1. Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy
- Author
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Elisa Boschetti, R. De Giorgio, Giovanna Cenacchi, Carla Giordano, Giuseppe Plazzi, Michio Hirano, Piero Parchi, Caterina Tonon, David Neil Manners, Fiorella Giancola, Roberto D'Angelo, Maria Lucia Valentino, Loris Pironi, Laura Ludovica Gramegna, Carlo Casali, Raffaele Lodi, Rita Rinaldi, Valerio Carelli, Leonardo Caporali, M. T. Dotti, Mariantonietta Capristo, Annalinda Pisano, Claudia Testa, Gramegna, L L, Pisano, A, Testa, C, Manners, David N, D'Angelo, R, Boschetti, E, Giancola, F, Pironi, L, Caporali, L, Capristo, M, Valentino, Maria Lucia, Plazzi, G, Casali, C, Dotti, M T, Cenacchi, G, Hirano, M, Giordano, C, Parchi, P, Rinaldi, R, De Giorgio, R, Lodi, R, Carelli, V, and Tonon, C
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Encephalopathy ,MNGIE ,mitochondrial ,Article ,030218 nuclear medicine & medical imaging ,White matter ,Leukoencephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Leukoencephalopathies ,Mitochondrial Encephalomyopathies ,Nuclear Medicine and Imaging ,medicine ,Humans ,Cytochrome c oxidase ,Radiology, Nuclear Medicine and imaging ,Thymidine phosphorylase ,biology ,business.industry ,Brain ,medicine.disease ,Hyperintensity ,Mitochondria ,Diffusion Magnetic Resonance Imaging ,medicine.anatomical_structure ,Gliosis ,Radiology, Nuclear Medicine and Imaging ,Neurology (clinical) ,Cerebral Small Vessel Diseases ,biology.protein ,Female ,medicine.symptom ,Radiology ,business ,030217 neurology & neurosurgery ,Mitochondrial DNA replication - Abstract
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.
- Published
- 2018
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