RT Journal Article
SR Electronic
T1 Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy
JF American Journal of Neuroradiology
JO Am. J. Neuroradiol.
FD American Society of Neuroradiology
SP 427
OP 434
DO 10.3174/ajnr.A5507
VO 39
IS 3
A1 L.L. Gramegna
A1 A. Pisano
A1 C. Testa
A1 D.N. Manners
A1 R. D'Angelo
A1 E. Boschetti
A1 F. Giancola
A1 L. Pironi
A1 L. Caporali
A1 M. Capristo
A1 M.L. Valentino
A1 G. Plazzi
A1 C. Casali
A1 M.T. Dotti
A1 G. Cenacchi
A1 M. Hirano
A1 C. Giordano
A1 P. Parchi
A1 R. Rinaldi
A1 R. De Giorgio
A1 R. Lodi
A1 V. Carelli
A1 C. Tonon
YR 2018
UL http://www.ajnr.org/content/39/3/427.abstract
AB 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.ADaxial diffusivityBWbrain waterFAfractional anisotropyMNGIEmitochondrial neurogastrointestinal encephalopathymtDNAmitochondrial DNA replicationMDmean diffusivityPLICposterior limbs of the internal capsulePO-WMparieto-occipital white matterRDradial diffusivity