Intracerebral hemorrhages in CADASIL

Intracerebral hemorrhage (ICH) has been described only sporadically for patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, cerebral microbleeds (CMBs) were found in 31% to 69% of the patients with CADASIL, and this predicted an increased risk of ICH. In this study, the authors found that 25% of the symptomatic patients with CADASIL had ICHs, and their development was closely related to the number of CMBs.     

Migraine with aura and white matter abnormalities: Notch3 mutation

The authors report on an Italian family with eight affected members who show autosomal dominant migraine with prolonged visual, sensory, motor, and aphasic aura. These symptoms are associated with white matter abnormalities on brain MRI. All living affected members carry a Notch3 mutation (Arg153Cys) previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). White matter abnormalities occur in a variable percentage of the general migraine population; CADASIL should be suspected in migraineurs with prolonged atypical aura and white matter abnormalities.     

A case of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy) with Notch 3 (Arg169Cys) mutation and typical granular osmiophilic materials in peripheral small arteries]

We report a 64-year-old Japanese woman with recurrent ischemic strokes and progressive dementia without any cardiovascular risk factors. Her first stroke was at 45 years old, and she has a family history of ischemic strokes compatible with an autosomal dominant trait. Marked leukoaraiosis and multiple lacunar infarcts were shown on brain MR images, and no atherosclerotic changes were observed in her extra- and intra-cranial arteries by cervical arterial echography and intracranial MR angiography. Excluded other inherited or metabolic diseases causing leukodystrophy by examination of her blood samples, her disease was diagnosed as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy). We demonstrated granular osmiophilic materials (GOM) on the wall of small arteries from a biopsied peripheral nerve tissue specimen and detected a mutation Arg169Cys of Notch 3 gene. Many CADASIL patients have been reported and over 28 kinds of mutations of the Notch 3 were identified in western countries, while few CADASIL patients have been reported in Japanese people. Among them, eleven CADASIL families have been reported and only five mutations (Arg133Cys, Cys174Phe, Arg213Lys, Arg90Cys and Arg141Cys) have been determined so far. The mutation of Notch 3 in our patient was determined as Arg169Cys, and this is the first report on a Japanese patient with CADASIL due to this mutation.     

R558C NOTCH3 Mutation in a CADASIL Patient with Intracerebral Hemorrhage: A Case Report with Literature Review

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic cerebral small-vessel disease, which is characterized by migraine, recurrent ischemic strokes, psychiatric disorder, progressive cognitive decline, and occasionally intracerebral hemorrhage (ICH). ICH events have been reported in a high proportion of East Asian CADASIL patients with R544C mutation in exon 11 of NOTCH3; however, whether any other specific NOTCH3 mutation determines the ICH phenotype has yet to be explored.Case presentationWe report the case of a 60-year-old male CADASIL patient with a novel R558C mutation in exon 11 of the NOTCH3 gene, who presented with ICH in the basal ganglia and cerebellum. Brain imaging revealed multiple confluent white matter hyperintensities and abundant cerebral microbleeds (CMBs) in the bilateral basal ganglia, thalamus, and cerebellum. The patient had been having recurrent ischemic strokes prior to this ICH event, and had taken antiplatelet and antihypertensive agents for six months. We analyzed the possible reasons for ICH onset in the patient to recommend certain guidelines for the clinic.ConclusionsNovel R558C mutation-related CADASIL vasculopathy and numerous CMBs, uncontrolled hypertension, and antiplatelet therapy could collectively contribute to ICH onset in the patient with CADASIL. These findings suggest that a diagnosis of CADASIL should also be considered when patients present with ICH, whenever MRI imaging reveals typical white matter abnormalities. Furthermore, this case report emphasizes the importance of CMB assessment, appropriate blood pressure control, and cautious assessment of the risk-benefits of antiplatelet medication in patients with CADASIL.     

伴皮质下梗死及白质脑病常染色体显性遗传性脑动脉病的NOTCH3基因诊断

目的 分析伴皮质下梗死及白质脑病常染色体显性遗传性脑动脉病((CADASIL)的NOTCH3基因突变类型.方法 对临床诊断为CADASIL的4例先证者、来自3个家系10例患者及4例无类似临床表现成员、以及100名健康对照者进行NOTCH3基因PCR扩增及变性高压液相色谱分析(DHPLC)检测;对DHPLC阳性结果进行DNA双向测序,明确致病性突变或多态类型.结果 在CADASIL先证者及其家系患者中共发现134半胱氨酸→酪氨酸(Cys134Tyr)、141精氨酸→半胱氨酸(Arg141Cys)、90精氨酸→半胱氨酸(Arg90Cys)3种突变类型,存在于第3、第4外显子,为杂合错义突变.同时发现15种多态类型.其中家系1和家系2中分别发现1名成员与先证者存在相同位点的NOTCH3基因致病性突变,尚未出现与先证者相应的临床表现,被确定为临床前期患者.结论 NOTCH3单基因突变是CADASIL的分子遗传学基础,第3、4外显子可能是中国CADASIL家系的热点突变区.第4外显子Cys134Tyr突变类型为国内首次报告.     

Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014

This study elucidates the genotypic and phenotypic spectrum and histopathological findings related to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Japan. For this single-center retrospective observational study, we enrolled 215 patients who were clinically suspected of having CADASIL and were examined at Kumamoto University from 1997 to 2014, and we diagnosed CADASIL in 70 patients. We found 19 different NOTCH3 mutations in the patients, with the NOTCH3 Arg133Cys mutation being found most frequently. We also found the Arg75Pro mutation, a cysteine-sparing NOTCH3 mutation. CADASIL patients with this Arg75Pro mutation were frequently found throughout Japan, and fewer patients with the Arg75Pro mutation showed MRI hyperintensity in the anterior temporal pole compared with patients with other NOTCH3 mutations. Significantly more CADASIL patients with the NOTCH3 Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation. We also showed postmortem pathological findings of the first Japanese CADASIL case with the NOTCH3 Arg133Cys mutation, and histopathological findings of fresh frozen skin biopsy specimens of CADASIL patients. In conclusions, the spectrum of NOTCH3 mutations in Japanese CADASIL patients may be partially explained by founder effects. Genotype–phenotype correlations may exist in CADASIL, which should be considered so as to make an accurate diagnosis of CADASIL in each population. Fresh frozen skin biopsy specimens may aid detection of Notch3 deposits on vascular walls for an improved diagnosis of CADASIL.     

Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and depression, but not migraine. A skin biopsy in the proband patient showed characteristic pathological findings of CADASIL on electron microscopy. Afterward, genetic analysis found an Arg332Cys mutation at exon 6 of NOTCH3. Neuropsychological evaluation showed vascular dementia in two of four affected people. Head MRI showed multiple infarcts in bilateral basal ganglia, thalami, periventricular white matter, external capsules, and brainstem, but involvement of the anterior temporal pole was found only in two people with milder symptoms. To our knowledge, the Arg332Cys NOTCH3 mutation at exon 6, which was identified in the studied family, has not been reported in Asian populations. Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL.     

Multiple Border-Zone Infarcts Triggered by Influenza A Virus Infection in a Patient With Cerebral Autosomal Dominant Arteriopathy Presenting With Subcortical Infarcts and Leukoencephalopathy

Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can develop multiple border-zone infarcts due to hypotension, hypovolemia, or surgery. We report the case of a 41-year-old woman with CADASIL who developed multiple border-zone infarcts due to influenza A virus infection. The patient had no apparent history or episode of stroke or altered consciousness following the onset of respiratory symptoms, which were due to the influenza A infection. Diffusion-weighted magnetic resonance images of the brain showed multiple acute-phase infarcts in border-zone areas of both cerebral hemispheres and the corpus callosum; fluid-attenuated inversion-recovery magnetic resonance images showed increased signal in the subcortical areas of both temporal poles. Gene analysis identified a heterozygous mutation c.160C>T in exon 2 of the NOTCH3 gene (p.Arg54Cys). A diagnosis of CADASIL was established. Our case demonstrates that infectious conditions such as influenza A can trigger multiple border-zone infarctions in patients with CADASIL.     

Mutations of the notch3 gene in non-caucasian patients with suspected CADASIL syndrome

The Notch3 gene has been recently identified as a causative gene for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). To investigate the genetic contribution of Notch mutations in familial cases with vascular leukoencephalopathy, we screened 13 patients from 11 unrelated families, which were selected on the basis of magnetic resonance imaging findings and positive family history. We identified three different missense mutations in 5 patients from 4 families. Two (Arg90Cys and Arg133Cys) are the same as previously reported in Caucasian patients, the other (Cys174Phe) is a novel mutation causing a loss of a cysteine in epidermal-growth-factor-like repeats of Notch3. These data indicate that the CADASIL Notch3 mutations were found in approximately 35% of familial cases with leukoencephalopathy, suggesting genetic heterogeneity of the disease.     

脑小血管病

目的探讨伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)患者脑微出血(cerebral microbleeds,CMBs)的分布特征及临床意义。方法回顾性纳入2017年6月-2019年12月北京协和医院基因确诊的连续CADASIL患者21例(CADASIL组),以及性别匹配的高血压动脉硬化性脑小血管病患者21例(高血压脑小血管病组)。所有患者均行头MRI检查(含T2^*/SWI序列),盲法读片并记录CMBs的数量和部位,分析两组CMBs分布的差异。结果CADASIL组年龄和常见血管病危险因素比例均低于高血压脑小血管病组。CADASIL组47.6%患者检出CMBs(共计115个),而高血压脑小血管病组高达95.2%(共计218个)。CADASIL组CMBs分布以丘脑最常受累(45.2%),其次是脑叶(皮层/皮层下,35.7%)、基底节(11.3%)。高血压脑小血管病组则以丘脑以外的基底节CMBs最多见(35.3%),其次是脑叶(26.6%)、丘脑(19.2%)、脑干(16.1%)。CADASIL患者丘脑CMBs/总CMBs比例、丘脑CMBs/(基底节CMBs+脑干CMBs)比例均高于高血压脑小血管病组(均P<0.001)。结论CADASIL患者CMBs分布以丘脑最常见,其次是皮层/皮层下区域,而高血压脑小血管病患者则以丘脑以外的基底节、脑干更常见。     

Report of a patient with CADASIL having a novel missense mutation of the Notch 3 gene--association with alopecia and lumbar herniated disk]

We report a 52-year-old man with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting dementia, alopecia and lumbar herniated disk. He had an episode of stroke and migraine-like headache lasting for 5 minutes. A lot of members had cerebral infarction in this family. Brain magnetic resonance imaging demonstrated, on T2-weighted images, numerous hyperintense lesions suggestive of small infarcts in the basal ganglia and diffuse hyperintense lesions in the cerebral white matter. The clinical symptoms, the family history and the MRI findings suggested the diagnosis of CADASIL. However, the patient also showed alopecia and lumbar herniated disk, both are characteristic features of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). The DNA analysis of the Notch 3 gene identified a novel missense mutation Cys174Phe in this patient. Our case report indicated the importance of the DNA analysis for the diagnosis of CADASIL.     

Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene

Abstract Here we describe clinical, neuropsychological and neuroradiological findings in 6 subjects belonging to two unrelated Italian cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) kindreds from the same geographic area who shared a common Arg1006Cys mutation. Subjects from Family A were virtually asymptomatic, and yet showed MRI pathological findings and a cluster of sub-clinical neuropsychological defects mainly centred on the visuospatial domain; patients from Family B had presented several clinically relevant episodes and showed a general cognitive impairment compatible with the clinical picture of vascular dementia. The present clinical observations are consistent with the hypothesis of a geographical clustering for CADASIL, and highlight that sub-clinical cognitive impairment may help to identify this syndrome in families presenting with only migraine.     

CADASIL in a patient with bilateral internal carotid artery agenesis

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a well-recognised cause of stroke in the young. Bilateral internal carotid artery (ICA) agenesis is a rare congenital malformation, with few previous reported cases in the literature. CADASIL is not reported to be associated with ICA agenesis. We report the case of a 41 year old man who presented with recurrent orthostatic symptoms associated with increasingly frequent falls. Initial investigation with CT angiography revealed absent bilateral ICAs with an ectatic vertebrobasilar arterial tree supplying the intracranial circulation. Skull base CT revealed simultaneous absence of ICAs and bilateral carotid canals, confirming agenesis of bilateral ICAs. MRI of the brain revealed extensive areas of confluent high T2 signal intensity in the subcortical and periventricular zones of both hemispheres. The patient subsequently developed episodic and progressive headache, dysarthria, ataxia, cognitive impairment and personality changes. Radiological progression of cerebral subcortical and periventricular abnormalities was demonstrated with established lacunar infarcts and generalised atrophic changes. Genetic testing confirmed the diagnosis of CADASIL with the presence of a heterozygous c.994C > T (p.Arg332Cys) mutation in exon 6 of the NOTCH 3 gene.We report the first case of coexistent bilateral ICA agenesis and CADASIL. This case highlights the need to consider CADASIL in patients with cerebral subcortical and periventricular imaging abnormalities, even with coexistent large vessel pathology.     

Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI

The aim of our work was to evaluate the early presence of white matter changes on magnetic resonance imaging (MRI) in young asymptomatic children of patients with full-blown cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in whom DNA analysis revealed a Notch3 Cys146Tyr missense mutation on chromosome 19. Brain MRI was performed in all subjects using axial and coronal spin-echo proton density and T2-weighted images, axial fluid-attenuated inversion recovery (FLAIR) and sagittal and axial T1-weighted images. In asymptomatic subjects with Notch3 gene mutation, MRI showed small T2 hyperintense foci in periventricular and subcortical white matter. Routine use of MRI in the initial phases of a CADASIL diagnostic work up and the subsequent recognition of early abnormal findings in asymptomatic subjects may lead to prompt diagnosis of the disease in these patients. Moreover, these findings suggest that genetic screening is warranted in the presence of a suspect clinical history with specific MRI abnormalities.     

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Associated With a Novel In-Frame Mutation in the NOTCH3 Gene in a Japanese Patient

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.     

Aspirin-associated intracerebral hemorrhage in a patient with CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease characterized by ischemic stroke, cognitive impairment, migraine and neuropsychological deficit. Although intracerebral hemorrhage (ICH) has been described in patients with CADASIL, the cause of such ICH is still unknown. We present a 39-year-old man with CADASIL who had two years history of untreated hypertension. In this patient, acute ICH developed only two weeks after the initiation of aspirin. Brain images demonstrated a 3cmx3cm hyperacute ICH in the left temporal lobe at the site of previous old hemorrhage. The presence of cerebral microbleed and use of antithrombotics may be associated with development of ICH in patients with CADASIL.     

A novel Notch3 Gly89Cys mutation in a Serbian CADASIL family

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. We present a family from Serbia presenting with stroke and depression in the lack of vascular risk factors, with brain MRI indicating CADASIL. A novel NOTCH3 Gly89Cys mutation was located in exon 3. This report illustrates that in the setting of a positive family history with typical clinical and MRI features, even with an atypical form of pedigree, a high suspicion of CADASIL should lead to genetic testing.     

CADASIL患者脑微出血分布特征及临床意义

目的 探讨伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy，CADASIL）患者脑微出血（cerebral microbleeds，CMBs）的分布特征及临床意义。 方法 回顾性纳入2017年6月-2019年12月北京协和医院基因确诊的连续CADASIL患者21例（CADASIL 组），以及性别匹配的高血压动脉硬化性脑小血管病患者21例（高血压脑小血管病组）。所有患者均 行头MRI 检查（含T2 */SWI序列），盲法读片并记录CMBs的数量和部位，分析两组CMBs分布的差异。 结果 CADASIL组年龄和常见血管病危险因素比例均低于高血压脑小血管病组。CADASIL组47.6% 患者检出CMBs（共计115个），而高血压脑小血管病组高达95.2%（共计218个）。CADASIL组CMBs分 布以丘脑最常受累（45.2%），其次是脑叶（皮层/皮层下，35.7%）、基底节（11.3%）。高血压脑小 血管病组则以丘脑以外的基底节CMBs最多见（35.3%），其次是脑叶（26.6%）、丘脑（19.2%）、脑干 （16.1%）。CADASIL患者丘脑CMBs/总CMBs比例、丘脑CMBs/（基底节CMBs+脑干CMBs）比例均高于高 血压脑小血管病组（均P＜0.001）。 结论 CADASIL患者CMBs分布以丘脑最常见，其次是皮层/皮层下区域，而高血压脑小血管病患者 则以丘脑以外的基底节、脑干更常见。     

1例CADASIL家系的临床特征与基因突变分析

目的 分析1例皖江地区CADASIL家系的临床表现及基因突变特征.方法 随访记录1例CADASIL家系先证者的临床表现、实验室检查及影像学检查,对其NOTCH3基因突变热点区行基因检测.结果 先证者为1例53岁男性患者,病程中反复发作脑卒中并有家族发病史,另表现假性球麻痹、情绪障碍、冷漠和轻度认知功能障碍,无偏头痛史.其头颅核磁共振显示对称性双侧颞极及外囊区白质高信号病变.患者NOTCH3基因突变分析发现4号外显子区已知致病突变（c.580T〉C）和常见核苷酸多态性（rs1043994）.结论 c.580T〉C突变是中国人CADASIL病例首次报道,基因检测是确诊CADASIL的金标准.     

Correlation of cognitive status, MRI- and SPECT-imaging in CADASIL patients

Although there is evidence for correlations between disability and magnetic resonance imaging (MRI) total lesion volume in autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the significance of structural MRI abnormalities for cognitive dysfunction remains controversial. We performed detailed neuropsychological testing, high resolution MRI, and Tc-99m-ethyl cysteinate-dimer SPECT in three CADASIL patients. MR-images were rated independently by two investigators for the presence of white matter lesions, lacunar infarcts, microbleeds, and ventricular enlargement. Cortical atrophy was quantified by the use of automatic morphometric assessment of the cortical thickness. In addition, laboratory and patients' history data were collected in order to assess the individual vascular risk factor profile. The differences in cognitive performance between the three patients are neither explained by structural-, or functional neuroimaging, nor by the patient-specific vascular risk factor profiles. The neuroradiologically least affected patient met criteria for dementia, whereas the most severely affected patient was in the best clinical and cognitive state. Conventional structural and functional neuroimaging is important for the diagnosis of CADASIL, but it is no sufficient surrogate marker for the associated cognitive decline. Detailed neuropsychological assessment seems to be more useful, particularly with respect to the implementation of reliable outcome parameters in possible therapeutic trials.