Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL

Abstract

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.

Monogenic causes of stroke: now and the future

“…This family was suspected of having CADASIL, but NOTCH3 sequencing showed no pathogenic mutations and skin biopsy showed no GOM. Linkage analysis showed no distinctive haplotype attributed to the affected family members [75]. Since then, a CADASIL-like syndrome not due to NOTCH3 mutations has been described, where clinical features are largely similar to CADASIL apart from a later age of onset of stroke and a later age of onset in family members [76].…”

Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease

“…The most common familial form of ischemic cerebral small-vessel disease is defined by cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited, dominant, late-onset syndrome that has been associated with mutations in NOTCH 3 (2), encoding one of the four vertebrate Notch receptor paralogues. Patients with CADASIL develop widespread arteriopathy that manifests itself most severely in brain vessels, eventually causing chronic ischemic degeneration of neurons and glia (2,(6)(7)(8)(9)(10)(11)(12). CADASIL brain pathology reveals severe leukoencephalopathy, vascular smooth muscle cell (vSMC) degeneration, and the appearance of pathognomonic granular osmiophilic deposits, termed granular osmiophilic material (GOM), of unknown composition (9,10).…”

Diagnosing Vascular Dementia by Skin Biopsy - Uniqueness of CADASIL

“…The Swedish family with multi-infarct dementia was previously thought to be the first published pedigree with CADASIL (Sourander and Walinder, 1977). The absence of GOM in the arteries was an important piece of evidence in addition to the negative genetic analyses in the demonstration that this family suffers from another hereditary vascular dementia (Low et al, 2007). On the other hand, another cerebral small vessels disease caused by a novel type of pathogenic mutation (p.Leu1515Pro) in the exon 25 of NOTCH3 outside the EGF like repeat rich domain, results in constitutively active NOTCH3 receptor (Fouillade et al, 2008).…”