title: [CADASIL].
abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant vascular encephalopathy that has been mainly reported in Europe and the United States. Recently, this disease has been reported in Japan and the increasing number of reported cases has been attracting attention. Currently, the clinical diagnosis of CADASIL is based on the satisfaction of the following conditions: (1) development of the condition at a relatively young age (40-50 years), (2) no risk for stroke, (3) repeated attacks of lacunar infarction with gradual progression to pseudobulbar paralysis and dementia (migraine, emotional disturbance, cerebral infarction, and dementia in 30%, 20%, 85%, and 30-90% of patients, respectively), and (4) family members with similar symptoms (autosomal dominant inheritance). The diagnosis is also established on the basis of the following findings of imaging and laboratory studies: the presence of (1) leukoaraiosis and multiple small infarcts in the bilateral deep white matter, basal ganglia, thalamus, and pons revealed by MRI; (2) granular osmiophilic material (GOM) around the vascular smooth muscles in the brain, skeletal muscle, peripheral nerves, and skin demonstrated by electron microscopy; and (3) Notch3 mutations revealed by DNA analysis. Characteristics of CADASIL patients in Japan: Between 1997 and 2008, 38 CADASIL families have been reported in Japan. The age at onset of local neurological symptoms ranged from 15 to 71 years (mean 42. 3 +/- 11.4 years). All patients except one with borderline hypertension were normotensive or hypotensive. Out of 45 patients, 18 (40%) had migraine; 37 (82.2%) had repeated cerebral ischemic attacks including transient ischemic attacks (TIA); and 22 (48.9%), including borderline cases, had intellectual impairment. Nine of 38 patients (23.7%) had pseudobulbar paralysis. The retinal arteries were narrowed in 4 of 16 patients. The patients were distributed nationwide. Mutations in exon 4 have been reported in 22 of 31 families (71%). It is expected that an increase in the number of reported cases will lead to the discovery of other mutations associated with this condition. The mechanism of development of CADASIL due to Notch3 mutations is still unknown. However, a recent study has revealed that the Notch3 ectodomain is a major component of GOM. On binding to its ligand, Notch3 normally undergoes proteolytic cleavage, resulting in the clearance of the extracellular domain. However, in CADASIL, it accumulates as GOM and potentially inhibit the normal metabolism of smooth muscle cells.
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 8608556, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Uchino
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D001921:Brain / Q000098:blood supply; D046589:CADASIL / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009154:Mutation; D010879:Piperazines / Q000008:administration & dosage; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011379:Prognosis; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism
chemical_list: D000925:Anticoagulants; C499374:NOTCH3 protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C052424:lomerizine