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    Extensive Leukoencephalopathy in Spastic Paraplegia Type 4: Possible Role of Cerebral Autosomal Arteriopathy With Subcortical Infarcts and Leukoencephelopathy. Jung Jin Ho,Seo Jung Hwa,Lee Sukyoon,Heo Young Jin,Kim Donghyun,Chung Eun Joo,Oh Seong-Il Journal of movement disorders Despite recent advances in next-generation sequencing, the underlying etiology of adult-onset leukoencephalopathy has been difficult to elucidate. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a representative hereditary adult-onset leukoencephalopathy associated with vasculopathy. Leukoencephalopathy in spastic paraplegia type 4 (SPG4) is known to be rare, but it might be underestimated because most spastic paraplegia with leukoencephalopathy is rarely considered. We report a case of co-occurring SPG4 and CADASIL. A 61-year-old male presented with sudden visual impairment after a headache. He showed a spastic gait and had a family history with similar symptoms. An SPG4 gene mutation and a pathogenic variant in the NOTCH3 gene were found. This case shows that the diverse and complex clinical manifestations of patients with extensive leukoencephalopathy are related to more than one gene mutation. We also suggest the necessity for relevant genetic tests in the diagnosis of adult-onset leukoencephalopathy. 10.14802/jmd.21091
    Cadasil - genetic and ultrastructural diagnosis. Case report. da Silva Julio Cesar Vasconcelos,Chimelli Leila,Sudo Felipe Kenji,Engelhardt Eliasz Dementia & neuropsychologia Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary disorder which affects the cerebral vasculature due to mutations in the NOTCH 3 gene. The diagnosis may be established through genetic testing for detection of these mutations and/or by skin biopsy. We report a case of the disorder in a female patient, who presented recurrent transient ischemic attacks that evolved to progressive subcortical dementia. Neuroimaging disclosed extensive leukoaraiosis and lacunar infarcts. The genetic analysis for NOTCH 3 was confirmatory. The ultrastructural examination of the skin biopsy sample, initially negative, confirmed the presence of characteristic changes (presence of granular osmiophilic material inclusions [GOM]), after the analysis of new sections of the same specimen. The present findings indicate that negative findings on ultrastructural examinations of biopsy should not exclude the diagnosis of the disease and that further analyses of the sample may be necessary to detect the presence of GOM. 10.1590/1980-57642015DN94000428
    A Patient with Combined CADASIL and MTHFR Homozygosity. Ibrikji Sidonie,El Halabi Tarek,Yamout Bassem Case reports in neurological medicine Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited disorder caused by a mutation in the NOTCH 3 gene, characterized by early onset of subcortical lacunar infarcts in the absence of vascular risk factors and cerebral microbleeds. Homozygosity for the factor Methylenetetrahydrofolate Reductase (MTHFR) is also associated with lacunar stroke risk and cerebral small-vessel disease regardless of the homocysteine level. The coexistence of MTHFR C677T homozygosity and NOTCH 3 mutation has never been reported in the literature previously, and that brings up the challenge of antithrombotic treatment in the presence of cerebral microbleeds. 10.1155/2020/4980847
    p.Arg332Cys mutation of NOTCH3 gene in two unrelated Japanese families with CADASIL. Sano Yasuteru,Shimizu Fumitaka,Kawai Motoharu,Omoto Masatoshi,Negoro Kiyoshi,Kurokawa Tetsu,Fujisawa Hirosuke,Suzuki Michiyasu,Okayama Naoko,Suehiro Yutaka,Hinoda Yuji,Kanda Takashi Internal medicine (Tokyo, Japan) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a cerebrovasuclar disease caused by NOTCH3 mutations, usually localized to exons 3 and 4. This report describes the clinical and neuroradiological findings of 2 subjects of two unrelated Japanese families who shared a common p.Arg332Cys mutation. The subject from family A presented syncope attacks as the sole clinical presentation at the beginning of his disease course. The subject from family B showed recurrent ischemic attacks, followed by a large intracranial hemorrhage. This is the first report to describe the detailed phenotypes of patients with a rare p.Arg332Cys mutation in Japan. 10.2169/internalmedicine.50.5418
    Cadasil syndrome: A case report with a literature review. Lahkim Mohamed,Laamrani Fatima Zahare,Andour Hajar,Gharbaoui Yasmine,Sanhaji Latifa,El-Fenni Jamal,En-Nouali Hassane Radiology case reports "CADASIL" is a genetic microangiopathy with autosomal dominant inheritance. Its epidemiology and physiopathogenesis are poorly specified, but it is proven that this disease is due to a mutation of the NOTCH3 gene resulting in a loss of elasticity of the media of the affected vessels. The clinical expression is variable, dominated by migraine attacks with aura, ischemic vascular accidents and psychiatric disorders, in particular depression. MRI is essential for diagnosis even in the pre-symptomatic phase. It shows signal abnormalities in the basal ganglia and white matter, characteristic especially when located in the anterior part of the temporal lobes. The management of CADASIL is multidisciplinary, psychological for the most part without specificity of a particular treatment. 10.1016/j.radcr.2021.08.023
    First patient with mosaic NOTCH3 gene pathogenic variant. Unrevealed mosaicisms and importance of their detection. Moreno-García Marta,Arteche-López Ana Rosa,Álvarez-Mora María Isabel,Palma Milla Carmen,Quesada Espinosa Juan Francisco,Lezana Rosales José Miguel,Sánchez Calvín María Teresa,Gómez Manjón Irene,Gómez Rodríguez María José,Mendez-Guerrero Antonio,Villarejo-Galende Alberto American journal of medical genetics. Part A Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants. Mosaicism is more common than previously thought because mosaic variants often stay unrevealed. An apparently de novo variant might actually be a consequence of a parental mosaicism undetectable with Sanger sequencing, especially in the case of low grade mosaicism. Parental testing by sensitive tools like deep targeted next-generation sequencing (NGS) analysis could detect cases of unrevealed medium or low level mosaicism in patients tested by Sanger sequencing. Here, we report the first patient with mosaic NOTCH3 gene pathogenic variant to our knowledge; the allelic fraction in the leucocyte DNA was low (13%); the pathogenic variant was inhered by his two daughters. The patient was diagnosed by deep targeted NGS analysis after studying his two affected daughters. This report highlights the importance of parental testing by sensitive tools like deep targeted NGS analysis. Detection of mosaicism is of great importance for diagnosis and adequate family genetic counseling. 10.1002/ajmg.a.61999
    Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) - Still to be Considered in the Presence of Vascular Risk Factors. Ganesan Dinesh Naidu,Coste Thibault,Venketasubramanian Narayanaswamy Case reports in neurology Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare hereditary vasculopathy that primarily affects the brain, caused mostly by missense mutations of the gene which is located on chromosome 19. Clinically, it manifests as transient ischemic attacks and strokes in individuals under the age of 60 years without vascular risk factors. We report a 46-year-old male with a 9 and 3-month history of progressive unilateral lower limb weakness and dysarthria, respectively. He had a history of diabetes mellitus but no hypertension, hyperlipidemia, or smoking history. Both parents had a stroke at the age of 65 years. Neurological examination was significant for moderate dysarthria and reduced right upper limb dexterity. Magnetic resonance imaging (MRI) of the brain revealed extensive white matter disease, lacunar infarcts, and a few microhemorrhages. Electron microscopy of his skin biopsy showed electron-dense deposits of extracellular osmiophilic granular material adjacent to smooth muscle cells. gene analysis revealed a heterozygous typical mutation in exon 6. He was commenced on aspirin and atorvastatin. Over time, he became more dysarthric and demented. MRI revealed the progression of the white matter disease and a new right subcortical infarct. His aspirin was switched to clopidogrel, and donepezil was added. CADASIL should be considered among younger stroke patients with vascular risk factors, especially in the presence of widespread white matter disease. Genetic counselling may be needed after the diagnosis is made. 10.1159/000507542
    Case Report: Progressive Asymmetric Parkinsonism Secondary to CADASIL Without Dementia. Guo Weihang,Xu Baolei,Sun Hong,Ma Jinghong,Mei ShanShan,Zeng Jingrong,Sun Junyan,Xu Erhe Frontiers in neurology Parkinsonism is a rare phenotype of cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL), all of which involve cognitive decline. Normal cognition has not been reported in previous disease studies. Here we report the case of a 60-year-old female patient with a 2-year history of progressive asymmetric parkinsonism. On examination, she showed severe parkinsonism featuring bradykinesia and axial and limb rigidity with preserved cognition. Magnetic resonance imaging (MRI) revealed white matter hyperintensity in the external capsule and periventricular region. Dopaminergic response was limited. A missense mutation c.1630C>T (p.R544C) on the gene was identified on whole-exome sequencing, which confirmed the diagnosis of vascular parkinsonism secondary to CADASIL. A diagnosis of CADASIL should be considered in asymmetric parkinsonism without dementia. Characteristic MRI findings support the diagnosis. 10.3389/fneur.2021.760164
    Psychiatric disturbances in CADASIL: a brief review. Valenti R,Poggesi A,Pescini F,Inzitari D,Pantoni L Acta neurologica Scandinavica BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by a variable combination of migraine, recurrent transient ischemic attack (TIA) or lacunar strokes, cognitive decline, and mood disturbances. However, the assessment of psychiatric disturbances in this disease has never been carried out systematically. METHODS:This paper presents a brief review of the literature regarding the occurrence of psychiatric disorders in CADASIL patients. RESULTS:The prevalence of psychiatric disorders in CADASIL patients is reported to range from 20% to 41%. The psychiatric disturbances reported with the highest frequency are mood disturbances (9-41%). Pooling together the studies and considering a total of 454 CADASIL patients reported in the literature, 106 of these were affected by mood disturbances (24%). The majority of studies however did not use any defined criteria to assess the presence of psychiatric disorders and diagnoses were mainly based on history or review of clinical records. CONCLUSIONS:The review of CADASIL literature suggests the need for a more structured approach to the investigation of these disturbances that are highly prevalent and may greatly impact quality of life in these patients. 10.1111/j.1600-0404.2008.01015.x
    Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Presenting as Migraine. Ameer Muhammad Atif,Bhutta Beenish Sohail,Asghar Neelma,Haseeb Muhammad Talha,Abbasi Raya Nasir Cureus Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy with a genetic predilection for the cerebral vessels. It is caused by mutations in the NOTCH3 gene and commonly occurs in middle-aged individuals. Clinical manifestations range from stroke, transient ischemic attack, and migraine to neuropsychiatric symptoms. We present a case of a 40-year-old patient who came in with headache, blurry vision, progressive right-sided weakness, and behavioral changes. The diagnostic workup included several possibilities, including central nervous system (CNS) infection, stroke, transient ischemic attack, and inherited disorders like mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS). After proper systemic and genetic workup, we diagnosed this as a case of CADASIL. 10.7759/cureus.15355
    [Skin Biopsy is a Useful Tool for the Diagnosis of Atypical CADASIL: A Case Report]. Tamaki Keiko,Fukae Jiro,Koga Kaori,Nagatoshi Akihito,Ueda Akihiko,Ouma Shinji,Ando Yukio,Tsuboi Yoshio Brain and nerve = Shinkei kenkyu no shinpo A 57-year-old man developed migraine at the age of 25 years. Thereafter, he developed depression at the age of 50 years, and was admitted to a psychiatric hospital at the age of 54 years because of deteriorating depression. He returned to his work after receiving treatment for depression; however, he made mistakes several times in his work. He was referred to our hospital for further neurological evaluation. The results of the neurological examination performed on admission were unremarkable. His Mini Mental State Examination (MMSE) score was 24/30, and neuropsycological evaluations revealed executive dysfunction. There was no family history of dementia or cerebral infarction. Magnetic resonance fluid attenuated inversion recovery (MR FLAIR) image of the brain showed hyperintense lesions around the lateral ventricle without involvement in the temporal pole and external capsule. Despite a lack of family history of dementia and cerebral infarction and non-specific brain MRI findings, his history of headache and depression were suggestive of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, skin biopsy was performed; electron microscopy of the biopsied sample revealed granular osmiophilic material deposits. Genetic analysis of the NOTCH3 gene showed a missense mutation with substitution of R427C in exon 8, i.e., out of the hot-spot, exon 3, and 4. Thus, skin biopsy is a useful tool for diagnosing atypical CADASIL. 10.11477/mf.1416200333
    Case report: bipolar disorder as the first manifestation of CADASIL. Park Soyeon,Park Boram,Koh Min Kyung,Joo Yeon Ho BMC psychiatry BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by variable manifestations of migraine, recurrent transient ischemic attack or lacunar strokes, cognitive decline, and mood disturbances. However, manic episodes have rarely been documented as an initial symptom of CADASIL and bipolar disorder presenting as the first manifestation in CADASIL has not been reported previously from evaluations by psychiatrists or psychological testing by psychologists. CASE PRESENTATION:A 53 year old woman developed symptoms of mania in her 50s leading to a personality change involving a continuously labile mood and irritability over a number of years. Neuropsychological testing revealed an intact memory, but impairment in attention and executive function. In the Rorschach test, she showed a high level of cognitive rigidity. Magnetic resonance imaging findings were very consistent with a diagnosis of CADASIL, which was confirmed by genetic testing for NOTCH3 mutations. Atypical antipsychotics proved to be helpful in treating her manic symptoms and for behavior control. CONCLUSION:We present a novel case of CADASIL that first presented as bipolar disorder. We contend that when patients show a late onset personality change or chronically irritable mood that deteriorates over many years, an organic cause such as CADASIL must be considered. Further studies are needed to better understand the exact impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients. 10.1186/1471-244X-14-175
    Novel Mutation of the NOTCH3 Gene in a Chinese Pedigree with CADASIL. Hou Xiaoxia,He Chuan,Jin Qingwen,Niu Qi,Ren Guang,Cheng Hong CNS & neurological disorders drug targets BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) results from NOTCH3 gene mutations, which lead to the degeneration of vascular smooth muscle cells (VSMCs). The clinical presentation of CADASIL patients is dependent on the impact of other vascular risk factors and the type of NOTCH3 mutation present. METHODS:Here, we report a rare pathogenic mutation on exon 14 of the NOTCH3 gene in a Chinese family affected by CADASIL with phenotypic peculiarities. We performed genetic testing, clinical and neuropsychological examination, brain magnetic resonance images (MRI), and electron microscopy (EM) in skin biopsies. RESULTS:NOTCH3 gene analysis revealed a c.2182CT substitution on exon 14, which is the first example of this mutation in a Chinese individual from the Han ancestry. Granular osmiophilic material (GOM) was found in the proband, and all patients had migraine, subcortical ischemic events, and mood disturbances, without progressive cognitive impairment. Cranial MRI further showed white matter hyperintensity, involving bilateral basal ganglia and multiple microbleeds (MBs), in the thalamus and brain stem. CONCLUSIONS:This study suggests that different missense mutations in NOTCH3 might contribute to atypical clinical features of CADASIL. This report also indicates that for individuals with a positive family history having clinical and neuroradiological findings suggestive of CADASIL, genetic testing and GOM detection should be performed. 10.2174/1871527315666161024125952
    [CADASIL with cysteine-sparing NOTCH3 mutation manifesting as dissociated progression between cognitive impairment and brain image findings in 3 years: A case report]. Tachiyama Keisuke,Shiga Yuji,Shimoe Yutaka,Mizuta Ikuko,Mizuno Toshiki,Kuriyama Masaru Rinsho shinkeigaku = Clinical neurology A 55-year-old man with no history of stroke or migraine presented to the clinic with cognitive impairment and depression that had been experiencing for two years. Neurological examination showed bilateral pyramidal signs, and impairments in cognition and attention. Brain MRI revealed multiple lacunar lesions and microbleeds in the deep cerebral white matter, subcortical regions, and brainstem, as well as diffuse white matter hyperintensities without anterior temporal pole involvement. Cerebral single-photon emission computed tomography (SPECT) revealed bilateral hypoperfusion in the basal ganglia. Gene analysis revealed an arginine-to-proline missense mutation in the NOTCH3 gene at codon 75. The patient was administered lomerizine (10 mg/day), but the patient's cognitive impairment and cerebral atrophy continued to worsen. Follow-up testing with MRI three years after his initial diagnosis revealed similar lacunar infarctions, cerebral microbleeds, and diffuse white matter hyperintensities to those observed three years earlier. However, MRI scans revealed signs of increased cerebral blood flow. Together, these findings suggest that the patient's cognitive impairments may have been caused by pathogenesis in the cerebral cortex. 10.5692/clinicalneurol.cn-001134
    Peripheral neuropathy in a case with CADASIL: a case report. Sakiyama Yusuke,Matsuura Eiji,Maki Yoshimitsu,Yoshimura Akiko,Ando Masahiro,Nomura Miwa,Shinohara Kazuya,Saigo Ryuji,Nakamura Tomonori,Hashiguchi Akihiro,Takashima Hiroshi BMC neurology BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized clinically by central nervous system dysfunctions. It is unclear whether CADASIL is involved in peripheral neuropathy. CASE PRESENTATION:A 67-year-old Japanese man with stepwise progression of sensory and motor neuropathy was admitted to our hospital. Peripheral neuropathy of the extremities was detected through electrophysiological and pathological studies, and brain magnetic resonance imaging revealed bilateral periventricular ischemic and thalamic hemorrhagic lesions. We diagnosed CADASIL after detecting granular osmiophilic material in the walls of the endoneurial vessels morphologically and identifying a heterozygous NOTCH3 mutation p.Arg75Pro. CONCLUSIONS:CADASIL is to be included in the work-up of not classified peripheral neuropathies. 10.1186/s12883-018-1131-3
    A Novel Mutation Outside of the EGFr Encoding Exons of NOTCH3 Gene in a Chinese with CADASIL. Wang Wan,Ren Zhixia,Shi Yingying,Zhang Jiewen Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vascular disease caused by the mutations of the NOTCH3 gene. The NOTCH3 gene consists of 33 exons. The pathogenic mutations of the NOTCH3 gene in CADASIL are located in 2-24 exons coding for the 34 EGFr (epidermal growth factor-like repeat) domains. The classical clinical manifestations are recurrent TIA or ischaemic stroke, migraine, cognitive disorder and affective disorder. The deposition of granular osmiophilic material (GOM) in the vascular wall is considered as a hallmark of the disease. METHODS:Here, we report a rare pathogenic mutation on exon 29 of the NOTCH3 gene in a Chinese family. Clinical data for the proband and available relatives is collected. Mutation analysis of the NOTCH3 gene was performed by screening the entire 33 exons in this family and 200 normal controls. A complete imaging evaluation and skin biopsy were performed on the proband. RESULTS:We identified a novel R1761H (c.5282G>A) mutation. The same mutation was not founded in 200 normal controls. The proband had recurrent stroke, depression, cognitive decline and cerebral lobe hemorrhage. Cranial MRI showed white matter lesions and multiple infarction. Susceptibility weighted imaging revealed numerous microbleeds.Most importantly, the deposition of GOM was found in the proband. CONCLUSION:33 exons of NOTCH3 gene should be performed for individuals with a convincing CADASIL phenotype and positive family history. 10.1016/j.jstrokecerebrovasdis.2020.105410
    CADASIL and Bipolar Affective Disorder. Lim Hong Kai,Millar Zachary A,Zaman Rashid Psychiatria Danubina Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare monogenic disorder caused by mutations in the NOTCH3 gene. The clinical features are primarily neurological, which include recurrent transient ischaemic attacks, strokes, and migraines. However, psychiatric manifestations which mainly include mood disturbances have also been reported in CADASIL. Manic symptoms and bipolar disorders are rarely documented in CADASIL and existing reports generally lack detailed descriptions of the psychiatric evaluation. We discuss a case of Bipolar Affective Disorder (BD) in a British woman with a family history of CADASIL. This case provides insight into the diagnosis and management of BD as well as the possible underlying aetiologies that should be considered. The similarities between BD and CADASIL in terms of imaging, genetic, and therapeutic aspects raise the possibility of common dysfunctional pathways. BD in CADASIL may warrant greater consideration by both psychiatrists as well as non-psychiatric specialists and further studies are required to understand the pathological significance.
    Homozygous NOTCH3 p.R587C mutation in Chinese patients with CADASIL: a case report. He Ruojie,Li Huan,Sun Yiming,Chen Menglong,Wang Liang,Zhu Yuling,Zhang Cheng BMC neurology BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations. CASE PRESENTATION:We recruited two affected individuals with CADASIL from a mainland Chinese family. The proband (Patient 1), a 60-year-old male, presented with slow progressive gait instability, severe cognitive impairment, and emotional disorder for more than 2 years with a history of ischemic stroke and hypertension. His younger brother (Patient 2) presented with apparent gait difficulties, dysarthria as well as cognitive decline at 59 years old. Brain magnetic resonance imaging (MRI) showed diffused white matter lesions involving bilateral periventricular white matter, semioval center region, and anterior temporal lobes. Molecular genetic testing identified a homozygous variant, c.1759C > T (p.R587C), in NOTCH3 gene in both patients. Pathological analysis revealed granular osmiophilic material (GOM) deposits in small arterial walls of skin from the proband. The diagnosis of CADASIL was confirmed. CONCLUSIONS:Our cases of CADASIL with homozygous mutation c.1759C > T (p.R587C) in NOTCH3 share similar manifestation to the patients with heterozygous same mutation reported previously. Other than genetic factors, vascular risk factors or environmental factors might contribute to the phenotypic variation of CADASIL. 10.1186/s12883-020-01660-0
    Not Described Variant of Notch3 Gen for Cadasil Disease. Mellinger Surai,Romero D,Visich A,Chanampa S,Ivetich G,Burgos M,Orzuza G Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), is a genetic disease caused by mutations in the Notch3 gene. More than 170 monogenic mutations leading to the development of CADASIL have been reported. We describe a case of a patient and her family with compatible symptoms of CADASIL disease, in which a variable not yet described in the Notch3 gene was detected, that generates a probably pathogenic change in the protein. 10.1016/j.jstrokecerebrovasdis.2020.104803
    A Chinese CADASIL Family with a Novel Mutation on Exon 10 of Notch3 Gene. Liu Yuan,Huang Shicun,Yu Liqiang,Li Tan,Diao Shanshan,Chen Zhiguo,Zhou Guoqing,Sheng Xihua,Xu Yuan,Fang Qi Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by the Notch3 gene mutation, has its unique clinical and imaging characteristics. Here we present a Chinese family with a novel mutation on exon 10 of Notch3 gene. METHODS:Clinical and MRI data of the three patients in the family during the 7-year follow-up were collected. The CADASIL Scale Score was calculated to evaluate the disease risk of the three patients at their first admission or clinic visit. Five family members underwent genetic test. RESULTS:Genetic test confirmed the diagnosis of CADASIL in this family. A novel mutation of p.C533S on exon 10 of Notch3 gene was detected. The CADASIL score of the proband and her sister was both 17 and that of her brother was 14. CONCLUSIONS:Our report not only expands the mutation spectrum of Notch3 gene in CADASIL, but also shows the distinct heterogeneity of CADASIL patients in the same family with the same mutation. 10.1016/j.jstrokecerebrovasdis.2021.105674
    A Chinese CADASIL family with p.R578C mutation at exon 11 of the NOTCH3 gene. Wu XuLing,Zhang AnNi,Li Ya,Lei XiaoYang,Guo ShiPeng,Tian Tian,Gong HuiLan,He Dian Clinical neurology and neurosurgery OBJECTIVE:To analyze one clinical case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL), and to perform analysis of the related gene mutation for the proband and her family. METHODS:Analysis of clinical data from the patient diagnosed with CADASIL, including clinical manifestations, blood test results and brain imaging results, followed by high-throughput sequencing of blood samples. Pathogenicity assessment of the gene mutation, and first generation verification were performed on some family members according to genetic variation interpretation standards and guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS:Onset of the proband occurred younger than 50-years-old with recurrent migraine attacks and positive family history of migraine and stroke, but without risk factors for cerebrovascular diseases. The craniocerebral magnetic resonance imaging (MRI) results showed diffusive white matter lesions and thus clinically met criteria for CADASIL diagnosis. NOTCH3 gene analysis showed a p.R578C mutation (1732 C > T) at the11th exon on chromosome 19 of the proband and some family members. CONCLUSIONS:NOTCH3 mutation is related to CADASIL. In this study, we observed a rather rare familial NOTCH3 mutation in China. This report further support the mutation site is pathogenic. 10.1016/j.clineuro.2021.106833
    Hereditary cerebral amyloid angiopathy mimicking CADASIL syndrome. Psychogios Klearchos,Xiromerisiou Georgia,Kargiotis Odysseas,Safouris Apostolos,Fiolaki Aidonio,Bonakis Anastasios,Paraskevas Georgios P,Giannopoulos Sotirios,Tsivgoulis Georgios European journal of neurology BACKGROUND:Small vessel disease (SVD), and most specifically hereditary forms like CADASIL and cerebral amyloid angiopathy (hCAA), are conditions of increasing clinical importance. We report a rare case of hCAA in a Greek family that presented with a CADASIL clinical and neuroimaging phenotype. METHODS:A 65-year-old man was admitted with recurrent transient episodes of right leg numbness. The patient's medical history started at the age of 50 years with depression and behavioral disorders. His family history was positive for stroke (father), dementia (father and brother), migraine (daughter) and depression (father and daughter). RESULTS:Neurological examination disclosed anomic aphasia with severely impaired cognitive status, and brisk reflexes. Brain computed tomography and magnetic resonance imaging showed CADASIL-like leukoencephalopathy (hyperintense lesions in bilateral temporopolar area, external capsule, thalami, centrum semiovale and superior frontal regions) with occipital calcifications and cerebral microbleeds. Screen for variants in NOTCH3 gene was negative. Exome sequencing revealed a novel pathogenic mutation for hCAA. CONCLUSIONS:We report a novel amyloid precursor protein mutation which results in a CADASIL-like clinical phenotype (progressive cognitive and motor decline, stroke, migraine and behavioral disorders) and CADASIL-leukoencephalopathy coupled with occipital calcifications. Earlier recognition and swift hCAA diagnosis may prompt rational preventive and potential disease-modifying interventions. 10.1111/ene.14981
    CADASIL: new advances in basic science and clinical perspectives. Ferrante Elisa A,Cudrici Cornelia D,Boehm Manfred Current opinion in hematology PURPOSE OF REVIEW:Recent advances in genetic evaluation improved the identification of several variants in the NOTCH3 gene causing Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Despite improved diagnosis, the disease mechanism remains an elusive target and an increasing number of scientific/clinical groups are investigating CADASIL to better understand it. The purpose of this review is to summarize the current knowledge in CADASIL. RECENT FINDINGS:CADASIL is a genotypically and phenotypically diverse condition involving multiple molecular systems affecting small blood vessels. Cerebral white matter changes observed by MRI are a key CADASIL characteristic in young adult patients often before severe symptoms and trigger NOTCH3 genetic testing. NOTCH3 mutation locations are highly variable, correlate to disease severity and consistently affect the cysteine balance within extracellular Notch3. Granular osmiophilic material deposits around blood vessels are also a unique CADASIL feature and appear to have a role in sequestering proteins that are essential for blood vessel homeostasis. As potential biomarkers and therapeutic targets are being actively investigated, neurofilament light chain can be detected in patient serum and may be a promising circulating biomarker. SUMMARY:CADASIL is a complex, devastating disease with unknown mechanism and no treatment options. As we increase our understanding of CADASIL, translational research bridging basic science and clinical findings needs to drive biomarker and therapeutic target discovery. 10.1097/MOH.0000000000000497
    Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases. Schoemaker Dorothee,Arboleda-Velasquez Joseph F The American journal of pathology Mutations in the NOTCH3 gene can lead to small-vessel disease in humans, including the well-characterized cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a condition caused by NOTCH3 mutations altering the number of cysteine residues in the extracellular domain of Notch3. Growing evidence indicates that other types of mutations in NOTCH3, including cysteine-sparing missense mutations or frameshift and premature stop codons, can lead to small-vessel disease phenotypes of variable severity or penetrance. There are currently no disease-modifying therapies for small-vessel disease, including those associated with NOTCH3 mutations. A deeper understanding of underlying molecular mechanisms and clearly defined targets are needed to promote the development of therapies. This review discusses two key pathophysiological mechanisms believed to contribute to the emergence and progression of small-vessel disease associated with NOTCH3 mutations: abnormal Notch3 aggregation and aberrant Notch3 signaling. This review offers a summary of the literature supporting and challenging the relevance of these mechanisms, together with an overview of available preclinical experiments derived from these mechanisms. It highlights knowledge gaps and future research directions. In view of recent evidence demonstrating the relatively high frequency of NOTCH3 mutations in the population, and their potential role in promoting small-vessel disease, progress in the development of therapies for NOTCH3-associated small-vessel disease is urgently needed. 10.1016/j.ajpath.2021.03.015
    A novel NOTCH3 mutation and its clinical, neuroimaging and pathological presentation in a Chinese patient with CADASIL: A case report. Medicine RATIONALE:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of familial cerebral small vessel disease in adults, and is caused by NOTCH3 mutations. However, individual symptom types, onset, and disease severity span a wide range. PATIENT CONCERNS:Herein, we report a case of chronic neurological symptoms including slurring of speech, recurrent weakness in both limbs and legs, and progressive memory loss. Cranial magnetic resonance imaging revealed recurrent acute lacunar subcortical infarction and extensive white matter hyperintensities. Skin biopsy revealed granular osmiophilic materials close to the cell surface of smooth muscle cells in an arteriolar vessel. The patient's genomic DNA showed a mutation c.635G>C[p.(Cys212Ser)] in exon 4. DIAGNOSIS:The patient was finally diagnosed with CADASIL. INTERVENTIONS:The patient was treated with antiplatelet therapy and extremity rehabilitation. OUTCOMES:There was no improvement in speech, extremity function, or memory. LESSONS:Accurate early diagnosis and appropriate treatment are crucial to improve the prognosis of patients with CADASIL. 10.1097/MD.0000000000028870
    Three Pediatric Siblings With CADASIL. Torres Marcela,Hamby Tyler,Tilley Jo,Schenk Allyson,Acosta Fernando,Kurjee Nehel,Russell Katherine Pediatric neurology BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a congenital small vessel disease of the brain due to NOTCH3 gene mutations. Although adult-onset CADASIL is well documented, more cases are being described within the pediatric population. We describe three siblings with NOTCH3 mutations with various symptomatic presentations of early-onset CADASIL and one sibling with concurrent moyamoya syndrome. METHODS:Review of electronic medical records of identified patients. RESULTS:A 19-year-old male who has experienced behavioral dysregulation, hallucinations, and memory loss along with a hyperintense signal abnormality in his temporal lobe; his 15-year-old sister who has the mildest presentation in terms of normal imaging results but experiences severe headaches, anxiety, and depression; and the youngest sibling, a 13-year-old with first reported case of a NOTCH3 mutation associated with moyamoya syndrome and a TREX1 gene mutation of uncertain clinical significance. She had multiple strokes before age five years. CONCLUSION:Our set of siblings share many similarities with other reported pediatric cases of CADASIL, all with NOTCH3 gene mutations and with early-onset symptoms that range from abnormalities in the cognitive/behavioral/psychiatric field to neurological deficits, migraines, and strokes. Gene testing and imaging studies in symptomatic children with a family history suggestive of CADASIL might aid in early diagnosis, even though there is no effective therapy. We believe that the correlation of clinical presentations and gene mutations together with increased research into the molecular mechanisms underlying CADASIL (and related arteriopathies such as moyamoya syndrome) are critical to the eventual development of targeted therapies. 10.1016/j.pediatrneurol.2022.01.003
    Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. Di Donato Ilaria,Bianchi Silvia,De Stefano Nicola,Dichgans Martin,Dotti Maria Teresa,Duering Marco,Jouvent Eric,Korczyn Amos D,Lesnik-Oberstein Saskia A J,Malandrini Alessandro,Markus Hugh S,Pantoni Leonardo,Penco Silvana,Rufa Alessandra,Sinanović Osman,Stojanov Dragan,Federico Antonio BMC medicine Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients. 10.1186/s12916-017-0778-8
    CADASIL: Treatment and Management Options. Bersano Anna,Bedini Gloria,Oskam Joshua,Mariotti Caterina,Taroni Franco,Baratta Silvia,Parati Eugenio Agostino Current treatment options in neurology OPINION STATEMENT:CADASIL is a life-threatening and disabling disease. Despite the progress achieved so far, no therapies able to limit the disease progression have been found and only empiric treatments can be employed to relieve the main disease symptoms. Further in vivo studies as well as data aggregation and multi-centre controlled clinical trials are needed to confirm the emerging findings in order to identify evidence-based therapies for CADASIL. 10.1007/s11940-017-0468-z
    Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. Muiño Elena,Gallego-Fabrega Cristina,Cullell Natalia,Carrera Caty,Torres Nuria,Krupinski Jurek,Roquer Jaume,Montaner Joan,Fernández-Cadenas Israel International journal of molecular sciences CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL. 10.3390/ijms18091964
    CADASIL. Wang Michael M Handbook of clinical neurology Cerebral small-vessel disease is a prevalent condition that is strongly associated with ischemic stroke and dementia. The most prevalent inherited cause of cerebral small-vessel disease is CADASIL, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a disorder linked to mutations in NOTCH3. The most common symptoms of CADASIL are small ischemic strokes and/or transient ischemic attacks and cognitive impairment, appearing in middle age, that may progress to frank vascular dementia. However, it is increasingly recognized that individual symptom types, onset, and disease severity span a wide spectrum, even among individuals in the same family. Magnetic resonance imaging in CADASIL reveals severe white-matter hyperintensities, evidence of prior subcortical strokes, and, in some cases, microhemorrhages. Several hundred mutations in NOTCH3 have been described worldwide in CADASIL, and virtually all of these mutations alter the cysteine content of the extracellular NOTCH3 gene product. This molecular genetic signature of CADASIL has led to the hypothesis that structural abnormalities in the vascular smooth-muscle protein NOTCH3 trigger arterial degeneration, vascular protein accumulation, and cerebrovascular failure. 10.1016/B978-0-444-64076-5.00047-8
    Clinical and research applications of magnetic resonance imaging in the study of CADASIL. Schoemaker Dorothee,Quiroz Yakeel T,Torrico-Teave Heirangi,Arboleda-Velasquez Joseph F Neuroscience letters Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited small vessel disease that leads to early cerebrovascular events and functional disability. It is the most common single-gene disorder leading to stroke. Magnetic resonance imaging (MRI) is a central component of the diagnosis and monitoring of CADASIL. Here we provide a descriptive review of the literature on three important aspects pertaining to the use of MRI in CADASIL. First, we review past research exploring MRI markers for this disease. Secondly, we describe results from studies investigating associations between neuroimaging abnormalities and neuropathology in CADASIL. Finally, we discuss previous findings relating MRI markers to clinical symptoms. This review thus provides a summary of the current state of knowledge regarding the use of MRI in CADASIL as well as suggestions for future research. 10.1016/j.neulet.2019.01.014
    Clinical and Genetic Aspects of CADASIL. Mizuno Toshiki,Mizuta Ikuko,Watanabe-Hosomi Akiko,Mukai Mao,Koizumi Takashi Frontiers in aging neuroscience Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease caused by mutations in , is characterized by recurrent stroke without vascular risk factors, mood disturbances, and dementia. MRI imaging shows cerebral white matter (WM) hyperintensity, particularly in the external capsule and temporal pole. Missense mutations related to a cysteine residue in the 34 EGFr on the NOTCH3 extracellular domain (N3ECD) are a typical mutation of CADASIL. On the other hand, atypical mutations including cysteine sparing mutation, null mutation, homozygous mutation, and other associate genes are also reported. From the viewpoint of gain of function apart from Notch signaling or loss of function of Notch signaling, we review the research article about CADASIL and summarized the pathogenesis of small vessel, stroke, and dementia in this disease. 10.3389/fnagi.2020.00091
    Ataxia Associated with CADASIL: a Pathology-Confirmed Case Report and Literature Review. Park Don Gueu,Min Je Hong,Sohn Seong Hyang,Sohn Young Bae,Yoon Jung Han Cerebellum (London, England) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is primarily characterized by migraine, stroke, mood disturbances, and cognitive decline. Ataxia has seldom been reported as a presenting symptom. Here, we review reports of CADASIL presenting as ataxia and compare these to the first pathologically confirmed case of CADASIL presenting with progressive ataxia. A 50-year-old woman presented with progressive truncal ataxia. Brain magnetic resonance imaging (MRI) revealed white matter hyperintensities in the bilateral anterior temporal lobes, external capsules, and periventricular areas, but not the cerebellum. Electron microscopy of skin biopsy material revealed multiple granular osmiophilic materials. Genetic testing confirmed a c.4552C > A mutation in exon 25 of the NOTCH3 gene. CADASIL is a rare cause of progressive ataxia, and only four cases of CADASIL presenting with ataxia have been reported in the literature. We also discuss the possible pathophysiology of cerebellar ataxia associated with CADASIL. 10.1007/s12311-020-01173-z
    CADASIL disease, an inherited slowly progressive vascular dementia: case report with radiologic and electron microscopic findings. Shuja Sania,Lindquist Justin,Lee Kevin P,Silliman Scott,Makary Raafat Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease, a genetically determined arteriopathy, is a rare cause of vascular dementia. We present a case report of a 50-year-old man with migraines associated with left-sided weakness since age 34 years, a stroke at age 43 years, followed by progressive dementia. Magnetic resonance imaging revealed diffuse leukoencephalopathy with involvement of bilateral anterior temporal lobes. Skin biopsy was performed because of clinical suggestion of CADASIL and positive family history. Electron microscopy revealed granular osmophilic material deposits in dermal arterioles, diagnostic for CADASIL disease. A brief discussion of reasons for false-negative skin biopsy findings, differential diagnosis, and treatment of patients with CADASIL disease is presented. 10.1016/j.jstrokecerebrovasdis.2009.02.004
    [CADASIL: brief report on a family with a new p.G296C mutation in exon 6 of the Notch-3 gene]. García-Estévez Daniel A,Barros-Angueira Francisco,Navarro Carmen Revista de neurologia INTRODUCTION:CADASIL is a dominant autosomal inborn systemic arteriopathy, whose genetic anomaly is located in the Notch-3 gene of chromosome 19. It is clinically characterised by migraine with aura, recurrent stroke and cognitive deterioration, and is one of the causes of strokes among the young. CASE REPORT:The propositus was a 57-year-old male who presented a clinical picture of dysarthria, loss of strength in the left extremities and alterations affecting balance with dysmetry in the left extremities, related with an acute ischaemic stroke in the cerebellar peduncle. An ultrastructural study of a biopsy specimen of the skin revealed the electron-dense deposits that characterise CADASIL. The genetic analysis identified a new mutation for this disease in codon 296 of exon 6 in the Notch-3 gene that produces a change of amino acid, from glycine to cysteine in protein (p.G296C). CONCLUSIONS:This communication reports the case of a family with CADASIL that was a carrier of a new p.G296C mutation located in exon 6 of the Notch-3 gene.
    CADASIL: how to avoid the unavoidable? Delgado Montserrat G,Coto Elicer,Tuñon Alberto,Sáiz Antonio BMJ case reports All three siblings (one female/two males) of a family presented successively with cerebrovascular events at the ages of 55, 63 and 65. The first one manifested extensive left subcortical haemorrhage and both the second and third patient, showed left lacunar ischemic stroke. Their mother had died from vascular dementia at the age of 60 after several subcortical ischaemic strokes. Their maternal grandfather had died in his fifties from haemorrhagic stroke. All of them showed extensive white matter involvement. The genetic study revealed a mutation in exon 11 of the Notch3 gene in two family members. They were diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Although CADASIL is a well-established disease, little is known about this disorder. The fact that all three siblings presented with CADASIL successively may appear disheartening, further studies are needed in order to control the clinical course of this devastating and unavoidable disorder. 10.1136/bcr.08.2011.4727
    First report of a pathogenic mutation on exon 24 of the NOTCH3 gene in a CADASIL family. Valenti Raffaella,Bianchi Silvia,Pescini Francesca,D'Eramo Camilla,Inzitari Domenico,Dotti Maria Teresa,Pantoni Leonardo Journal of neurology Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetically transmitted small vessel disease clinically characterized by migraine, recurrent subcortical strokes, and cognitive and mood disorders. Pathogenic mutations are located on any of the exons of the NOTCH3 gene coding for epidermal-growth factor (EGF)-like repeats of the extracellular domain of the NOTCH3 receptor. Because the gene is large and the mutations cluster on some exons, many laboratories restrict the analysis to these exons. We report the first missense mutation involving exon 24 and causing CADASIL in a 64-year-old man. The patient was admitted to the hospital for a loss of consciousness accompanied by profuse sweating. On examination, some parkinsonian features were present. Over the last 4 years, he had developed postural instability and gait disturbances with repeated falls, behavioral disorders, and cognitive impairment. A diagnostic hypothesis of atypical parkinsonism had been advanced. The presence of multiple subcortical lacunar infarcts and leukoencephalopathy extended to the external capsule on cerebral MRI suggested the presence of CADASIL. The diagnosis was confirmed by finding a heterozygous mutation leading to a cysteine substitution on exon 24 of the NOTCH3 gene. One proband's brother, who had progressive gait disturbances, unilateral action tremor and bradykinesia, and an asymptomatic niece also resulted affected. This report underlines that when CADASIL is suspected the genetic analysis should be performed on all the NOTCH3 exons coding for EGF-like repeats including exon 24 and confirms that CADASIL may have heterogeneous phenotypes. 10.1007/s00415-011-5983-3
    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Krsmanović Zeljko,Dincić Evica,Kostić Smiljana,Lacković Vesna,Bajcetić Milos,Lackovć Maja,Bosković Zeljko,Raicević Ranko Vojnosanitetski pregled INTRODUCTION:Fast and precise diagnostics of the disease from the large group of adult leukoencephalopathy is difficult but responsible job, because the outcome of the disease is very often determined by its name. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by the mutation of Notch 3 gene on chromosome locus 19p13. Beside the brain arterioles being the main disease targets, extracerebral small blood vessels are affected by the pathological process. Clinically present signs are recurrent ischemic strokes and vascular dementia. CADASIL in its progressive form shows a distinctive pattern of pathological changes on MRI of endocranium. The diagnosis is confirmed by the presence of granular osmiophilic material (GOM) in histopathological skin biopsies. CASE REPORTS:Two young adult patients manifested ischemic strokes of unknown etiology, cognitive deterioration, migraine and psychopathological phenomenology. MRI of endocranium pointed on CADASIL. Ultrastructural examination of skin biopsy proved the presence of GOM in the basal lamina and near smooth muscle cells of arteriole dermis leading to CADASIL diagnosis. The presence of GOM in histopathological preparation is 100% specific for CADASIL. The patients were not searched for mutation in Notch 3 gene on chromosome 19, because some other leukoencephalopathy was disregarded. CONCLUSION:Suggestive clinical picture, distinctive finding of endocranium MRI, the presence of GOM by ultrastructural examination of histopathological skin biopsies are sufficient to confirm CADASIL diagnosis.
    Intelligence impairment, personality features and psychopathology disturbances in a family affected with CADASIL. Domínguez-Sánchez Francisco Javier,Lasa-Aristu Amaia,Goñi-Imízcoz Miguel The Spanish journal of psychology Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a small-vessel disease of the brain that is characterized by headache, recurring lacunar strokes, mood changes and progressive cognitive deterioration. The disease is transmitted with an autosomal dominant pattern and usually starts during midadulthood (at 30-50 years of age). Cognitive deficits in patients with CADASIL develop slowly. The dementia causes frontal-like symptoms and it typically develops after a history of recurrent stroke. We describe three patients from one Spanish family affected by this disease. All three cases underwent comprehensive clinical and neuropsychological examination, and were monitored for seven years. The results obtained in this study describe a) a significant loss of the intelligence quotient (IQ) and noticeable damage to abstract ability (g factor), b) mood and psychopathological disturbances (major depression and dysthymia), and c) a personality with neurotic features. 10.5209/rev_sjop.2011.v14.n2.39
    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy affecting an African American man: identification of a novel 15-base pair NOTCH3 duplication. Lee Soo Jung,Meng He,Elmadhoun Omar,Blaivas Mila,Wang Michael Mei-Hwa Archives of neurology BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the best characterized genetic cause of vascular dementia and stroke and has been extensively reported in European and Asian populations. OBJECTIVE:To report the pathological and genetic analysis of CADASIL in an African American man with a 15-base pair NOTCH3 duplication. DESIGN:Case report. SETTING:University hospital. PATIENT:A 78-year-old man with dementia, recurrent strokes, a family history of similar neurological disease, and white matter abnormalities seen on brain magnetic resonance imaging. MAIN OUTCOME MEASURES:Brain pathology and genetic analysis of NOTCH3. RESULTS:The patient's brain showed widespread arteriopathy in large and small arteries. Using electron microscopy, granular osmiophilic material typical of CADASIL was identified abutting the plasma membrane of smooth muscle cells. Brain extracts contained elevated NOTCH3 protein levels. Sequencing of the NOTCH3 gene revealed a novel 15-base pair heterozygous duplication in exon 7, which is predicted to direct expression of a protein that contains 5 extra amino acids, including a cysteine residue. CONCLUSIONS:To our knowledge, this is the first reported pathological and genetic analysis of an African American patient with CADASIL. The mutation in NOTCH3 is the longest duplication within this gene yet reported. 10.1001/archneurol.2011.781
    The feasibility of a structured cognitive training protocol to address progressive cognitive decline in individuals with vascular dementia. Mayer Jamie F,Bishop Lilli A,Murray Laura L American journal of speech-language pathology PURPOSE:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, better known as CADASIL, is a rare, genetic form of early-onset vascular dementia. The purpose of this study was to use a modified version of Attention Process Training--II (APT-II; Sohlberg, Johnson, Paule, Raskin, & Mateer, 2001) with an individual with early-stage CADASIL. METHOD:APT-II, modified to include strategy training, was applied in an A-B, multiple-probe design for an individual who had been diagnosed with early-stage CADASIL. Outcome measures included pre-post neuropsychological testing of attention, memory, and executive function; within-treatment probes of visual and auditory attention; and a measure of subjective experience of cognitive functioning in daily living. RESULTS:The participant demonstrated nominal gains on visual and auditory attention probes but improved performance on several posttreatment measures of processing speed and executive function. The participant also reported substantially improved functional outcomes following the intervention protocol. CONCLUSION:This case illustrates the potential utility of behavioral intervention for individuals with CADASIL and highlights issues for speech-language pathologists to consider when using structured cognitive training protocols in the setting of progressive cognitive decline. These data suggest that further controlled studies for treating this population are warranted. 10.1044/1058-0360(2012/11-0066)
    Homozygosity and severity of phenotypic presentation in a CADASIL family. Vinciguerra Claudia,Rufa Alessandra,Bianchi Silvia,Sperduto Antonio,De Santis Monica,Malandrini Alessandro,Dotti Maria Teresa,Federico Antonio Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology Most of causative mutations of the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are missense point mutations either creating or deleting one cysteine residue, inherited in a heterozygous state. Only few homozygous patients are reported to date and some of them showed phenotypic peculiarities. We here describe a CADASIL family in which a member showed homozygous mutation and compare its clinical profile with five subjects throughout three generation of the pedigree, carrying the same mutation in heterozygosity. The index patient was a 44-year-old Italian man, born from consanguineous parents (first cousins). Symptoms started at 23 years and progressing with recurrent ischemic stroke episode. Diffuse leukoencephalopathy and a severe cognitive impairment were evident, GOMs were detected in skin specimens and a homozygous p.Cys183Ser mutation of the NOTCH3 gene was found. Among the other five heterozygous relatives for the same mutation, both parents developed stroke in advanced age and all the others were clinically asymptomatic. We discuss these findings in relationship to previous data from the literature in CADASIL and in other dominant neurological disorders. 10.1007/s10072-013-1580-9
    Detection of early cognitive impairment using AD8 in a young patient with stroke with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome: a case report. Hsieh I-Chieh,Kuan Ta-Shen,Hsieh Pei-Chun,Chen Shu-Min,Yen Wei-Jang,Chang Wen-Chen,Lin I-Ling,Lin Yu-Ching American journal of Alzheimer's disease and other dementias Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome is a hereditary disease resulting from NOTCH3 gene mutation. The clinical presentations include migraine, recurrent stroke, and cognitive impairment. The severity of cognitive impairment varies in different stages, and early recognition poses a challenge. A 47-year-old lady presented with chronic migraine and sudden onset of hemiparesis. Magnetic resonance imaging revealed compatible findings of CADASIL, which was confirmed by mutation analysis of NOTCH3 gene. Early cognitive impairment was detected by her score of 3 in Ascertain Dementia 8 (AD8) questionnaire and confirmed by detailed neuropsychological assessments. After 21 months of follow-up, deterioration in her cognition and ability to perform instrumental activities of daily living were significant with a follow-up AD8 score of 7. Ascertain Dementia 8 questionnaire is an easy and valid screening tool for early cognitive impairment in patients with CADASIL syndrome. 10.1177/1533317513511289
    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy without anterior temporal pole involvement: a case report. Kobayashi Junpei,Sato Shoichiro,Okumura Kosuke,Miyashita Fumio,Ueda Akihiko,Ando Yukio,Toyoda Kazunori Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association The location of white matter lesions, especially in the anterior temporal poles (ATP), is helpful in the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We report a 49-year-old man with CADASIL who developed migraine with atypical aura, silent lacunar infarcts, and leukoencephalopathy without involvement of the ATP. The prevalence of migraine with aura in subjects with CADASIL is several times greater than that in the general population. Particularly in patients with CADASIL, the aura is often atypical (hemiplegic, basilar, or prolonged). A diagnosis of CADASIL should be considered in patients with lacunar infarcts, leukoencephalopathy, and migraine with atypical aura, even in the absence of white matter lesion in the ATPs. 10.1016/j.jstrokecerebrovasdis.2013.10.013
    [A case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in which lomerizine hydrochloride was suggested to prevent recurrent stroke]. Shimizu Hisao,Nagami Shuhei,Takahashi Nobuyuki Rinsho shinkeigaku = Clinical neurology A 60-year-old man visited our hospital because of left hemiparesis in September 2006. Magnetic resonance imaging (MRI) revealed a high-intensity lesions in the right corona radiata on diffusion-weighted images and a high-intensity lesions in the basal ganglia and deep white matter on T2-weighted images. He recovered with no sequelae. Antithrombotic agents such as aspirin were given to prevent stroke, but stroke recurred three times over the course of 3 years. In February 2009, neurological examination revealed right hemiparalysis and dysarthria. Dysphagia and cognitive decline had been progressing gradually. We suspected cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) on the basis of the clinical and family history. An Arg75Pro mutation in the Notch3 gene was found, but did not involve a cysteine residue. Antithrombotic agents were ineffective. We tried lomerizine hydrochloride, which was reported to prevent stroke in a patient with CADASIL. In Japan, lomerizine hydrochloride is used to prevent migraine and to selectively inhibit cerebral artery contraction. During treatment with lomerizine hydrochloride (5 mg/day) for more than 3 years, there was no recurrence of cerebral infarction and no further deterioration of cognitive function or MRI findings. There is no evidence supporting the efficacy of antithrombotic agents in CADASIL patients. Moreover, antithrombotic agents have been reported to increase the frequency of clinically silent microbleeds on MRI in CADASIL. Lomerizine hydrochloride might therefore be one option for the treatment of CADASIL.
    CADASIL with a novel NOTCH3 mutation (Cys478Tyr). Ozaki Kokoro,Irioka Takashi,Ishikawa Kinya,Mizusawa Hidehiro Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Recently, an increasing number of NOTCH3 mutations have been described to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here, we report 2 CADASIL patients from a Japanese family, who were found to possess a novel NOTCH3 mutation. The proband only had chronic headache, and her mother had previously suffered a minor stroke. Although the patients' clinical symptoms were mild, their distinctive magnetic resonance imaging (MRI) features suggested CADASIL. Genetic analysis revealed that both patients had a novel heterozygous NOTCH3 mutation (p.Cys478Tyr) leading to stereotypical cysteine loss. The present finding suggests that genetic testing for NOTCH3 mutations in patients with distinctive MRI features, even if the symptoms are as mild as chronic headache, should help to broaden the mutational and clinical spectrum of CADASIL. 10.1016/j.jstrokecerebrovasdis.2014.11.022
    Neoplastic lesions in CADASIL syndrome: report of an autopsied Japanese case. Hassan Wael Abdo,Udaka Naoka,Ueda Akihiko,Ando Yukio,Ito Takaaki International journal of clinical and experimental pathology Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common heritable causes of stroke and dementia in adults. The gene involved in the pathogenesis of CADASIL is Notch3; in which mutations affect the number of cysteine residues in its extracellular domain, causing its accumulation in small arteries and arterioles of the affected individuals. Besides the usual neurological and vascular findings that have been well-documented in CADASIL patients, this paper additionally reports multiple neoplastic lesions that were observed in an autopsy case of CADASIL patient; that could be related to Notch3 mutation. The patient was a 62 years old male, presented with a past history of neurological manifestations, including gait disturbance and frequent convulsive attacks. He was diagnosed as CADASIL syndrome with Notch3 Arg133Cys mutation. He eventually developed hemiplegia and died of systemic convulsions. Autopsy examination revealed-besides the vascular and neurological lesions characteristic of CADASIL- multiple neoplastic lesions in the body; carcinoid tumorlet and diffuse idiopathic pulmonary neuro-endocrine cell hyperplasia (DIPNECH) in the lungs, renal cell carcinoma (RCC), prostatic adenocarcinoma (ADC) and adenomatoid tumor of the epididymis. This report describes a spectrum of neoplastic lesions that were found in a case of CADASIL patient that could be related to Notch3 gene mutations.
    Injuries of neural tracts in a patient with CADASIL: a diffusion tensor imaging study. Jang Sung Ho,Seo You Sung BMC neurology BACKGROUND:We report a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), who showed injuries of the neural tracts, which was demonstrated by diffusion tensor tractography (DTT). CASE PRESENTATION:A 64-year-old male patient and seven age-matched control volunteers were recruited. Since approximately 1.5 years ago, he had felt mild weakness of the right arm and was diagnosed as CADASIL by the finding of the exon 11 mutation of the NOTCH3 gene approximately 10 months ago. T2-weighted and FLAIR brain MRI images obtained at admission showed high signal intensity lesions in the subcortical gray matter and periventricular white matter. He showed mild quadriparesis, mild dysarthria, mild cognitive impairment, and emotional problems. Diffusion tensor imaging was performed and nine neural tracts (corticospinal tract, corticobulbar tract, corticofugal tract from the supplementary motor area, corticofugal tract from the premotor cortex, thalmoprefrontal tract [TPT] to the dorsolateral prefrontal cortex, TPT to the ventrolateral prefrontal cortex, TPT to the orbitoprefrontal cortex, fornix, and cingulum) were reconstructed. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume of each neural tract were measured. All neural tracts except for the left fornix showed at least one more abnormality in terms of DTT parameters (decrement of FA, increment of MD, or decrement of tract volume). CONCLUSION:We demonstrated injuries of the neural tracts in a patient with CADASIL. It appears that clinical manifestations in this patient were related to injuries of the neural tracts. 10.1186/s12883-015-0434-x
    CADASIL Presenting as Acute Bilateral Multiple Subcortical Infarcts without a Characteristic Temporal Pole or Any External Capsule Lesions. Ando Takashi,Goto Yoji,Mano Kazuo,Ueda Akihiko,Ando Yukio,Mizuta Ikuko,Mizuno Toshiki Internal medicine (Tokyo, Japan) A 37-year-old man was hospitalized for an evaluation of acute bilateral multiple subcortical infarcts. There were no specific signal abnormalities in the temporal pole or external capsule. An abdominal skin biopsy showed granular, electron-dense, osmiophilic material (GOM) in the smooth muscle cells on electron microscopy. A direct sequencing analysis of NOTCH3 revealed a heterozygous c.986G>A substitution in exon 6, resulting in a Cys329Tyr amino acid replacement. According to these findings, the patient was diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencehalopathy (CADASIL). Thus, early phases of CADASIL can present as acute bilateral multiple subcortical infarcts without a characteristic temporal pole or any external capsule lesions. 10.2169/internalmedicine.55.7123
    First Report of Arg587Cys Mutation of Notch3 Gene in Two Chinese Families with CADASIL. You Jinsong,Liao Shaojun,Zhang Foming,Ma Zhaohui,Li Guifu Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association OBJECTIVE:To explore Notch3 mutation sites of Chinese patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS:Direct sequencing of all exons in Notch3 gene was performed on 12 unrelated suspected CADASIL cases from mainland China. RESULT:A missense p.Arg587Cys (1759C>T) mutation in exon 11 was identified in 2 patients through genetic analysis. CONCLUSION:Chinese patients with CADASIL of R587C mutation in exon 11 was firstly reported. 10.1016/j.jstrokecerebrovasdis.2016.09.014
    A large number of cerebral microbleeds in CADASIL patients presenting with recurrent seizures: a case report. Anamnart Chumpol,Songsaeng Dittapong,Chanprasert Sirisak BMC neurology BACKGROUND:Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy associated with the NOTCH3 gene. Clinical manifestations include strokes, transient ischaemic events, psychiatric disturbances, dementia, and migraines. We report a case of a Thai man with a severe CADASIL phenotype who presented with recurrent seizures and acute ischaemic stroke and classic vascular risk factors. CASE PRESENTATION:A 50-year-old man with a history of mood disorder and progressive cognitive decline for 20 years as well as well-controlled diabetes mellitus and hypertension presented with recurrent generalized seizures and acute right-sided weakness. An MRI of the brain showed acute infarction of the left pons, a large number of cerebral microbleeds throughout the brain and white matter abnormalities without classic anterior temporal lobe lesions. Molecular genetic testing identified a homozygous pathologic variant, c.1672C > T (p. Arg558Cys), in the NOTCH3 gene. The diagnosis of CADASIL was confirmed. His clinical symptoms deteriorated, and he died of tracheobronchitis with secretion obstruction. CONCLUSION:This case raises awareness of an uncommon cause of acute ischaemic stroke in patients with classic vascular risk factors and emphasizes the need for a complete evaluation in cases with unexpected clinical presentation or unexpected diagnostic study results. 10.1186/s12883-019-1342-2
    CADASIL with Atypical Clinical Symptoms, Magnetic Resonance Imaging, and Novel Mutations: Two Case Reports and a Review of the Literature. Sari U Serpil,Kisabay Aysin,Batum Melike,Tarhan Serdar,Dogan Nihal,Coskunoglu Aysun,Cam Sirri,Yilmaz Hikmet,Selcuki Deniz Journal of molecular neuroscience : MN Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy with adult onset caused by a missense mutation in the NOTCH3 gene in chromosome 19p13. It presents with autosomal dominant arteriopathy, subcortical infarctions, and leukoencephalopathy. Its common clinical presentations are seen as recurrent strokes, migraine or migraine-like headaches, progressive dementia, pseudobulbar paralysis, and psychiatric conditions. Two patients with CADASIL syndrome, whose diagnosis was made based on clinical course, age of onset, imaging findings, and genetic assays in the patients and family members, are presented here because of new familial polymorphisms. The first patient, with cerebellar and psychotic findings, had widespread non-confluent hyperintense lesions as well as moderate cerebellar atrophy in cranial magnetic resonance scanning. The other patient, with headache, dizziness, and forgetfulness, had gliotic lesions in both cerebral hemispheres. CADASIL gene studies revealed a new polymorphism in exon 33 in the first patient. In the other patient, the NOTCH3 gene was identified as a new variant of p.H243P (c.728A > C heterozygous). By reporting a family presenting with various clinical symptoms in the presence of new polymorphisms, we emphasize that CADASIL syndrome may present with various clinical courses and should be considered in differential diagnoses. 10.1007/s12031-019-01313-z
    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) presenting with stroke in a young man. Dunphy Louise,Rani Amir,Duodu Yaw,Behnam Yousef BMJ case reports Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations in the gene which maps to the short arm of chromosome 19 and encodes the NOTCH3 receptor protein, predominantly expressed in adults by vascular smooth muscle cells and pericytes. The receptor has a large extracellular domain with 34 epidermal growth factor-like repeats encoded by exons 2-24, the site at which CADASIL mutations are most commonly found. Migraine with aura is often the earliest feature of the disease, with an increased susceptibility to cortical spreading depression suggested as a possible aetiological mechanism. Stroke, acute encephalopathy and cognitive impairment can also occur. Hypertension and smoking are associated with early age of onset of stroke. It diffusely affects white matter, with distinct findings on T2- weighted MRI, involving the external capsule, anterior poles of the temporal lobe and superior frontal gyri, displaying a characteristic pattern of leucoencephalopathy. Affected individuals have a reduced life expectancy. An effective treatment for CADASIL is not available. The authors describe a 35-year-old manwith an unremarkable medical history, presenting to the emergency department with slurred speech and increased confusion 3 days following a fall. He was a smoker and consumed 16 units of alcohol weekly. He was hypertensive and tachycardic. Physical examination confirmed increased tone in his lower limbs and dysarthria. His CT head showed severe cerebral atrophy, multiple small old infarcts and moderate background microvascular disease. Further investigation with an MRI head confirmed multiple white matter abnormalities with microhaemorrhages. The possibility of a hereditary vasculopathy was rendered as the appearances were thought consistent with a diagnosis of CADASIL. Genetic testing identified the gene thus confirming the diagnosis. This paper provides an overview of the aetiology, clinical presentation, pathogenesis, investigations and management of CADASIL. 10.1136/bcr-2019-229609
    Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Associated With a Novel In-Frame Mutation in the NOTCH3 Gene in a Japanese Patient. Takeshi Yuho,Suda Satoshi,Shimoyama Takashi,Aoki Junya,Suzuki Kentaro,Okubo Seiji,Mizuta Ikuko,Mizuno Toshiki,Kimura Kazumi Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Here, we report a case involving a 67-year-old Japanese woman with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) associated with a novel in-frame complex rearrangement in the NOTCH3 gene. The patient had gradually developed cognitive impairment since the occurrence of an ischemic stroke at the age of 53 years. Her mother had a history of stroke and dementia. Fluid-attenuated inversion recovery magnetic resonance imaging of the brain showed hyperintense lesions in the bilateral temporal poles, external capsules, and periventricular white matter accompanied by multiple cerebral microbleeds on T2*-weighted gradient-echo imaging. A novel in-frame mutation (c.598_610delinsAGAACCC) resulting in the loss of Cys201 in the fifth epidermal growth factor-like repeat of NOTCH3 was identified; this led to a diagnosis of CADASIL. In summary, we report a novel pathogenic mutation (NOTCH3 c.598_610delinsAGAACCC; p.Pro200_Ser204delinsArgThrPro) associated with CADASIL. Further investigations should elucidate the genotype-phenotype correlations in patients with this in-frame complex rearrangement. 10.1016/j.jstrokecerebrovasdis.2019.104482
    Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Kashyap Priyanka Vikas,Bhat Sunil Jee,Bhatt Sunil,Dhasmana Manira The Journal of the Association of Physicians of India Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is one of the most common heritable cerebral arteriopathy. Responsible for stroke and dementia in young adults and can be diagnosed by skin biopsy. We report a case of a 42 year old man with recurrent transient ischemic attacks (TIA). A detailed neurologic examination revealed poor score in MMSE (20/30) defect mainly seen in recall, repetitions. Executive dysfunction, memory and language impairment were also found. Motor system examination revealed grade 3 power in right upper and lower limb with more severe weakness of distal muscles in form of grip weakness and slippage of chappals. Neuroimaging and genetic analysis for Notch-3 confirmed the diagnosis. Imaging studies suggested greater involvement in the temporal and frontal lobes along with deep areas of the brain.
    Arg133Cys mutation of Notch3 in two unrelated Japanese families with CADASIL. Uyama E,Tokunaga M,Suenaga A,Kotorii S,Kamimura K,Takahashi K,Tabira T,Uchino M Internal medicine (Tokyo, Japan) OBJECTIVE:More than 80 unrelated, but all Caucasian, patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), originating from various communities around the world, have been molecularly identified. To clarify the occurrence of CADASIL in Orientals, we investigated Japanese families presenting as CADASIL. METHODS:We performed the PCR-SSCP and sequence analyses using genomic DNA, isolated from venous blood of participants under informed consent. PATIENTS:We identified two unrelated Japanese families with CADASIL, including 5 affected members through 2 generations. RESULTS:Each of the affected individuals developed recurrent strokes without risk factors resulting in progressive dementia, pseudobulbar palsy, and gait disturbances which started after the fifth decade of life. Although affected individuals had no vascular risk factors, they showed various degrees of narrowing of retinal arteries. Their MRI/CTs showed characteristics of the disease; bilateral small infarcts in the thalamus, basal ganglia, brain stem, and deep white matter in addition to the findings of leukoaraiosis. On SPECT imaging, there was severe hypoperfusion in the cortex as well as in the white matter. Ultrastructural studies revealed an abnormal deposition of granular osmiophilic materials (GOM) within the basal lamina of pericytes in muscular capillaries. On PCR-SSCP and sequence analyses, a heterozygous Arg133Cys mutation was present, in the affected individuals, in the exon 4 of Notch3 gene which is the hot spot region for CADASIL mutations in Caucasian families. None of the non-affected members nor the 50 Japanese normal controls revealed this mutation. CONCLUSION:Thus, our results confirm that CADASIL is a geographically widespread disorder caused by a Notch3 mutation. 10.2169/internalmedicine.39.732