CADASIL患者的临床、影像学特征及NOTCH3基因突变研究
发布时间：2018-08-14 12:01
【摘要】：研究背景和目的 伴有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)是一种非动脉硬化、非淀粉样变的遗传性动脉疾病,是一种成年发病的单基因遗传性卒中疾病。因CADASIL患者的临床表现和影像学特征复杂多变,确诊仍有赖于皮肤活检或基因检测。目前皮肤小动脉平滑肌细胞外噬锇颗粒的沉积,被认为是CADASIL的特征性病理学改变,然而,电子显微镜(electron microscope,EM)评估皮肤小动脉的噬锇颗粒不够敏感,假阴性率可高达50%；不同的研究也表明该检查的敏感性是千差万别的。故目前NOTCH3基因突变检测仍然是诊断CADASIL的金标准。 现全世界已报道该病的500多个家系,已发现190多种不同NOTCH3基因突变,包括错义点突变,剪切突变和缺失突变,其中95%为点突变,几乎90%的突变位于2-6号外显子,尤以4号、3号外显子多见。为此,对于临床疑似患者,行上述局限性外显子检查,可以对疾病作出快速诊断。但是,最近研究发现,不同地域CADASIL患者的基因突变好发位点和基因检出率存在不同,这可能是种族差异所致,也可能存在其它因素,因即使在同一种族人群,位于不同地域的患者的基因突变好发位点也存在不同。故在制定基因检查策略时需要考虑患者的种族、地域差异性,通过基因检测进一步完善疾病的诊断。迄今为止,国内报道的外显子突变无明显聚集性,已发现的突变位于2号、3号、4号、6号、10号、11号、18号和20号外显子,也尚无较大样本OTCCH3基因突变检出率的研究。 另外由于OTCH3基因存在33个外显子,目前检测到的突变位点广泛分布在2-23号外显子内,基因突变检测价格昂贵,耗费时间长,不能作为诊断疾病的常规方法。如何能够根据临床特征,影像学特征分析,发现有效的特征用于筛选合适的基因检测患者,也是目前临床研究的热点之一。 本课题对一组临床疑诊为CADASIL的患者进行NOTCH3基因2-23号外显子突变研究,在此基础上对其临床特征和影像学特征进行比较分析,旨在(1)了解该组患者的NOTCH3基因突变情况,明确诊断并了解我国国内CADASIL患者基因突变的热点分布情况和基因突变检出率情况,为制定合适的基因诊断流程提供依据；(2)根据基因检测结果,对突变组和无突变组的临床特点,影像学特征进行比较分析,并对突变组内患者的临床特点和影像学特征进行分析,以期发现可用于判断适合基因筛查的有效特征。 研究包括以下两个部分： 第一部分WTCH3基因突变的研究 目的 明确该组患者的NOTCH3基因突变情况,明确诊断并了解我国国内CADASIL患者基因突变的热点分布情况和基因突变检出率情况,为制定合适的基因诊断流程提供依据。 方法 对来自我国华东地区的35个无关家庭的35例临床疑诊为CADASIL的患者行NOTCH3基因2-23号外显子基因突变分析；同时对先证者存在NOTCH3基因突变的8个家系的17例家系内成员进行相应突变外显子检测；通过设立家系外100例正常健康对照来验证所有检测到致病突变；根据检测结果,计算NOTCH3基因突变检出率,并结合文献分析我国国内OTCH3基因的突变热点分布区。结果 我们在13个家系中检测到了9种不同的错义点突变(p.C43Y,p.R90C, p.R110C, p.R133C, p.R141C, p.C144S, p.R153C, p.C155W, p.R182C),其中p.C43Y突变和p.C155W突变在国际上首次被发现；该组患者中NOTCH3基因的突变检出率为37.1%(13/35),所有检测到的致病突变均位于2号、3号和4号外显子中。另外在1个家系的22号外显子中检测到一目前意义不明的多态改变(p.R1175W),在3号和4号外显子分别检测到一个不涉及氨基酸改变的多态c.C303T和c.A606G. 结论 1)p.C43Y突变和p.C155W突变是两种新的错义点突变,目前国内外尚未报道。 2) NOTCH3基因4号外显子和3号外显子是我国大陆华东地区CADASIL患者的突变热点分布区。 3)该组临床疑诊CADASIL患者的NOTCH3基因突变检出率仅为37.1%,提示可能存在其他致病基因。 4) NOTCH3基因22号外显子p.R1175W改变可能与CADAS几发病有关。 第二部分CADASIL的临床和影像学特征研究 目的 在基因检测基础上,对NOTCH3基因突变组和无突变组的临床特点,影像学特征进行分析,以期发现可用于判断适合基因筛查的有效特征。 方法 对能获得详细的临床资料并完成头颅磁共振扫描的25例NOTCH3基因突变患者和22例NOTCH3基因无突变患者的临床特点和影像学特征进行比较分析,并对突变组患者的临床特点,影像学特征以及认知功能与影像学特征之间的关系进行分析。应用SPSS14.0统计学软件进行分析,计量资料以±s表示,并行独立样本t检验或Mann-Whitney U分析,计数资料行Fisher精确检验,统计学显著性水平定为双侧检验,P0.05为差异有统计学意义。 结果 1.临床特点方面：两组在发病年龄(38.36±7.98vs49.05±8.41,p0.001),入组年龄(45.52±9.61vs51.91±8.71,P=0.022),阳性家族史(78.6%vs33.3%,p=0.015),高血压病患病率(8.0%vs40.9%,p=0.014)和既往降压药物使用(8.0%vs40.9%,p=0.014)的差异有统计学意义,而其他脑血管病危险因素,以及既往降压,抗栓药物使用方面的差异无统计学意义； 2.影像学方面：基因突变组脑白质高信号体积(70.81±44.90vs42.24±22.24,p=0.025)与无突变组相比差异有统计学意义,且累及颞极(72.0%vs27.3%,p=0.003),外囊(84.0%vs27.3%,p0.001)明显较基因无突变组高,两组之间有统计学差异,但两组在脑干白质高信号,脑内腔隙灶的检出率,分布部位(皮质下,皮层,脑干)两组之间的差异无统计学意义,而在脑内腔隙灶数目上(5.33±3.96vs2.00±2.45,p=0.007),突变组明显较无突变组增多,差异有统计学意义。脑内微出血灶发生率,脑内微出血灶数目和MRA上颅内大动脉狭窄均无统计学差异。突变组患者的MMSE评分与脑白质高信号体积、脑内腔梗灶数目呈负相关,而与脑内微出血程度无明显相关。3.对存在MRA颅内大动脉狭窄的NOTCH3基因突变患者进一步分析发现,有颅内大动脉病变的CADASIL患者高胆固醇血症的患病率(62.5%vs17.6%,p＝0.061)和高血压患病率(40.0%vs0.0%,p＝0.065)较无颅内大动脉病变的CADASIL有增高的趋势,但因受病例数少的影响,没有明显的统计学差异。两者在临床特征、脑血管病危险因素及影像学特征方面的差异均无统计学差异。结论 1、影像学上出现严重脑白质病变累及颞极和基底节外囊区,阳性家族史可以作为临床诊断CADASIL的有利指标,发病年龄小于45岁有利于CADASIL诊断,而临床表现(头痛,卒中,精神障碍和认知功能障碍)和影像学上出现皮质下腔梗灶、皮层梗死灶和脑内微出血不能用于区分NOTCH3基因突变患者与无突变患者。 2、存在脑血管病危险因素和颅内大动脉狭窄不能作为CADAS几的排除标准。 3、CADASIL患者认知功能可能与脑白质高信号体积、脑内腔隙灶数目呈负相关,但与脑内微出血的严重程度无明显相关。
[Abstract]:Research background and purpose
Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-atherosclerotic, non-amyloid, inherited arterial disease, and a monogenic, inherited stroke disease in adults. The clinical manifestations and imaging features of CADASIL are complex and changeable, and the diagnosis still depends on skin biopsy or gene detection. At present, the deposition of osmium-phagocytic granules in the smooth muscle cells of cutaneous arterioles is considered to be a characteristic pathological change of CADASIL. However, electron microscopy (EM) is used to evaluate osmium-phagocytic granules in cutaneous arterioles. Insufficient sensitivity, false negative rate can be as high as 50%; different studies also show that the sensitivity of the test is very different. Therefore, NOTCH3 gene mutation detection is still the gold standard for the diagnosis of CADASIL.
More than 190 NOTCH3 gene mutations, including missense point mutation, shear mutation and deletion mutation, have been found in more than 500 families worldwide. Of these mutations, 95% are point mutations, and almost 90% are located in exons 2-6, especially exons 4 and 3. For this reason, the above-mentioned limited exons were examined in clinically suspected patients. Rapid diagnosis can be made. However, recent studies have found that CADASIL patients in different regions have different gene mutation prone sites and gene detection rates, which may be due to racial differences, but there may also be other factors, because even in the same ethnic group, patients in different regions of the gene mutation prone sites are not there. So far, there is no obvious aggregation of exon mutations reported in China, and the mutations are located in exons 2, 3, 4, 6, 10, 11, 18 and 20, and there is no large sample OTCCH3. Detection rate of gene mutation.
Because there are 33 exons in OTCH3 gene, the mutation sites detected are widely distributed in exon 2-23. The detection of gene mutation is expensive and time-consuming, so it can not be used as a routine method to diagnose diseases. Detection of patients is also one of the hot topics in clinical research.
The purpose of this study was to investigate the mutation of NOTCH3 gene exon 2-23 in a group of patients suspected of CADASIL, and to compare the clinical and imaging features of NOTCH3 gene mutation in order to (1) understand the mutation of NOTCCH3 gene in this group, diagnose and understand the hot spot distribution of gene mutation in CADASIL patients in China. (2) According to the results of gene detection, the clinical characteristics and imaging characteristics of mutation group and non-mutation group were compared and analyzed, and the clinical characteristics and imaging characteristics of patients in mutation group were analyzed, so as to find out the suitable gene for gene diagnosis. The effective characteristics of screening.
The research includes the following two parts:
Part one research on the mutation of WTCH3 gene
objective
To determine the mutation of NOTCH3 gene in this group, to diagnose and understand the hotspot distribution of gene mutation and the detection rate of gene mutation in CADASIL patients in China, and to provide the basis for the establishment of appropriate genetic diagnosis process.
Method
The exon 2-23 mutation of NOTCH3 gene was analyzed in 35 suspected CADASIL patients from 35 unrelated families in eastern China, and the corresponding mutation exons were detected in 17 members of 8 families with NOTCH3 gene mutation in the proband, and 100 normal controls were set up outside the family. To verify all detected pathogenic mutations, NOTCH3 gene mutation detection rate was calculated according to the results of detection, and the mutation hotspot distribution of OTCH3 gene in China was analyzed combined with the literature.
Nine different missense point mutations (p.C43Y, p.R90C, p.R110C, p.R133C, p.R141C, p.C144S, p.R153C, p.C155W, p.R182C) were detected in 13 families, of which p.C43Y mutation and p.C155W mutation were first found in the world; the mutation rate of NOTCH3 gene in this group was 37.1% (13/35) and all the detected pathogenic mutations were found. In addition, an unidentified polymorphism (p.R1175W) was detected in exon 22 of one family, and a polymorphism c.C303T and c.A606G were detected in exons 3 and 4, respectively.
conclusion
1) p.C43Y mutation and p.C155W mutation are two new missense point mutations, which have not been reported at home and abroad.
2) Exon 4 and exon 3 of NOTCH3 gene are mutation hotspots of CADASIL patients in eastern China.
3) The detection rate of NOTCH3 gene mutation in suspected CADASIL patients was only 37.1%, suggesting the existence of other pathogenic genes.
4) the change of p.R1175W in exon 22 of NOTCH3 gene may be related to the pathogenesis of CADAS.
The second part is the clinical and imaging features of CADASIL.
objective
On the basis of gene detection, the clinical features and imaging features of NOTCH3 gene mutation group and non-mutation group were analyzed in order to find out the effective features for gene screening.
Method
The clinical and imaging characteristics of 25 patients with NOTCH3 gene mutation and 22 patients without NOTCH3 gene mutation were compared and analyzed. The clinical and imaging characteristics of the patients with NOTCH3 gene mutation and the relationship between cognitive function and imaging characteristics were analyzed. SPSS14.0 statistical software was used to analyze the data. The measurement data were expressed as (+) s, and the independent sample t test or Mann-Whitney U analysis were performed. The counting data were analyzed by Fisher exact test. The statistical significance level was determined as bilateral test, and the difference was statistically significant (P 0.05).
Result
1. Clinical characteristics: The age of onset (38.36+7.98 vs 49.05+8.41, P 0.001), the age of admission (45.52+9.61 vs 51.91+8.71, P = 0.022), the positive family history (78.6% vs 33.3%, P = 0.015), the incidence of hypertension (8.0% vs 40.9%, P = 0.014) and the use of antihypertensive drugs (8.0% vs 40.9%, P = 0.014) had statistical significance, while the other cerebrovascular diseases (78.6% vs 33.3%, P = 0.015) had statistical significance. There was no significant difference in risk factors and past hypotension and anticoagulant use.
2. Imaging: The high signal volume (HSV) of white matter in the mutant group was significantly higher than that in the non-mutant group (70.81 44.90 vs 42.24 6550 No significant difference was found between the two groups in the detection rate of intracerebral lacunar foci and the location of their distribution (subcortical, cortical and brainstem). However, in the number of intracerebral lacunar foci (5.33 [3.96] vs 2.00 [2.45, P = 0.007], the number of intracerebral microbleeding foci, the number of intracerebral microbleeding foci and the upper cranium of MRA in the mutant group was significantly higher than that in the non-mutant group. There was no significant difference between the two groups. The MMSE score was negatively correlated with white matter hyperintense signal volume and the number of intracerebral infarcts, but not with the degree of intracerebral microhemorrhage. 3. Further analysis of the patients with NOTCH3 gene mutation with MRA intracranial large artery stenosis showed that the patients with intracranial large artery disease had CAD ASIL. The prevalence of hypercholesterolemia (62.5% vs 17.6%, P = 0.061) and hypertension (40.0% vs 0.0%, P = 0.065) were higher than that of CAD ASIL without intracranial arterial lesions, but there was no significant statistical difference because of the fewer cases. There was no statistical difference.
1. Severe leukoencephalopathy involving the temporal and basal ganglia extracapsular areas on imaging. Positive family history can be used as a useful indicator for clinical diagnosis of CADASIL. Less than 45 years of age is helpful for the diagnosis of CADASIL. Clinical manifestations (headache, stroke, mental disorders and cognitive impairment) and imaging findings include subcortical infarction, cortical infarction. Foci and intracerebral microbleeds can not be used to distinguish between NOTCH3 mutation patients and non mutation patients.
2, risk factors for cerebrovascular disease and intracranial artery stenosis can not be used as exclusion criteria for CADAS.
3. Cognitive function of CADASIL patients may be negatively correlated with high signal volume of white matter and the number of intracerebral lacunar lesions, but not with the severity of intracerebral microhemorrhage.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R743.3
本文编号：2182795
[Abstract]:Research background and purpose
Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-atherosclerotic, non-amyloid, inherited arterial disease, and a monogenic, inherited stroke disease in adults. The clinical manifestations and imaging features of CADASIL are complex and changeable, and the diagnosis still depends on skin biopsy or gene detection. At present, the deposition of osmium-phagocytic granules in the smooth muscle cells of cutaneous arterioles is considered to be a characteristic pathological change of CADASIL. However, electron microscopy (EM) is used to evaluate osmium-phagocytic granules in cutaneous arterioles. Insufficient sensitivity, false negative rate can be as high as 50%; different studies also show that the sensitivity of the test is very different. Therefore, NOTCH3 gene mutation detection is still the gold standard for the diagnosis of CADASIL.
More than 190 NOTCH3 gene mutations, including missense point mutation, shear mutation and deletion mutation, have been found in more than 500 families worldwide. Of these mutations, 95% are point mutations, and almost 90% are located in exons 2-6, especially exons 4 and 3. For this reason, the above-mentioned limited exons were examined in clinically suspected patients. Rapid diagnosis can be made. However, recent studies have found that CADASIL patients in different regions have different gene mutation prone sites and gene detection rates, which may be due to racial differences, but there may also be other factors, because even in the same ethnic group, patients in different regions of the gene mutation prone sites are not there. So far, there is no obvious aggregation of exon mutations reported in China, and the mutations are located in exons 2, 3, 4, 6, 10, 11, 18 and 20, and there is no large sample OTCCH3. Detection rate of gene mutation.
Because there are 33 exons in OTCH3 gene, the mutation sites detected are widely distributed in exon 2-23. The detection of gene mutation is expensive and time-consuming, so it can not be used as a routine method to diagnose diseases. Detection of patients is also one of the hot topics in clinical research.
The purpose of this study was to investigate the mutation of NOTCH3 gene exon 2-23 in a group of patients suspected of CADASIL, and to compare the clinical and imaging features of NOTCH3 gene mutation in order to (1) understand the mutation of NOTCCH3 gene in this group, diagnose and understand the hot spot distribution of gene mutation in CADASIL patients in China. (2) According to the results of gene detection, the clinical characteristics and imaging characteristics of mutation group and non-mutation group were compared and analyzed, and the clinical characteristics and imaging characteristics of patients in mutation group were analyzed, so as to find out the suitable gene for gene diagnosis. The effective characteristics of screening.
The research includes the following two parts:
Part one research on the mutation of WTCH3 gene
objective
To determine the mutation of NOTCH3 gene in this group, to diagnose and understand the hotspot distribution of gene mutation and the detection rate of gene mutation in CADASIL patients in China, and to provide the basis for the establishment of appropriate genetic diagnosis process.
Method
The exon 2-23 mutation of NOTCH3 gene was analyzed in 35 suspected CADASIL patients from 35 unrelated families in eastern China, and the corresponding mutation exons were detected in 17 members of 8 families with NOTCH3 gene mutation in the proband, and 100 normal controls were set up outside the family. To verify all detected pathogenic mutations, NOTCH3 gene mutation detection rate was calculated according to the results of detection, and the mutation hotspot distribution of OTCH3 gene in China was analyzed combined with the literature.
Nine different missense point mutations (p.C43Y, p.R90C, p.R110C, p.R133C, p.R141C, p.C144S, p.R153C, p.C155W, p.R182C) were detected in 13 families, of which p.C43Y mutation and p.C155W mutation were first found in the world; the mutation rate of NOTCH3 gene in this group was 37.1% (13/35) and all the detected pathogenic mutations were found. In addition, an unidentified polymorphism (p.R1175W) was detected in exon 22 of one family, and a polymorphism c.C303T and c.A606G were detected in exons 3 and 4, respectively.
conclusion
1) p.C43Y mutation and p.C155W mutation are two new missense point mutations, which have not been reported at home and abroad.
2) Exon 4 and exon 3 of NOTCH3 gene are mutation hotspots of CADASIL patients in eastern China.
3) The detection rate of NOTCH3 gene mutation in suspected CADASIL patients was only 37.1%, suggesting the existence of other pathogenic genes.
4) the change of p.R1175W in exon 22 of NOTCH3 gene may be related to the pathogenesis of CADAS.
The second part is the clinical and imaging features of CADASIL.
objective
On the basis of gene detection, the clinical features and imaging features of NOTCH3 gene mutation group and non-mutation group were analyzed in order to find out the effective features for gene screening.
Method
The clinical and imaging characteristics of 25 patients with NOTCH3 gene mutation and 22 patients without NOTCH3 gene mutation were compared and analyzed. The clinical and imaging characteristics of the patients with NOTCH3 gene mutation and the relationship between cognitive function and imaging characteristics were analyzed. SPSS14.0 statistical software was used to analyze the data. The measurement data were expressed as (+) s, and the independent sample t test or Mann-Whitney U analysis were performed. The counting data were analyzed by Fisher exact test. The statistical significance level was determined as bilateral test, and the difference was statistically significant (P 0.05).
Result
1. Clinical characteristics: The age of onset (38.36+7.98 vs 49.05+8.41, P 0.001), the age of admission (45.52+9.61 vs 51.91+8.71, P = 0.022), the positive family history (78.6% vs 33.3%, P = 0.015), the incidence of hypertension (8.0% vs 40.9%, P = 0.014) and the use of antihypertensive drugs (8.0% vs 40.9%, P = 0.014) had statistical significance, while the other cerebrovascular diseases (78.6% vs 33.3%, P = 0.015) had statistical significance. There was no significant difference in risk factors and past hypotension and anticoagulant use.
2. Imaging: The high signal volume (HSV) of white matter in the mutant group was significantly higher than that in the non-mutant group (70.81 44.90 vs 42.24 6550 No significant difference was found between the two groups in the detection rate of intracerebral lacunar foci and the location of their distribution (subcortical, cortical and brainstem). However, in the number of intracerebral lacunar foci (5.33 [3.96] vs 2.00 [2.45, P = 0.007], the number of intracerebral microbleeding foci, the number of intracerebral microbleeding foci and the upper cranium of MRA in the mutant group was significantly higher than that in the non-mutant group. There was no significant difference between the two groups. The MMSE score was negatively correlated with white matter hyperintense signal volume and the number of intracerebral infarcts, but not with the degree of intracerebral microhemorrhage. 3. Further analysis of the patients with NOTCH3 gene mutation with MRA intracranial large artery stenosis showed that the patients with intracranial large artery disease had CAD ASIL. The prevalence of hypercholesterolemia (62.5% vs 17.6%, P = 0.061) and hypertension (40.0% vs 0.0%, P = 0.065) were higher than that of CAD ASIL without intracranial arterial lesions, but there was no significant statistical difference because of the fewer cases. There was no statistical difference.
1. Severe leukoencephalopathy involving the temporal and basal ganglia extracapsular areas on imaging. Positive family history can be used as a useful indicator for clinical diagnosis of CADASIL. Less than 45 years of age is helpful for the diagnosis of CADASIL. Clinical manifestations (headache, stroke, mental disorders and cognitive impairment) and imaging findings include subcortical infarction, cortical infarction. Foci and intracerebral microbleeds can not be used to distinguish between NOTCH3 mutation patients and non mutation patients.
2, risk factors for cerebrovascular disease and intracranial artery stenosis can not be used as exclusion criteria for CADAS.
3. Cognitive function of CADASIL patients may be negatively correlated with high signal volume of white matter and the number of intracerebral lacunar lesions, but not with the severity of intracerebral microhemorrhage.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R743.3
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