal
L L Gramegna1,2, A Pisano3, C Testa1,4,2
1From the Functional MR Unit (L.L.G., C.T., D.N.M., R.L., C.T.).
Background And Purpose:
Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology.
Materials And Methods:
Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient.
Results:
All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed.
Conclusions:
Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.
Insights
Mitochondrial neurogastrointestinal encephalopathy causes brain leukoencephalopathy due to thymidine phosphorylase gene mutations. Vascular damage and mitochondrial dysfunction are key mechanisms, impacting white matter integrity.
Area of Science:
- Neurology
- Mitochondrial Diseases
- Neuroimaging
Background:
- Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare genetic disorder caused by thymidine phosphorylase (TP) gene mutations.
- TP deficiency impairs mitochondrial DNA replication, leading to gastrointestinal issues and leukoencephalopathy.
Purpose of the Study:
- To investigate the mechanisms of brain leukoencephalopathy in MNGIE.
- Correlate multimodal neuroimaging findings with postmortem pathology.
Main Methods:
- Brain MRI, including MR spectroscopy and diffusion imaging, in seven MNGIE patients.
- Comparison of metabolite concentrations and diffusion metrics with healthy controls.
- Histologic, immunohistochemical, and molecular analyses of brain tissue from one patient.
Main Results:
- MNGIE patients exhibited white matter hyperintensities and reduced white matter metabolites (NAA, creatine, choline).
- Increased radial water diffusivity was observed in affected white matter.
- Postmortem analysis revealed vascular smooth muscle fibrosis, mitochondrial DNA depletion, and cytochrome c oxidase deficiency, without neuronal loss or gliosis.
Conclusions:
- Vascular and histologic changes drive leukoencephalopathy in MNGIE.
- Thymidine toxicity and impaired mitochondrial DNA replication may cause microangiopathy and blood-brain barrier dysfunction.
- Periependymal cytochrome c oxidase deficiency contributes to periventricular white matter impairment.
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