Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL
1 Institute for Ageing and Health and Department of Neuropathology, Newcastle General Hospital Newcastle upon Tyne 2 Department of Neuropathology, Frenchay Hospital Bristol 3 Department of Neurology, Gloucestershire Royal Hospital Gloucester 4 Department of Mental Health, University of Aberdeen Aberdeen, UK 5 Department of Medical Genetics, University of Turku Turku 6 Department of Neuropathology, Helsinki University Helsinki, Finland 7 Institute of Neuroscience and Physiology, Sahlgrenska Academy at Göteborg University Göteborg 8 Departments of Neurology and Medical Genetics, Sahlgrenska Hospital Göteborg 9 Department of Genetics and Pathology, Uppsala University Uppsala 10 Department of Clinical Neurosciences, Karolinska Institute Huddinge Hospital, Stockholm, Sweden
Correspondence to: Prof. RN Kalaria, Institute for Ageing and Health, Wolfson Research Centre (Neuropathology), Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK E-mail: r.n.kalaria{at}ncl.ac.uk
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.
Key Words: CADASIL; genetics; multi-infarct dementia; NOTCH3; vascular dementia
Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy; EM, electron microscopy; MID, multi-infarct dementia; SI, sclerotic index; SVD, small vessel disease
Received August 3, 2006. Revised October 27, 2006. Accepted November 29, 2006.
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