Cerebral mitochondrial microangiopathy leads to leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy

L. L. Gramegna, A. Pisano, C. Testa, D. N. Manners, R. D'Angelo, E. Boschetti, F. Giancola, L. Pironi, L. Caporali, M. Capristo, M. L. Valentino, G. Plazzi, C. Casali, M. T. Dotti, G. Cenacchi, M. Hirano, C. Giordano, P. Parchi, R. Rinaldi, R. De GiorgioR. Lodi, V. Carelli, C. Tonon

Research output: Contribution to journalArticle

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 mitochondrialDNAreplication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochromeCoxidase 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.

Original languageEnglish
Pages (from-to)427-434
Number of pages8
JournalAmerican Journal of Neuroradiology
Volume39
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

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Cerebral Small Vessel Diseases
Leukoencephalopathies
Thymidine Phosphorylase
Brain
DNA Replication
Mitochondrial DNA
Water
Cytochrome-c Oxidase Deficiency
Gliosis
Creatine
Myelin Sheath
Choline
Blood-Brain Barrier
Vascular Smooth Muscle
Neuroimaging
Thymidine
Brain Stem
Smooth Muscle Myocytes
Smooth Muscle
Blood Vessels

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Clinical Neurology

Cite this

Gramegna, L. L., Pisano, A., Testa, C., Manners, D. N., D'Angelo, R., Boschetti, E., ... Tonon, C. (2018). Cerebral mitochondrial microangiopathy leads to leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. American Journal of Neuroradiology, 39(3), 427-434. https://doi.org/10.3174/ajnr.A5507

Cerebral mitochondrial microangiopathy leads to leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. / Gramegna, L. L.; Pisano, A.; Testa, C.; Manners, D. N.; D'Angelo, R.; Boschetti, E.; Giancola, F.; Pironi, L.; Caporali, L.; Capristo, M.; Valentino, M. L.; Plazzi, G.; Casali, C.; Dotti, M. T.; Cenacchi, G.; Hirano, M.; Giordano, C.; Parchi, P.; Rinaldi, R.; De Giorgio, R.; Lodi, R.; Carelli, V.; Tonon, C.

In: American Journal of Neuroradiology, Vol. 39, No. 3, 01.03.2018, p. 427-434.

Research output: Contribution to journalArticle

Gramegna, LL, Pisano, A, Testa, C, Manners, DN, D'Angelo, R, Boschetti, E, Giancola, F, Pironi, L, Caporali, L, Capristo, M, Valentino, ML, Plazzi, G, Casali, C, Dotti, MT, Cenacchi, G, Hirano, M, Giordano, C, Parchi, P, Rinaldi, R, De Giorgio, R, Lodi, R, Carelli, V & Tonon, C 2018, 'Cerebral mitochondrial microangiopathy leads to leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy', American Journal of Neuroradiology, vol. 39, no. 3, pp. 427-434. https://doi.org/10.3174/ajnr.A5507
Gramegna, L. L. ; Pisano, A. ; Testa, C. ; Manners, D. N. ; D'Angelo, R. ; Boschetti, E. ; Giancola, F. ; Pironi, L. ; Caporali, L. ; Capristo, M. ; Valentino, M. L. ; Plazzi, G. ; Casali, C. ; Dotti, M. T. ; Cenacchi, G. ; Hirano, M. ; Giordano, C. ; Parchi, P. ; Rinaldi, R. ; De Giorgio, R. ; Lodi, R. ; Carelli, V. ; Tonon, C. / Cerebral mitochondrial microangiopathy leads to leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. In: American Journal of Neuroradiology. 2018 ; Vol. 39, No. 3. pp. 427-434.
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T1 - Cerebral mitochondrial microangiopathy leads to leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy

AU - Gramegna, L. L.

AU - Pisano, A.

AU - Testa, C.

AU - Manners, D. N.

AU - D'Angelo, R.

AU - Boschetti, E.

AU - Giancola, F.

AU - Pironi, L.

AU - Caporali, L.

AU - Capristo, M.

AU - Valentino, M. L.

AU - Plazzi, G.

AU - Casali, C.

AU - Dotti, M. T.

AU - Cenacchi, G.

AU - Hirano, M.

AU - Giordano, C.

AU - Parchi, P.

AU - Rinaldi, R.

AU - De Giorgio, R.

AU - Lodi, R.

AU - Carelli, V.

AU - Tonon, C.

N1 - Ricercatori distaccati presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Valentino Maria Lucia, Plazzi Giuseppe, Parchi Piero, Carelli Valerio). Richiesto CORRIGENDUM per affiliazione imprecisa.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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 mitochondrialDNAreplication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochromeCoxidase 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.

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