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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: a Genetic Cause of Cerebral Small Vessel Disease

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Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: a Genetic Cause of Cerebral Small Vessel Disease REVIEW Print ISSN 1738-6586 / On-line ISSN 2005-5013 J Clin Neurol 2010;6:1-9 10.3988/jcn.2010.6.1.1 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Genetic Cause of Cerebral Small Vessel Disease Jay Chol Choi, MD, PhD Department of Neurology and Institute of Medical Science, Jeju National University School of Medicine, Jeju, Korea Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the Notch3 gene. The exact prevalence of this disorder was unknown currently, and the number of reported CADASIL families is steadily increasing as the clinical picture and diagnostic ex- aminations are becoming more widely known. The main clinical manifestations are recurrent st- Received September 17, 2009 roke, migraine, psychiatric symptoms, and progressive cognitive impairment. The clinical course Revised November 25, 2009 of CADASIL is highly variable, even within families. The involvement of the anterior temporal Accepted November 25, 2009 lobe and the external capsule on brain magnetic resonance imaging was found to have high sen- Correspondence sitivity and specificity in differentiating CADASIL from the much more common sporadic cere- Jay Chol Choi, MD, PhD bral small-vessel disease (SVD). The pathologic hallmark of the disease is the presence of gran- Department of Neurology ular osmiophilic material in the walls of affected vessels. CADASIL is a prototype single-gene and Institute of Medical Science disorder that has evolved as a unique model for studying the mechanisms underlying cerebral Jeju National University, SVD. At present, the incidence and prevalence of CADASIL seem to be underestimated due to School of Medicine, limitations in clinical, neuroradiological, and genetic diagnoses of this disorder. 1753-3 Ara-dong, J Clin Neurol 2010;6:1-9 Jeju 690-756, Korea Tel +82-70-7791-3233 Key Wordszzcerebral autosomal dominant arteriopathy with subcortical infarcts and leukoen- Fax +82-64-717-1109 cephalopathy, ischemic stroke, migraine, small-vessel disease, Notch3. E-mail [email protected] Introduction the number of reports about patients with CADASIL. This review summarizes the historical background, epidemiology, Cerebral small-vessel diseases (SVDs) are a major disease genetics, pathophysiology, characteristic clinical findings, burden in most developed countries.1 SVDs usually manifest neuroimaging, and treatment of this unique disorder. with lacunar infarction, intracerebral hemorrhage (ICH), and subcortical vascular dementia. Although hypertension and History diabetes mellitus are known to be important risk factors for SVDs, many hereditary or idiopathic SVDs have also been CADASIL was possibly first reported in 1955, when Van identified. Among them, cerebral autosomal dominant arteri- Bogaert described two sisters with rapidly progressive sub- opathy with subcortical infarcts and leukoencephalopathy cortical encephalopathy of Binswanger’s type.3 In 1977, Sou- (CADASIL) is the most common single-gene disorder of the rander and Walinder reported a Swedish family with multi- cerebral small blood vessels and is caused by mutations in infarct dementia of autosomal dominant inheritance.4 They the Notch3 gene.2 The main clinical manifestations are recur- presented with pyramidal, bulbar, and cerebellar symptoms, rent stroke, cognitive deficits, migraines, and psychiatric dis- a relapsing course, and gradually evolving severe dementia. turbances. Although the exact prevalence of this disorder is The illnesses began in early adulthood (ranging from 29 to not known, CADASIL has been reported worldwide in many 38 years of age) and generally lasted for 10 to 15 years. Post- ethnic groups. The increasing availability of diagnostic ex- mortem studies showed multiple small cystic infarctions, lo- pertise and genetic testing has lead to a gradual increase in calized in the central gray matter, white matter, and pons, Copyright © 2010 Korean Neurological Association 1 CADASIL caused by an occlusion of small intracerebral and leptomen- clinical picture becomes more widely recognized and genetic ingeal arteries. In the same year, Stevens et al.5 described fa- testing becomes available. Most large reported clinical series milial vascular dementia in an English family with autoso- have been from European countries including France, Ger- mal dominant inheritance. However, their mean age at the on- many, the UK, Finland, Italy, and the Netherlands.11-17 Re- set was 50 years (ranging from 39 to 57 years), and their ports from North America are relatively sparse, especially mean age at death was 60 years (ranging from 56 to 65 considering the high level of academic activity in this region. years). The affected patients presented with a wide variety of CADASIL families have been increasingly described in oth- transient motor, sensory, and other symptoms of vascular ori- er world regions, including Asia, the Middle East, Australia, gin. The episodes varied considerably in frequency and se- South America, and Africa. verity within a family. The progressive phase of this illness was characterized by dementia, bulbar palsy with immobili- Pathophysiology ty, and urinary incontinence. Multiple small infarctions were seen in the basal ganglia, thalamus, and cerebral white mat- The Notch3 gene encodes cell-surface receptors that trans- ter at autopsy. Small arteries and arterioles showed medial duce signals between neighboring cells.18 The Notch signal- swelling with vacuolar degeneration of smooth-muscle cells. ing pathway is highly conserved during evolution and is im- A recent study demonstrated that hereditary multi-infarct de- portant for cell fate during embryonic development. Notch3 mentia in the Swedish family reported by Sourander and expression is restricted to vascular smooth-muscle cells (VS- Walinder was unrelated to CADASIL. This disorder does not MC) in adults and participates in vascular development, dif- affect the Notch3 gene, and these patients do not show char- ferentiation, and remodeling.19,20 The NOTCH3 receptor is a acteristic features of CADASIL on pathologic examination.6 single-pass transmembrane receptor of 2,321 amino acids. It From the late 1980s to early 1990s there were several Euro- consists of a large extracellular domain (ECD) with 34 tan- pean reports of autosomal dominant cerebral SVDs charac- dem epidermal growth factor (EGF)-like repeats, three Notch/ terized by recurrent stroke, progressive dementia, and mi- Lin12 repeats, a transmembrane domain, and an intracellular graine. In 1993, Tournier-Lasserve et al.7 applied linkage domain. Each EGF-like repeat contains six cysteine residues. analysis to two large, unrelated French families presenting The large ECD is noncovalently bound to the intracellular with CADASIL (they used the acronym CADASIL for the domain. Ligand binding leads to a proteolytic cleavage that first time), and localized the disease to a locus on chromo- translocates the intracellular domain to the nucleus. The in- some 19q12. Joutel et al.2,8 subsequently confirmed that the tracellular domain activates the transcription factor RBPJk affected gene was Notch3 and identified several mutations and other coactivators. therein. Knowledge of the effects of CADASIL-associated muta- tions on NOTCH3 function is important to understanding the Epidemiology molecular pathogenesis of this disorder. A small number of mutations located in the ligand-binding domain (EGF repeats The exact prevalence of CADASIL is not known. According 10 and 11) produce a significant reduction in transcriptional to a study from west Scotland, the disease prevalence was activity.21 However, greater numbers of mutations outside the 1.98 per 100,000 adults with a probable CADASIL mutation ligand-binding domain lead to normal levels of signaling ac- prevalence of 4.14 per 100,000 adults.9 The researchers esti- tivity. Researchers have recently investigated the effects of mated the prevalence of CADASIL based on data from the mutations located in the ligand-binding domain in compari- regional registry. However, this figure could underestimate son with other common mutations.22 the true prevalence because CADASIL was frequently mis- Patients with mutations in the ligand-binding domain showed diagnosed at that time and they screened only four exons. significantly higher scores on cognitive scales, suggesting Dong et al.10 determined the prevalence of CADASIL in a that reduced Notch3 signaling acts only as a modifier of the stroke population by screening exons 3, 4, 5, and 6 of the CADASIL phenotype. Therefore, Notch3 mutations do not Notch3 gene in 218 subjects with lacunar stroke. Only one cause functional abnormalities in the Notch canonical path- young patient exhibited a mutation in exon 4. The overall way, and loss of function of the Notch3 gene is probably not carrier frequency of the CADASIL mutation was 0.05%, and the cause of CADASIL. it was 2.0% and 11.1% for those with disease onset at ≤65 Accumulation of the NOTCH3 ECD in the arterial wall is years and ≤50 years, respectively. CADASIL has been re- a characteristic finding of patients with CADASIL.19 A re- ported worldwide in many ethnic groups. The number of re- cent study showed that both wild-type and CADASIL-mu- ported cases of CADASIL is gradually increasing as the tated NOTCH3 ECDs spontaneously form oligomers and 2 J Clin Neurol 2010;6:1-9 Choi JC higher order multimers in vitro.23 Notably, mutations
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