Blood vessel ultrastructural picture in a CADASIL patient diagnosed at an advanced age

Lewandowska, Eliza; Felczak, Paulina; Buczek, Julia; Gramza, Karolina; Rafałowska, J

doi:10.5114/fn.2014.47846

Cited by 7 publications

(7 citation statements)

References 23 publications

(24 reference statements)

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“…As mice aged 6 months only showed stages I-III GOM, individual GOM deposits seem to increase in size and become increasingly amorphous over time, and new GOM seem to be continuously formed. This is further illustrated by the observation that GOM deposits of stage I and II are also present in post-mortem CADASIL patient brain microvessels, next to the more extensive GOM pathology, including patches of confluent GOM (stage V) [7,25,26].…”

Section: Discussionmentioning

confidence: 91%

“…Brulin et al analysed GOM in skin biopsies of CADASIL patients of different ages, and found that the number GOM deposits increase up to 50 years of age, but also found that the number of GOM seems to decrease in elderly patients [11]. The latter may either be attributed to other endstage vessel wall changes hampering the visualization of GOM, or because GOM seem to become confluent and disintegrate over time [26]. Whether different GOM stages in skin biopsies of CADASIL patients are associated with disease severity and disease progression, therefore, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

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Progression and Classification of Granular Osmiophilic Material (GOM) Deposits in Functionally Characterized Human NOTCH3 Transgenic Mice

Gravesteijn

Munting

Overzier

et al. 2019

Transl. Stroke Res.

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CADASIL is a NOTCH3-associated cerebral small vessel disease. A pathological ultrastructural disease hallmark is the presence of NOTCH3-protein containing deposits called granular osmiophilic material (GOM), in small arteries. How these GOM deposits develop over time and what their role is in disease progression is largely unknown. Here, we studied the progression of GOM deposits in humanized transgenic NOTCH3 Arg182Cys mice, compared them to GOM deposits in patient material, and determined whether GOM deposits in mice are associated with a functional CADASIL phenotype. We found that GOM deposits are not static, but rather progress in ageing mice, both in terms of size and aspect. We devised a GOM classification system, reflecting size, morphology and electron density. Six-month-old mice showed mostly early stage GOM, whereas older mice and patient vessels showed predominantly advanced stage GOM, but also early stage GOM. Mutant mice did not develop the most severe GOM stage seen in patient material. This absence of end-stage GOM in mice was associated with an overall lack of histological vascular pathology, which may explain why the mice did not reveal functional deficits in cerebral blood flow, cognition and motor function. Taken together, our data indicate that GOM progress over time, and that new GOM deposits are continuously being formed. The GOM staging system we introduce here allows for uniform GOM deposit classification in future mouse and human studies, which may lead to more insight into a potential association between GOM stage and CADASIL disease severity, and the role of GOM in disease progression.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Progression and Classification of Granular Osmiophilic Material (GOM) Deposits in Functionally Characterized Human NOTCH3 Transgenic Mice

Gravesteijn

Munting

Overzier

et al. 2019

Transl. Stroke Res.

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“…Presence of multiple deposits of GOM at ultrastructural examination of brain or skin vessels is the pathognomonic hallmark of CADASIL [1,8,11], with 100% specificity and 96% sensitivity [7]. Nevertheless, the origin, chemical nature and function of GOM deposits are still not clear.…”

Section: Abstract: Cadasil Notch3 Granular Osmiophilic Material Gmentioning

confidence: 99%

Letter to Editors Are granular osmiophilic material deposits an epiphenomenon in CADASIL?

Erro¹,

Moccia²,

Cervasio³

et al. 2015

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“…As the majority of the mutation is present in exon 4 of NOTCH3, the genetic analysis should begin from screening this exon, and later should be extended to exons 2, 3, 5, 6 and 11 [20]. Mutations only in exons 3, 4, 6, 8 and 12 of NOTCH3 have been identified in Polish CADASIL patients so far [2,7,[21][22][23]. The mutations in exon 4 of the NOTCH3 gene found in Polish patients include R133C [22], C185R and C212G [7].…”

Section: Discussionmentioning

confidence: 99%

Clinical presentation of Y189C mutation of the NOTCH3 gene in the Polish family with CADASIL

Dorszewska

Kowalska

Grzegorski

et al. 2020

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Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary, progressive ischemic disease of small vessels of the brain characterized by migraine with aura (MA), recurrent subcortical ischemic episodes, cognitive decline and psychiatric disorders. CADASIL is caused by mutations in the NOTCH3 gene. We identified the NOTCH3 Y189C mutation as a genetic cause of CADASIL in a Polish family and provided its first clinical manifestation. Material and methods: The study included twelve subjects from one family. The NOTCH3 mutation, APOE and MTHFR polymorphisms were determined by high-resolution melting analyses (HRMA) and Sanger sequencing. Neuroimaging included CT and MRI. Ultrastructural examination of skin-muscle biopsy material of the proband was performed. Results: The NOTCH3 Y189C mutation was present in a 36-year-old woman and her two sisters (aged 40 and 27) from 6 siblings. The MA was found in all of them, and started or became more severe after childbirth. The numerous T2/FLAIR hyperintense lesions were shown in the brain MRI. The deposition of granular osmiophilic material in the wall of small vessels of the proband observed in histopathological analysis confirmed the high degree of CADASIL severity. Conclusions: Patients with the Y189C mutation of NOTCH3 from the same family display a similar phenotype of CADASIL.

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Blood vessel ultrastructural picture in a CADASIL patient diagnosed at an advanced age

Abstract: A b s t r a c tWe report the case of an 84-year-old

Cited by 7 publications

References 23 publications

Progression and Classification of Granular Osmiophilic Material (GOM) Deposits in Functionally Characterized Human NOTCH3 Transgenic Mice

Progression and Classification of Granular Osmiophilic Material (GOM) Deposits in Functionally Characterized Human NOTCH3 Transgenic Mice

Letter to Editors Are granular osmiophilic material deposits an epiphenomenon in CADASIL?

Clinical presentation of Y189C mutation of the NOTCH3 gene in the Polish family with CADASIL

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