title: [Carasil].
abstract: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a single-gene disorder directly affecting the cerebral small blood vessels, that is caused by mutations in the HTRA1 gene encoding HtrA serine peptidase/protease 1 (HTRA1). CARASIL is the second known genetic form of ischemic, nonhypertensive, cerebral small-vessel diseases with an identified gene, following CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The exact prevalence of CARASIL is currently unknown, and so far about 50 patients have been reported, most of them from Japan and two from China. Genetically no founder haplotype has been identified, and so the disease is expected to be found more widely. The main clinical manifestations are ischemic stroke or stepwise deterioration in brain functions, progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. The most characteristic brain MRI findings are homogeneously confluent white-matter changes and multiple lacunar infarctions in the basal ganglia and thalamus. Histopathologically, CARASIL is characterized by intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials (GOM) or amyloid deposition. CARASIL is a prototype single-gene disorder of cerebral small vessels, secondary to and distinct from CADASIL. CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress transforming growth factor-β (TGF-β) family signaling, indicating that the increased TGF-β signaling causes arteriopathy in CARASIL. Therefore, HTRA1 represents another new gene to be considered in future studies of the mechanisms and therapeutic strategies of cerebral small-vessel diseases, as well as alopecia and degenerative vertebral/disk diseases.
authors.affiliation: Department of Neurology, Kameda Medical Center, Chiba, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Fukutake
mesh_terms: D000328:Adult; D000505:Alopecia / Q000235:genetics / Q000473:pathology; D001808:Blood Vessels / Q000473:pathology; D001921:Brain / Q000473:pathology; D002544:Cerebral Infarction / Q000235:genetics / Q000473:pathology; D015140:Dementia, Vascular / Q000235:genetics / Q000473:pathology; D005808:Genes, Recessive; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal / Q000235:genetics / Q000473:pathology; D017116:Low Back Pain / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012697:Serine Endopeptidases / Q000235:genetics*; D055009:Spondylosis / Q000235:genetics / Q000473:pathology; D013577:Syndrome; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases