الملخص
Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke. Despite being the most prevalent vascular hereditary disease, clinical data regarding the Brazilian population are scarce. Considering that the Brazilian population has one of the most heterogeneous genetic constitutions in the world, knowledge about genetic and epidemiological profiles is mandatory. The present study aimed to elucidate the epidemiological and clinical features of CADASIL in Brazil. Methods We performed a case series study comprising 6 rehabilitation hospitals in Brazil and reported the clinical and epidemiological data from the medical records of patients admitted from 2002 to 2019 with genetic confirmation. Results We enrolled 26 (16 female) patients in whom mutations in exons 4 and 19 were the most common. The mean age at the onset of the disease was of 45 years. Ischemic stroke was the first cardinal symptom in 19 patients. Cognitive impairment, dementia, and psychiatric manifestations were detected in 17, 6, and 16 patients respectively. In total, 8 patients had recurrent migraines, with aura in 6 (75%) of them. White matter hyperintensities in the temporal lobe and the external capsule were found in 20 (91%) and 15 patients (68%) respectively. The median Fazekas score was of 2. Lacunar infarcts, microbleeds, and larger hemorrhages were observed in 18 (82%), 9, and 2 patients respectively. Conclusion The present is the most extensive series of Brazilian CADASIL patients published to date, and we have reported the first case of microbleeds in the spinal cord of a CADASIL patient. Most of our clinical and epidemiological data are in accordance with European cohorts, except for microbleeds and hemorrhagic strokes, for which rates fall in between those of European and Asian cohorts.
Resumo Antecedentes Arteriopatia cerebral autossômica dominante com enfartes subcorticais e leucoencefalopatia (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, CADASIL, em inglês) é uma causa genética de acidente vascular cerebral (AVC) isquêmico e a forma mais comum de acidente vascular cerebral não aterosclerótico. Apesar de ser a doença vascular hereditária mais prevalente que há, os dados clínicos para a população brasileira são escassos. Considerando que o Brasil tem uma das constituições genéticas mais heterogêneas do mundo, o conhecimento sobre perfis genéticos e epidemiológicos é obrigatório. Este estudo teve como objetivo elucidar as características clínicas e epidemiológicas de pacientes com CADASIL no Brasil. Métodos Apresentamos uma série de casos envolvendo 6 hospitais de reabilitação no Brasil, e relatamos dados clínicos e epidemiológicos de prontuários de pacientes admitidos entre 2002 e 2019 com confirmação genética. Resultados incluímos 26 pacientes (16 mulheres) em que as mutações nos éxons 4 e 19 eram as mais comuns. A idade média de início da doença foi de 45 anos. O AVC isquêmico foi o primeiro sintoma cardinal em 19 pacientes. Comprometimento cognitivo, demência e manifestações psiquiátricas foram detectados em 17, seis e 16 pacientes, respectivamente. Ao todo, 8 pacientes apresentavam enxaqueca, sendo com aura em 6 (75%) pacientes. Hiperintensidades de substância branca no polo temporal e na cápsula externa foram encontradas em 20 (91%) e 15 pacientes (68%), respectivamente. A pontuação mediana na escala de Fazekas foi de 2. Infartos lacunares, microssangramentos e macro-hemorragias foram observadas em 18 (82%), 9 (41%) e 2 (9%) pacientes, respectivamente. Conclusão O presente estudo representa a mais extensa série de pacientes brasileiros com CADASIL publicada até o momento, e relatamos o primeiro caso de micro-hemorragia na medula espinhal de um paciente com CADASIL. A maior parte dos nossos dados clínicos e epidemiológicos está de acordo com as coortes europeias, exceto para micro-hemorragias e macro-hemorragias, para as quais as taxas se enquadram entre as das coortes europeias e asiáticas.
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Introducción: El virus SARS-Cov-2 se ha asociado a múltiples manifestaciones neurológicas, incluyendo accidente cerebrovascular agudo. La manifestación cerebrovascular reportada con mayor secuencia es accidente cerebrovascular secundario a trombosis de grandes vasos. La arteriopatía cerebral autosómica dominante con infartos subcorticales y leucoencefalopatía (CADASIL, por las siglas en inglés), es la enfermedad genética más frecuente asociada a lesiones de sustancia blanca e infartos lacunares múltiples. Se desconoce como el SARS-Cov-2 podría afectar en los pacientes con CADASIL. El objetivo de este trabajo es reportar la manifestación neurológica del COVID-19 en un paciente con CADASIL. Métodos: Se buscó información clínica y de laboratorio en los registros clínicos. Información adicional se obtuvo del informe de la evaluación de neuropsicología y de la entrevista con el paciente. Resultados: Paciente en la sexta década de la vida consulta a servicio de urgencias por confusión, desorientación, dificultad para expresarse y debilidad en su mano y pierna a derecha. La resonancia magnética cerebral demostró lesiones subcorticales múltiples agudas en áreas limítrofe y lesiones de sustancia blanca crónicas en capsula externa y polos de los lóbulos temporales, ambas típicas del CADASIL. El examen genético arrojó mutación sin sentido en el gen NOTCH3. El paciente fue seguido durante 10 meses, aunque presentó mejoría de su condición neurológica, persistió el déficit cognitivo con repercusión en sus actividades instrumentales de la vida diaria. Conclusión: Los pacientes con CADASIL que se infectan con SARS-Cov-2 pueden manifestarse con accidentes cerebrovasculares de zona limítrofe y encefalopatía. El COVID19 podría acelerar la declinación cognitiva descripta en los pacientes con CADASIL.
Introduction: The SARS-Cov-2 is associated with many neurological manifestations, including acute cerebrovascular disease. The most common reported stroke manifestation is ischemic stroke secondary to large vessels occlusion. The cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent genetic disease associated with white matter disease and multiple lacunar strokes. How the SARS-Cov-2 could affect CADASIL patients is unknown. Our aim is to report the neurologic presentation of COVID19 in a CADASIL patient. Method: With searched laboratory data and patient history in clinical registers. Additional information was obtained from the neuropsychologic report and patient's family interview. Results: A patient on his fifties consulted to the emergency department for disorientation, difficulty with language and weakness of his right arm and leg. The magnetic resonance showed multiple acute subcortical border zone lesions and other chronic white matter lesions affecting the pole of the temporal lobes and external capsule, both typical of CADASIL. The genetic examination confirmed a missense mutation on the NOTCH3 gene. The patient was followed up for 10 months and although there was an improvement in his neurologic condition, he remained with cognitive deficits that impacted in his instrumental activities of daily living. Conclusion: CADASIL patients infected with SARS-Cov-2 can suffer of multiple border zone infarcts and encephalopathy. The COVID19 could accelerated the cognitive decline of CADASIL patients.
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a common hereditary cerebral small vessel disease, and white matter lesion is its classic pathological feature. MRI showed T 2 white matter hyperintensity, its pathogenesis is complex, and the effective preventive measures are still lacking. This article reviews the possible mechanism of white matter lesion in patients with CADASIL, and provides new ideas for clinical alleviation of white matter lesion and improvement of prognosis.
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Cerebral small vessel disease (CSVD) is a series of clinical, imaging, and pathological syndromes resulting from various etiologies affecting small arteries (microarteries, capillaries, microvenules, and small veins in the brain). The diagnosis of CSVD is based on imaging presentations, but the high cost and bleeding risk of cranial imaging methods make the diagnosis of rare CSVD more difficult. Retinal vessels are the only vasculature visible in vivo and share anatomical and embryological features with small brain vessels. Retinal vascular abnormalities have been shown to exist in rare CSVD such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral amyloid angiopathy (CAA) and moyamoya disease (MMD). Retinal vascular examination may provide new ideas for the study of rare CSVD.
الملخص
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary small vessel disease originated from adult onset, which is caused by the mutation of NOTCH3 gene located in the region of chromosome 19p13. Its clinical features include recurrent ischemic stroke, progressive cognitive impairment, migraine and mental disorders. Recent studies have shown that the mutations in the EGFr region of NOTCH3 gene are associated with the course, clinical manifestations and imaging features of CADASIL. This article reviews the research progress of the NOTCH3 gene EGFr region mutation genotype, clinical phenotype of CADASIL and their correlation, hoping to provide ideas for the early diagnosis and pathogenesis of CADASIL.
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Objective:To report the clinical features, imaging findings and gene mutation features of a Chinese family with cerebral autosomal dominant arteriopathy with subcritical infarcts and leukoencephalopathy (CADASIL).Methods:We summarized the clinical and imaging features of a CADASIL family confirmed by gene sequencing. NOTCH3 gene sequencing was conducted for the proband, and the structure of the protein encoded by the mutant gene was predicted. Results:The patients in this family mainly presented with recurrent lacunar infarction and hypertension, without headache and emotional disorders such as anxiety or depression. Head MRI of the proband showed multiple lacunar infarctions and extensive white matter degeneration. Susceptibility-weighted imaging showed multiple small intracranial hemorrhages. The analysis of NOTCH3 gene showed that the proband had c.697T>A mutation. The 3D structure prediction of the protein encoded by this mutation locus showed that this locus could lead to the conversion of cysteine to serine at the 233rd position. Conclusions:The patients of this CADASIL family have a c.697T>A mutation of NOTCH3 gene. This mutation may cause the change of amino acid in the structure of the wild type Notch3 protein, which may lead to increased formation of β-folding structures in the surrounding region, thus changing the structure and function of protein and causing disease.
الملخص
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3 gene mutation. The main manifestations of the disease are migraine,cerebral ischemic stroke, progressive cognitive impairment, psychological abnormality which developed at different stage of disease. Multiple cerebral lacunar infarctions, white matter T 2 hyperintensities and cerebral microbleeds can be seen on brain magnetic resonance imaging. The definite diagnosis evidence of CADASIL is the presence of granularosmiophilic material on the surface of arteriolar smooth muscle cells and (or) the identification of pathogenic variants of NOTCH3 gene. With the wide application of second-generation sequencing, more and more patients with CADASIL have been diagnosed. This article will give a summary on the pathogenesis mechanism, clinical manifestations, diagnostic workup, and management of CADASIL.
الملخص
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common single gene hereditary cerebral small vessel disease in adults. With the development of gene sequencing technology and imaging, the disease is more and more recognized by people. In this paper, according to the research progress in recent years, the mutation types of NOTCH3 gene in CADASIL patients, the hot spot regions and sites of mutation in different populations, and the relationship between genotype and phenotype were summarized from the perspective of genetics. The future gene therapy of the disease was prospected.
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Abstract Various neuropathologies produce hyperintense signals on T2-weighted or fluid-attenuated inversion recovery sequences of the temporal lobes. Recognition of the distribution pattern and associated findings may narrow the spectrum of differential diagnoses or suggest a specific disease. This pictorial essay aims to illustrate the relatively common diseases that affect the temporal lobe, such as herpes simplex encephalitis, neurosyphilis, limbic encephalitis, postictal edema, neoplasia, and multiple sclerosis, as well as those that are less common, such as myotonic dystrophy type 1, CADASIL, and CARASIL, together with the particularities of each entity.
Resumo Diversas neuropatologias apresentam hipersinal em T2 ou FLAIR nos lobos temporais, porém, o reconhecimento do padrão de distribuição e achados associados podem estreitar o espectro de diagnósticos diferenciais ou sugerir uma doença específica. Este ensaio iconográfico visa demonstrar doenças que acometem o lobo temporal e que são relativamente comuns no dia-a-dia dos radiologistas, como encefalite herpética, neurossífilis, encefalite límbica, edema pós-crise convulsiva, glioma e esclerose múltipla, e outras nem tão comuns como distrofia miotônica tipo I, CADASIL e CARASIL, atentando para as particularidades de cada entidade que auxiliam no diagnóstico.
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ABSTRACT The purpose of this study was to report the main speech-language disorders in a patient with CADASIL diagnosis, attending the Speech Therapy School Clinic of a Higher Education Institution from 2008 to 2013. Clinical evaluation of the speech organs was carried out, verifying reduced mobility and tonus of lips, tongue and cheeks, with major repercussions on deglutition in the last two years of care. Multiple swallowing were observed for pasty consistency, and coughing, for the liquid one, with "wet" vocal quality and cervical auscultation without alterations, after multiple swallowing. A hoarse vocal quality with asthenia, weak loudness, hypernasal resonance and imprecise articulation were observed regarding the patient's voice. The speech therapy aimed at maintaining food intake and communication, improving the patient's quality of life.
RESUMO O objetivo deste estudo foi relatar as principais alterações fonoaudiológicas encontradas em um caso de uma paciente com diagnóstico de CADASIL, atendida na clínica-escola de Fonoaudiologia de uma Instituição de Ensino Superior, no período de 2008 a 2013. Foi realizada a avaliação clínica verificando alterações quanto aos órgãos fonoarticulatórios, mobilidade e tônus de lábios, língua e bochechas reduzidos, com maiores repercussões na deglutição nos dois últimos anos de atendimento. Na avaliação evidenciaram-se deglutições múltiplas na consistência pastosa e presença de tosse na consistência líquida, com qualidade vocal "molhada" e ausculta cervical sem alterações, após várias deglutições. Já a voz, apresentou qualidade vocal rouco-soprosa, astenia, loudness fraca, ressonância hipernasal e articulação imprecisa. A conduta fonoaudiológica objetivou manter a alimentação e a comunicação oral, contribuindo para melhor qualidade de vida.
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@#Myotonic dystrophy type 1 is the most common type of muscular dystrophy in adults characterized by progressive myopathy, myotonia, and occasional systemic involvement. This is a case of myotonic dystrophy type 1 with cognitive decline showing brain magnetic resonance image abnormality mimicking cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
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La esclerosis múltiple (EM) es la enfermedad inflamatorio-desmielinizante del Sistema nervioso central más prevalente en adultos. La resonancia magnética (RM) juega un rol cada vez más importante en el estudio de esta patología, en especial en su diagnóstico precoz, por lo que la diferenciación imagenológica de variantes frecuentes e infrecuentes de EM con otras patologías de sustancia blanca que comprometen encéfalo y médula espinal es esencial. Mediante una revisión pictórica se ilustrarán características típicas en RM del compromiso por EM y de variantes menos habituales de lesión desmielinizante, y se ilustrarán hallazgos característicos de lesiones relacionadas a vasculopatías inflamatorias y no inflamatorias, encefalomielitis diseminada aguda (ADEM), neuromielitis óptica (NMO) y enfermedades vasculares de la médula espinal que pueden simular EM, con énfasis en el diagnóstico diferencial radiológico.
Multiple sclerosis (MS) is the most prevalent inflammatory-demyelinating disease of the central nervous system in adult population. Magnetic resonance imaging (MRI) has an increasingly important role, especially in early diagnosis, so the imaging differentiation of frequent and infrequent variants of MS with other white matter diseases of brain and spinal cord is essential. Through a pictorial essay we show typical MR features of MS and more infrequent variants of demyelinating lesions and illustrate characteristic imaging findings of inflammatory and non-inflammatory vasculopathies, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO) and vascular diseases of spinal cord that may simulate MS, with emphasis on imaging differential diagnosis.
الموضوعات
Humans , Multiple Sclerosis/diagnostic imaging , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Neuromyelitis Optica/diagnostic imaging , Diagnosis, Differential , Encephalomyelitis, Acute Disseminated/diagnostic imaging , Susac Syndrome/diagnostic imagingالملخص
Objective To summarize the phenotypic spectrum of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Fujian population,evaluate the efficiency of the scale and try to adjust it.Methods Thirty-eight CADASIL patients and 64 CADASIL-like patients were recruited based on the CADASIL scale and gene tests,who visited the First Affiliated Hospital of Fujian Medical University and Fujian Neurology Research Institute from May 2011 to November 2017.Their clinical and neuroimaging characteristics were analyzed.Results The migraine,migraine with aura,transient ischemic attack / stroke,early onset age,psychiatric disturbances,cognitive decline,leukoencephalopathy,subcortical infarcts showed no statistically significant differences between the two groups.Instead,compared with CADASIL-like patients (10/64,15.6%;47/64,73.4%;10/64,15.6%),CADASIL patients demonstrated higher percentages of temporal pole involvements (13/38,34.2%;x5=4.716,P=0.030),external capsule involvements (36/38,94.7%;P=0.008) and family history in at least two generations (13/38,34.2%;x2=4.716,P=0.030).According to the scale,the scores showed statistically significant difference between CADASIL (14.84 ± 3.03) and CADASIL-like patients (13.34 ± 3.31;t=2.282,P=0.025) with an area under receiver operating characteristic curve of 0.622.Conclusions CADASIL showed no specific symptoms in Fujian population.The neuroimaging features were proposed to be focused on,especially the external capsule involvements.CADASIL scale could improve diagnostic efficiency,but still needs to be adjusted for Fujian population.The weight value of migraine,migraine with aura and cognitive decline was suggested to be decreased.
الملخص
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient's iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.
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Objective@#To explore the relationship between the cognitive impairment and cerebral lesions using 7.0 Tesla magnetic resonance imaging (MRI) in CADASIL patients. @*Methods@#Thirty five CADASIL patients confirmed by serum NOTCH3 gene detection in Peking University First Hospital from June 2015 to November 2018 were enrolled, including 19 males and 16 females, of which the age of onset was (39.28±8.31) years, the age of admission was (44.61±8.42) years, and the course of disease was (5.29±3.65) years. 7.0 Tesla MRI was performed in all the patients. The numbers of lacunar infarcts and microbleeds were counted and the white matter changes were evaluated with age-related white matter rating scale (ARWMrs). Neuropsychological tests were used to evaluate the global cognition, memory, attention, executive function, visuo-spatial function and language function separately. The z score was calculated to evaluate the impairment extent in different scales. The correlation analysis was performed between image changes and neuropsychological tests. Thirty nine normal controls including 20 males and 19 females with age of (42.54±8.92) years were also enrolled, and the same neuropsychological tests were performed in these subjects. @*Results@#The numbers of microbleeds and lacunar infarcts were 13.71±10.29 and 5.89 (8.74). The ARWMrs score was 11.26±5.31. There were 21 patients (60%) presented with cognitive impairment. In comparison with the controls, the patients presented with global cognitive impairment (MMSE score 26.87±3.95 vs 29.08±0.95), including executive (finishing time of Stroops-c: 80.00 (103.75) s vs 67.79 (16.00) s, correct number of Stroops-c: 48.00 (44.26) vs 50.00 (2.00), time of trail making A test: 55.5 (81.5) s vs 39.0 (5.0) s, time of trail making B test: 171.0 (159.5) s vs 103.0 (54.0) s, false number of trail making B test: 0(2) vs 0(0)), memory (number of register memory: 16.13±5.41 vs 21.1±15.21, number of long term recall: 4.78±2.83 vs 7.41±2.24, number of cue recall memory: 4(6) vs 8(4), number of recognition memory: 10.00 (2.25) vs 11.00 (2.00)), attention (number of digital span: 4.42±1.46 vs 7.89±1.65, correct number of symbol digitalis modality test: 38.47±17.29 vs 51.41±13.00), visuo-spatial (Rey-osterrich: 34 (5) vs 36 (2)) and language function (number of semantic fluency: 14.70±5.54 vs 17.46±5.63) (P<0.05). The z score demonstrated impaired executive function, followed by visuo-spatial dysfunction. The number of lacunar infarcts and microbleeds significantly correlated with short term recall memory (r=-0.404, -0.393), long term recall memory (r=-0.375, -0.395), cue memory (r=-0.395, -0.437), Stroops-c time (r=0.412, 0.503), trails making A test time (r=0.400, 0.434)(P<0.05). The number of lacunar infarcts significantly correlated with symbol digitalis modality test (r=-0.475) (P<0.05). The number of microbleeds significantly correlated with digital span test (r=-0.390), Boston naming test (r=-0.382) and semantic fluency (r=-0.449) (P<0.05). ARWMrs score significantly correlated with MMSE score (r=-0.357), rigister memory (r=-0.342), trails making A finishing time (r=0.425), trails making B finishing time (r=0.463) and correct numbers of trails making B (r=0.392) (P<0.05). @*Conclusions@#CADASIL presented with global cognitive impairment, especially executive function and visuo-spatial function. The white matter changes, lacunar infarcts and microbleeds affected different cognitive function.
الملخص
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an inherited small vessel diseases caused by mutations in the Notch3 gene. In Caucasian patients, the average life expectancy was 65 years for men and 71 years for women. However, this does not seem to be the case in patient with R544C mutation, which is a rare mutation in Caucasian patients. Herein we report two patients with R544C mutation who were older than 90 years who were not previously reported.
الموضوعات
Female , Humans , Male , CADASIL , Leukoencephalopathies , Life Expectancyالملخص
Persistent aura without infarction is defined as an aura persisting for 1 week or more without evidence of infarction on neuroimaging. It is difficult to differentiate persistent visual aura without infarction from occipital lobe epilepsy. We report a Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy patient with prosopometamorphopsia and visual field defect improved by valproic acid. We also review ambiguity between visual aura in migraine and occipital lobe epilepsy.
الموضوعات
Humans , CADASIL , Epilepsies, Partial , Epilepsy , Infarction , Migraine Disorders , Neuroimaging , Valproic Acid , Visual Fieldsالملخص
Objective To investigate the frequency and location of cerebral microbleeds in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) to understand the imaging and clinical features of the disease.Methods Cranial magnetic resonance imaging and susceptibility-weighted imaging were assessed in seven symptomatic CADASIL patients in People's Hospital of Zhengzhou University from 2014 to 2017.Imaging features and clinical significance of these patients were analyzed retrospectively.Results The seven patients were diagnosed by Notch3 gene detection.Mutations were found in exon 11 in four cases,and in exon 4 in three cases.All the seven patients with CADASIL had cerebral microbleeds,the number of which was 108 (4-36).The number of cerebral microbleeds was found to be higher in cortico-subcortical region than in any other regions.One of CADASIL patients with cerebral microbleeds had intracerebral hemorrhage located in external capsule.The patient with intracerebral hemorrhage had hypertension and multiple cerebral microbleeds.Conclusions Cerebral microbleeds are common imaging characteristics in symptomatic CADASIL,most of which locate in cortico-subcortical region.Cerebral hemorrhage is one of the clinical manifestations of CADASIL patients.
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The aim of this study was to find related pathogenic genes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in (CADASIL)-like patients. The direct sequencing and high-throughput multiplex polymerase chain reaction (PCR) was performed to screen for related genes. The clinical and imaging data of a CADASIL-like patient (the pro-band) and his family members were collected. At first, the known hereditary cerebral vascular genes of the pro-band were screened with direct sequencing to find candidate gene mutations. High-throughput multiplex PCR was then used to analyze the single nucleotide polymorphism of the candidate gene in the family members. The results showed that there was missense mutation of the high temperature requirement protease A1 (HTRA1) gene in the pro-band, which may be a pathogenic factor according to the biological software analysis. The following SNP results revealed that the other family members also had the HTRA1 gene mutation. Thus, the CADASIL-like family disease may be caused by heterozygous HTRA1 gene mutation, which leads to autosomal dominant hereditary cerebral small vessel disease.
الموضوعات
Humans , Male , Female , Adult , Mutation, Missense/genetics , CADASIL/genetics , High-Temperature Requirement A Serine Peptidase 1/genetics , Pedigree , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Multiplex Polymerase Chain Reaction , Genotype , Heterozygoteالملخص
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy(CADASIL)is a common hereditary disease caused by NOTCH3 gene. The major clinical manifestations includerecurrent small-vessel ischaemic events, migraine, dementia and mood disturbance. Herein, wereport a 32-years-old male presented with right leg weakness and persistent migraine. We carried outneurological exams, genetic testing, blood and cerebrospinal fluid analysis (CSF) as well as magneticresonance imaging (MRI) for the brain and spinal cord. There were no anti-aquaporin-4 antibodiesand oligoclonal bands in the CSF and blood investigations were within the normal range. MRI scansrevealed multiple hyperintense regions in the brain and longitudinally hyperintense signal in spinal cord.Further, we identified a c.383G>A(p.Cys128Tyr) mutation in NOTCH3 gene. Therefore, the patientwas diagnosed with CADASIL concurrent with spinal cord lesion. The patient’s condition slightlyimproved after two weeks treatment with daily dosage of 0.5 g citicoline and 75 mg clopidogrel.