L L Gramegna1,2, A Pisano3, C Testa1,4,2, D N Manners1,2, R D'Angelo4, E Boschetti5, F Giancola5, L Pironi5, L Caporali2,6, M Capristo2,6, M L Valentino2,6, G Plazzi2,6, C Casali7, M T Dotti8, G Cenacchi2, M Hirano9, C Giordano3, P Parchi2,6, R Rinaldi4, R De Giorgio5, R Lodi10,2, V Carelli2,6, C Tonon1. 1. From the Functional MR Unit (L.L.G., C.T., D.N.M., R.L., C.T.). 2. Departments of Biomedical and Neuromotor Sciences (L.L.G., C.T., D.N.M., L.C., M.C., M.L.V., G.P., G.C., P.P., R.L., V.C., C.T.). 3. Departments of Radiology, Oncology, and Pathology (A.P., C.G.). 4. Neurology Unit (R.D., R.R.), S.Orsola-Malpighi Hospital, Bologna, Italy. 5. Surgical and Medical Sciences (E.B., F.G., L.P., R.D.G.), University of Bologna, Bologna, Italy. 6. Istituto di Ricovero e Cura a Carattere Scientifico Institute of Neurological Sciences (L.C., M.C., M.L.V., G.P., P.P., V.C.), Bologna, Italy. 7. Medico-Surgical Sciences and Biotechnologies (C.C.), Sapienza, University of Rome, Rome, Italy. 8. Department of Medicine, Surgery, and Neuroscience (M.T.D.), University of Siena, Siena, Italy. 9. Department of Neurology (M.H.), Columbia University Medical Centre, New York, New York. 10. From the Functional MR Unit (L.L.G., C.T., D.N.M., R.L., C.T.) raffaele.lodi@unibo.it.
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.
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. Thymidinetoxicity 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.
Authors: Laura L Gramegna; Stefania Evangelisti; Lidia Di Vito; Chiara La Morgia; Alessandra Maresca; Leonardo Caporali; Giulia Amore; Lia Talozzi; Claudio Bianchini; Claudia Testa; David N Manners; Irene Cortesi; Maria L Valentino; Rocco Liguori; Valerio Carelli; Caterina Tonon; Raffaele Lodi Journal: Ann Clin Transl Neurol Date: 2021-05-05 Impact factor: 4.511
Authors: Michelle Levene; Murray D Bain; Nicholas F Moran; Niranjanan Nirmalananthan; Joanna Poulton; Mauro Scarpelli; Massimiliano Filosto; Hanna Mandel; Andrew D MacKinnon; Lynette Fairbanks; Dario Pacitti; Bridget E Bax Journal: J Clin Med Date: 2019-04-05 Impact factor: 4.241