Document Detail

Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation.
MedLine Citation:
PMID:  11486103     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation. METHODS: The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically. RESULTS: The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient's heterozygous son had his first transient ischemic attack-like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient. CONCLUSIONS: Our homozygous patient's phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.
S Tuominen; V Juvonen; K Amberla; T Jolma; J O Rinne; S Tuisku; T Kurki; R Marttila; M Pöyhönen; M L Savontaus; M Viitanen; H Kalimo
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Publication Detail:
Type:  Case Reports; Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Stroke; a journal of cerebral circulation     Volume:  32     ISSN:  1524-4628     ISO Abbreviation:  Stroke     Publication Date:  2001 Aug 
Date Detail:
Created Date:  2001-08-03     Completed Date:  2001-08-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0235266     Medline TA:  Stroke     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1767-74     Citation Subset:  IM    
Department of Neurology, Turku University Hospital and University of Turku, Finland.
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MeSH Terms
Arteries / pathology,  ultrastructure
Blood Flow Velocity / genetics
Brain / blood supply,  pathology,  radionuclide imaging
DNA Mutational Analysis
Dementia, Multi-Infarct / diagnosis*,  genetics*
Disease Progression
Genes, Dominant
Magnetic Resonance Imaging
Middle Aged
Neuropsychological Tests
Proto-Oncogene Proteins / genetics*
Receptors, Cell Surface*
Receptors, Notch
Severity of Illness Index
Skin / blood supply,  pathology
Tomography, Emission-Computed
Reg. No./Substance:
0/NOTCH3 protein, human; 0/Proto-Oncogene Proteins; 0/Receptors, Cell Surface; 0/Receptors, Notch

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