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'Raisin bread sign' feature of pontine autosomal dominant microangiopathy and leukoencephalopathy.

ABSTRACT: Pontine autosomal dominant microangiopathy and leukoencephalopathy is one of hereditary cerebral small vessel diseases caused by pathogenic variants in COL4A1 3'UTR and characterized by multiple small infarctions in the pons. We attempted to establish radiological features of this disease. We performed whole exome sequencing and Sanger sequencing in one family with undetermined familial small vessel disease, followed by clinicoradiological assessment and a postmortem examination. We subsequently investigated clinicoradiological features of patients in a juvenile cerebral vessel disease cohort and searched for radiological features similar to those found in the aforementioned family. Sanger sequencing was performed in selected cohort patients in order to detect variants in the same gene. An identical variant in the COL4A1 3'UTR was observed in two patients with familial small vessel disease and the two selected patients, thereby confirming the pontine autosomal dominant microangiopathy and leukoencephalopathy diagnosis. Furthermore, postmortem examination showed that the distribution of thickened media tunica and hyalinized vessels was different from that in lacunar infarctions. The appearance of characteristic multiple oval small infarctions in the pons, which resemble raisin bread, enable us to make a diagnosis of pontine autosomal dominant microangiopathy and leukoencephalopathy. This feature, for which we coined the name 'raisin bread sign', was also correlated to the pathological changes.

SUBMITTER: Kikumoto M

PROVIDER: S-EPMC10636559 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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'Raisin bread sign' feature of pontine autosomal dominant microangiopathy and leukoencephalopathy.

Kikumoto Mai M Kurashige Takashi T Ohshita Tomohiko T Kume Kodai K Kikumoto Osamu O Nezu Tomohisa T Aoki Shiro S Ochi Kazuhide K Morino Hiroyuki H Nomura Eiichi E Yamashita Hiroshi H Kaneko Mayumi M Maruyama Hirofumi H Kawakami Hideshi H

Brain communications 20231022 6

Pontine autosomal dominant microangiopathy and leukoencephalopathy is one of hereditary cerebral small vessel diseases caused by pathogenic variants in <i>COL4A1</i> 3'UTR and characterized by multiple small infarctions in the pons. We attempted to establish radiological features of this disease. We performed whole exome sequencing and Sanger sequencing in one family with undetermined familial small vessel disease, followed by clinicoradiological assessment and a postmortem examination. We subse ...[more]

PMID: 37953842

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Project description:Background and purposeMitochondrial 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 methodsSeven 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.ResultsAll 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.ConclusionsVascular 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.

Project description:Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of types I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine-altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of types I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of types I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Types I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for types I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, types I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL.

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'Raisin bread sign' feature of pontine autosomal dominant microangiopathy and leukoencephalopathy.

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'Raisin bread sign' feature of pontine autosomal dominant microangiopathy and leukoencephalopathy.

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