uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
Show others and affiliations
2007 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 130, no Part 2, 357-367 p.Article in journal (Refereed) Published
Abstract [en]

Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.

Place, publisher, year, edition, pages
2007. Vol. 130, no Part 2, 357-367 p.
Keyword [en]
Adult, Brain/blood supply/ultrastructure, CADASIL/*genetics, Chromosome Mapping/methods, DNA Mutational Analysis/methods, Dementia; Multi-Infarct/*genetics/metabolism/pathology, Female, Humans, Intracranial Arteriosclerosis/genetics/pathology, Magnetic Resonance Imaging, Male, Microcirculation/metabolism, Middle Aged, Mutation, Pedigree, Polymerase Chain Reaction/methods, Receptors; Notch/*genetics/metabolism, Skin/ultrastructure
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-10696DOI: 10.1093/brain/awl360ISI: 000243810500012PubMedID: 17235124OAI: oai:DiVA.org:uu-10696DiVA: diva2:38464
Available from: 2007-04-19 Created: 2007-04-19 Last updated: 2011-02-18Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=17235124&dopt=Citation

Search in DiVA

By author/editor
Kalimo, Hannu
By organisation
Department of Genetics and Pathology
In the same journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 148 hits
ReferencesLink to record
Permanent link

Direct link