脊髓小脑性共济失调系统评价和三峡库区脊髓小脑性共济失调临床研究
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摘要
脊髓小脑性共济失调(spinocerebellar ataxias, SCAs)是一种常染色体显性遗传性疾病,累及人类神经系统的主要遗传疾病之一,也是遗传性共济失调的主要类型。1992年第一个亚型SCA1被基因定位以来,随着研究的深入,越来越多的基因亚型被发现,已经发现28个基因位点和9个致病基因[1-28]。由于脊髓小脑性共济失调具有极强的遗传异质性和基因多效性,因此该疾病的基因诊断日益引起人们的重视。
本课题开展了脊髓小脑性共济失调三个部分的研究:(1)对脊髓小脑性共济失调流行病学研究的系统评价;(2)研究三峡库区范围脊髓小脑性共济失调患者的临床表现和影像学特点;(3)研究三峡库区脊髓小脑性共济失调患者的基因诊断、症状前患者的基因诊断和产前诊断。
第一部分:脊髓小脑性共济失调的系统评价
目的:
从系统评价角度主要采取定性分析方法详细了解脊髓小脑性共济失调在世界和中国的流行、分布、临床表现特点和治疗研究进展。
对象和方法:
1.中文文献取自“中国期刊全文数据库”、“中国维普数据库”,手工检索未被上述数据库收录的临床医学文献。检索策略为在“题目”中检索:脊髓小脑性共济失调OR脊髓小脑性共济失调OR MJD OR马查多-约瑟夫病。
2.外文文献取自“PUBMED”数据库,手工检索未被上述数据库收录的临床医学文献。检索检索策略为在“内容”中检索:spinocerebellar ataxia OR MJD OR Machado-Jespho disease OR Joseph disease OR Machado disease.
3.根据纳入标准和排除标准筛查后,采集研究文献报道各个国家地区的名称、研究机构名称、发表文献年限、是否开展基因诊断、家系数及基因型、家系患者病例数、性别及基因型、散发患者病例数、性别及基因型、症状前患者例数、发病年龄、性别及基因型及患者的临床表现(主要分析共济失调、构音障碍、震颤、认知功能及其他临床表现)等。
结果:
一、脊髓小脑性共济失调的研究历史
1.全世界总共有39个国家地区203家单位报道过脊髓小脑性共济失调,其中已开始开展SCA基因诊断研究的科研医疗机构有21个国家地区的100家单位。目前全世界已报道的类型有SCA1- SCA30共28个亚型(无SCA9和SCA24)。
2.中国20个省市(包括香港特别行政区和台湾地区)40家单位报道过脊髓小脑性共济失调,其中已开始开展SCA基因诊断研究的科研医疗机构25家单位。中国内地目前已报道的类型有SCA1、SCA2、MJD/SCA3、SCA6、SCA7和SCA12共6种亚型,香港特别行政区报道SCA1、SCA3和SCA6共3个亚型。台湾地区目前报道的类型有SCA1、SCA2、SCA3、SCA6、SCA7、SCA8、SCA17和SCA22共8个亚型。澳门特别行政区无SCAs相关文献。
二、脊髓小脑性共济失调的分布概况
1.世界首次报道是1861年高加索地区,而后在全世界6大洲(北美洲、南美洲、欧洲、亚洲、非洲和大洋洲)39个国家和地区人员居住地均发现了脊髓小脑性共济失调的患者。
2.中国20个省市地区报道了脊髓小脑性共济失调,主要集中在东部和南部地区。
3.世界各大洲、国家和地区脊髓小脑性共济失调亚型分布有所区别。
三、脊髓小脑性共济失调的临床特征
1.脊髓小脑性共济失调患者的性别男女比差异不明显,符合常染色体显性遗传规律。
2.脊髓小脑性共济失调大多数亚型30岁以后发病,但SCA6亚型发病年龄较晚,一般在50岁后发病。
3.脊髓小脑性共济失调患者病程比较:SCA2患者病程较长,病情进展较慢;SCA1和SCA7患者的病程较短,病情进展要快于其他3个亚型。
4.脊髓小脑性共济失调临床表现具有高度的异质性,但每个亚型具有一些自身特点引导临床医师对基因亚型的初步判定。
四、脊髓小脑性共济失调的诊断
1.中国内地总共发现482个SCAs家系,中国台湾共发现251个SCAs家系,中国香港共发现13个SCAs家系。
2.中国内地总共发现1133个SCAs患者,台湾地区总共发现601个SCAs患者,香港地区总共发现16个SCAs患者。
3.中国内地总共发现288个SCAs散发患者,台湾地区发现68名散发患者。
4.中国内地总共发现45个SCAs症状前患者,台湾地区共发现41名SCAs症状前患者患者。中国至今还未发现SCA6亚型的症状前患者。
五、脊髓小脑性共济失调的治疗
目前对遗传性脊髓小脑型共济失调治疗无显著进展,新的药物如Gabapentin、Tandospirone、Lamotrigine、Tetrahydrobiopterin、Varenicline和A型肉毒毒素主要用以改善脊髓小脑性共济失调患者的部分症状。
结论:
1.脊髓小脑性共济失调是一个世界范围的神经系统遗传疾病,遍布全球6大洲39个国家地区。SCA3是世界上发生率最高的脊髓小脑性共济失调亚型。
2.中国内地发现SCA1-3、SCA6-7、SCA12共6个亚型;中国香港发现SCA1、SCA3和SCA6共3个亚型;中国台湾发现SCA1-3、SCA6-8、SCA17、SCA22共8个亚型
3.中国内地目前报道脊髓小脑性共济失调的家系482个、家系患者1133例、散发患者288例、症状前患者45例。
4.中国台湾报道脊髓小脑性共济失调家系251个、家系患者601例、散发患者68例、症状前患者患者41例。
第二部分:三峡库区脊髓小脑性共济失调的临床特点和影像学分析
目的:
观察中国三峡库区范围内脊髓小脑性共济失调患者的临床表现特征和进行影像学分析。
对象和方法:
所有来自三峡库区范围患者就诊于第三军医大学第三附属医院神经内科。33名来自6个脊髓小脑性共济失调家系的家系患者和9名散发患者。对患者进行一般资料、临床表现、头颅MRI检查、ICARS评分分析。10名行头颅MRI检查的正常人作为MRI分析的对照。
结果:
一、三峡库区脊髓小脑性共济失调的临床表现
1.三峡库区脊髓小脑性共济失调家系患者与散发患者的发病年龄、病程无显著性区别。
2.言语不清和视力减退是部分散发脊髓小脑性共济失调患者的首发症状。
3.不区分亚型的脊髓小脑性共济失调家系患者的遗传早现不显著,但SCA3家系患
者遗传早现明显。
4.脊髓小脑性共济失调家系患者眼球震颤和肌张力异常显著高于散发患者。
二、三峡库区脊髓小脑性共济失调影像学分析
1.无论是脊髓小脑性共济失调家系患者或散发患者,小脑均出现不同程度的异常改变。散发患者桥脑、延髓异常改变比较明显。
2.家系患者第四脑室扩大较明显,家系患者和散发患者小脑都出现萎缩,尤其以散发患者更为严重。散发患者除小脑萎缩外,桥脑萎缩也比较明显,而家系患者桥脑的萎缩程度不及散发患者。
三、三峡库区脊髓小脑性共济失调危险因素分析
1.生活环境对三峡库区脊髓小脑性共济失调患病有一定影响,以农村人口居多。
2.三峡库区脊髓小脑性共济失调患者普遍受教育程度不高,以小学及以下为主。
3.三峡库区脊髓小脑性共济失调患者以汉族人口为主。
4.三峡库区范围内脊髓小脑性共济失调家系患者交通不便、婚恋范围狭窄可能是第一代患者发病的原因之一,而随着交通状况的改善、婚恋范围的扩大,脊髓小脑性共济失调家系内发病率逐代降低。
5.脊髓小脑性共济失调家系患者ICARS评分与病程呈正相关关系,而散发患者病程、所有患者的发病年龄与ICARS评分相关性不明显。
结论:
1.三峡库区脊髓小脑性共济失调患者的首发症状以行走不稳为主,部分散发患者表现言语不清和视力减退。
2.三峡库区脊髓小脑性共济失调患者均出现共济失调表现,家系患者的眼球震颤、肌张力异常发生率明显高于散发患者。
3.三峡库区脊髓小脑性共济失调患者均出现不同程度的小脑萎缩,散发患者桥脑萎缩比较明显。
4.三峡库区脊髓小脑性共济失调家系可能由于婚恋范围扩大、交通情况改善,脊髓小脑性共济失调发病率逐代降低。
5.三峡库区脊髓小脑性共济失调家系患者的病程与ICARS总评分呈正相关关系。
第三部分三峡库区脊髓小脑性共济失调的基因诊断及产前诊断
目的:
在以重庆为中心的三峡库区范围内开展脊髓小脑性共济失调的基因诊断及产前诊断,建立三峡库区脊髓小脑性共济失调患者数据库、基因库,为进一步研究三峡库区脊髓小脑性共济失调提供平台。
对象和方法:
收集13名脊髓小脑性共济失调家系患者、9名散发患者和30名家系内成员的全血基因组DNA,收集20名孕妇的羊水脱落细胞基因组DNA,采用PCR扩增的方法,建立SCA1-3,SCA6-7和SCA12的基因诊断和产前诊断的方法。
结果:
1.所采用的PCR扩增方法能够进行脊髓小脑性共济失调1-3,6-7和12的基因诊断。3%琼脂糖凝胶电泳可用于初步判定患者的基因亚型。
2.三峡库区脊髓小脑性共济失调仅发现SCA3一个亚型,包括2个家系、20名家系患者和1名散发患者。
3.三峡库区发现5名脊髓小脑性共济失调3型症状前患者。
4.孕龄16-22周,B超定位下进行羊水穿刺术提取羊水脱落细胞的基因组DNA,采用与全血基因组DNA相同的PCR扩增方法可以用于脊髓小脑性共济失调患者或症状前患者的产前诊断。
结论:
1.脊髓小脑性共济失调的基因诊断可以采用3%琼脂糖凝胶电泳初步判断。
2.三峡库区首次确诊2个脊髓小脑性共济失调3型家系,其中有20名家系患者。
3.三峡库区首次确诊1名脊髓小脑性共济失调3型散发患者。
4.三峡库区首次确诊5名脊髓小脑性共济失调3型症状前患者。
5.建立羊水脱落细胞基因组DNA用于脊髓小脑性共济失调的产前诊断方法。
全文结论:
一、脊髓小脑性共济失调发病遍布全球6大洲39个国家地区。SCA3是世界上最高发生率的脊髓小脑性共济失调亚型。中国内地发现6个亚型;中国香港3个亚型;中国台湾8个亚型。中国共报道脊髓小脑性共济失调的家系746个、家系患者1210例、散发患者356例、症状前患者86例。
二、三峡库区脊髓小脑性共济失调患者的首发症状以行走不稳为主,部分散发患者表现言语不清和视力减退。三峡库区脊髓小脑性共济失调患者头颅MRI均出现不同程度的小脑萎缩,散发患者桥脑萎缩明显。三峡库区脊髓小脑性共济失调家系患者的病程与ICARS总评分呈正相关关系。
三、脊髓小脑性共济失调的基因诊断可采用3%琼脂糖凝胶电泳进行初步判断。羊水脱落细胞基因组DNA可以用于脊髓小脑性共济失调的产前诊断。三峡库区范围内首次确诊2个脊髓小脑性共济失调3型家系、20名家系患者、1名散发患者和5名症状前患者。
Spinocerebellar ataxias (SCAs) are rare (incidence between 8 and 10 per 100,000) autosomal dominant hereditary neurological disorders with unified characteristic of progressive ataxia due to the cerebellar degeneration and its connections. Since the first identification of the gene, spinocerebellar ataxia type 1 (SCA 1), involved in dominant ataxia in 1992, twenty-eight genetically distinct subtypes (designated from SCA2 to SCA30,without SCA9 and SCA24) have been described. Because of the clinical overlap among various SCAs and the phenotypic variability of single subtypes, it is difficult to predict the SCA genotype in individual patients.
To clarify the clinical characteristics of the Three Gorge Reservoir Area, the following three parts of work were performed: (1) Systemic review about spinocerebellar ataxias, especially in China; (2)Study on clinical features and image characteristics of spinocerebellar ataxias in Three Gorge Reservoir Area; (3) Study on gene diagnosis and antenatal diagnosis of spinocerebellar ataxia patients and presymptomatic patients in Three Gorge Reservoir Area.
Part I: Systematic review about spinocerebellar ataxias
Objectives: The aim of this study was to clearify the prevalence, distribution, clinical features and therapy progress of spinocerebellar ataxias in China and other countries.
Methods:
Chinese articles: Chinese articles were researched online from CNKI full-text databases and Vip databases and were obtained by manual retrieval for other related articles out of the two main databases. Those words were formulated for the retrieval that spinocerebellar ataxia OR MJD OR Machado-Joseph disease.
Foreign languages articles: English articles were retrieved online from PUBMED, while those not included in the databases were obtained manually. Search formulas were spinocerebellar ataxia OR MJD OR Machado-Joseph disease OR Machado disease OR Joseph disease.
The following information of the enrolled articles were investigated: 1) the country or area, institutes or hospitals where the studies were performed and the publishing dates; 2) presence or absence of genetic diagnosis, genotypes, numbers of pedigrees, numbers of the familial or sporadic patients and asymptomatic patients; 3) gender, age at onset, duration and clinical features of the patients with spinocerebellar ataxia.
Results:
1. Research history of spinocerebellar ataxias
Two hundred and three research institutes or hospitals in thirty-nine countries or areas reported spinocerebellar ataxias patients. Among them, one hundred institutes or hospitals in 21 countries or areas used genetic approaches for diagnosis. In totally, there are 28 types of spinocerebellar ataxias in the world.
In China, spinocerellar ataxias cases were reported in forty research institutes or hospitals in 20 provinces. Twenty five units are able to perform a genetic diagnosis., Six types of spinocerebellar ataxias were reported in mainland including SCA1, SCA2, MJD/SCA3, SCA6, SCA7 and SCA12, 3 types were reported in Hong Kong of SCA1, SCA3 and SCA6, and 8 types in Taiwan of SCA1, SCA2, MJD/SCA3, SCA6, SCA7, SCA8, SCA17 and SCA22. However, there was no report in Macao.
2. Distribution of spinocerebellar ataxias
From the first patient reported in Caucasia Area in 1861, the cases of spinocerebellar ataxia had been reported in 39 counties or area in six continents (North America, South America, European, Asia, Africa and Oceania).
In China, patients of spinocerebellar ataxia have been diagnosed in 20 provinces or areas, distributed mainly in east and south of China.
3. Clinical characteristics of spinocerebellar ataxias
There was no significant difference on gender in family patients and sporadic patients of spinocerebellar ataxia. Many spinocerebellar ataxia onset after 30 years old, except SCA6 which often occurs after 50 years old.
Disease duration of SCA2 was longer than other types of spinocerebellar ataxias, while SCA1 and SCA7 were shorter than others with a possible faster progress.
Every subtype of spinocerebellar ataxias has some own special characters, so physicians could estimate the gene type of patient.
4. Diagnosis of spinocerebellar ataxias
There were 482 Chinese pedigrees of spinocerebellar ataxias in mainland, 13 in Hong Kong and 251 in Taiwan.
There were 1,750 patients of spinocerebellar ataxias in China. Among them, 1,133, 16 and 601 were reported in mainland, Hong Kong and Taiwan, respectively, including 288 and 68 sporadic patients in mainland and Taiwan.
There were 45 asymptomatic patients in mainland of China and 41 in Taiwan and there are no any reports of asymptomatic patients with SCA6 in China.
5. Therapy of spinocerebellar ataxias
There are no effective drugs for spinocerebellar ataxias.
Conclusions:
1. Spinocerebellar ataxias is a global disease which were reported in 6 continents including 39 countries or areas. Spinocerebellar ataxia type 3 is the main subtype in 28 types of spinocerebellar ataxias.
2. In mainland of China, there were 6 types of spinocerebellar ataxia reported which were SCA1-3, SCA6-7 and SCA12. In Hong Kong, 3 types of SCA1, SCA3 and SCA6 were observed. In Taiwan, there were 8 types of spinocerebellar ataxia reported which were SCA1-3,SCA6-8,SCA17 and SCA22.
3. In mainland of China, there were 482 pedigrees,1133 familial patients,288 sporadic patients and 45 presymptomatic patients of spinocerebellar ataxias.
4. In Taiwan, there were 251 pedigrees, 601 familial patients, 68 sporadic patients and 41 presymptomatic patients of spinocerebellar ataxias.
Part II: Clinical and imaging characteristics of spinocerebellar ataxias in Three Gorge Reservoir Area.
Objectives: To investigate the clinical and imaging characteristics of spinocerebellar ataxias patients in the Three Gorges Reservoir Area.
Methods: All the patients of spinocerebellar ataxias in the Neurology Department of the Chongqing Daping Hospital were assessed. To analysis the 33 familial patients in the 6 unrelated Chinese pedigrees and 9 sporadic patients from the Three Gorge Reservoir Area, all of them were evaluated by International Cooperative Ataxia Rating Scale (ICARS), in addition to neurological examination and brain MRI scans at our hospital,.
Results:
1. Clinical features of spinocerebellar ataxias patients in the Three Gorge Reservoir Area
There were not differences in onset age and disease duration of familial and sporadic patients in the Three Gorges Reservoir Area.
Early-onset symptoms of some sporadic patients of spinocerebellar ataxias in Three Gorge Reservoir Area were tongue trips and vision impaired.
Genetic anticipations were not clearly in all familial patients. But our 2 SCA3 pedigrees in Three Gorge Reservoir Area had significant genetic anticipation.
Nystagmus and abnormal muscle tension were common in familial patients in the Three Gorge Reservoir Area.
2. Image characters of spinocerebellar ataxias patients in the Three Gorge Reservoir Area
All familial and sporadic patients had the imaging results of cerebellum atrophy. Some sporadic patients could have pons and medulla oblongata atrophy.
Enlargement of fourth ventricle of familial patients were more significant compared to sporadic patients, whereas cerebellum and brain stem atrophy was more severe in sporadic patients.
3. Risk factors of spinocerebellar ataxia patients in the Three Gorges Reservoir Area.
Most spinocerebellar ataxia patients lived in countryside and got low education degree. Most spinocerebellar ataxia patients were Han Chinese.
Poor traffics and consanguineous marriage were potential reasons in fist generation patients. With the improvement of those factors, disease genes of spinocerebellar ataxias were gradually weakened for the genetic dilution.
Disease duration was associated with ICARS in the familial patients, but not in sporadic patients as well as the onset age.
Conclusions:
1. Onset symptom of spinocerebellar ataxias was gait instability and some sporadic patients featured of tongue trips and vision impaired in the Three Gorge Reservoir Area.
2. The rate of nystagmus and abnormal muscle tension in familial patients was higher than sporadic patients in the Three Gorge Reservoir Area.
3. The atrophy of cerebellum in head MRI of sporadic patients were more severe than those in familial patients in the Three Gorge Reservoir Area.
4. By enlarging marriage circle and improving traffic condition, the incidence of spinocerebellar ataxias in pedigrees might be gradually decreased in the Three Gorge Reservoir Area.
5. The disease duration was correlated to ICARS in familial patients of spinocerebellar ataxias in the Three Gorge Reservoir Area.
Part III: Gene diagnosis and antenatal diagnosis of spinocerebellar ataxias in the Three Gorge Reservoir Area
Objectives: To develop a method of gene diagnosis and antenatal diagnosis and to build database of spinocerebellar ataxias in the Three Gorge Reservoir Area.
Methods: Five ml whole blood was obtained from each health member and patient in the affected family, sporadic patient of spinocerebellar ataxias. In addition, 5ml amniotic fluid was collected from every of 20 normal pregnant women. Gene DNA extracting from blood cell and cast-off cell in amniotic fluid were used to perform polymerase chain reaction. It was a way of antenatal diagnosis and gene diagnosis for patients with or without symptom of spinocerebellar ataxias.
Results:
The gene types of spinocerebellar ataxias could be a preliminary determined by 3% agarose gel electrophoresis. The polymerase chain reactions were useful to perform gene diagnosis of spinocerebellar ataxias type 1-3, 6-7 and 12.
We totally observed the only type (type 3) of spinocerebellar ataxia, in the Three Gorges Reservoir Area, including 2 SCA3 pedigree, 20 familial patients and 1 sporadic patient.
In the Three Gorge Reservoir Area, 5 asymptomatic patients of spinocerebellar ataxia type 3 were diagnosed. Gene DNA extracting from cast-off cell in amniotic fluid could be used for antenatal diagnosis, the same way as the blood cell for diagnosis making in asymptomatic patients.
Conclusions:
1.3% agarose gel electrophoresis could be used for a preliminary determination of gene type in spinocerebellar ataxias type 1-3, 6-7 and 12.
2. We diagnosised 2 spinocerebellar ataxia type 3 pedigrees, including 20 familial patients, for the first time in the Three Gorge Reservoir Area.
3. We diagnosised 1 sporadic patients of spinocerebellar ataxia type 3 for the first time in the Three Gorge Reservoir Area.
4. We diagnosised 5 asymptomatic patients of spinocerebellar ataxia type 3 for the first time in the Three Gorge Reservoir Area.
5. Gene DNA extracting from cast-off cell in amniotic fluid could be used to perform antenatal diagnosis of spinocerebellar ataxia type 1-3, 6-7 and 12.
本课题开展了脊髓小脑性共济失调三个部分的研究:(1)对脊髓小脑性共济失调流行病学研究的系统评价;(2)研究三峡库区范围脊髓小脑性共济失调患者的临床表现和影像学特点;(3)研究三峡库区脊髓小脑性共济失调患者的基因诊断、症状前患者的基因诊断和产前诊断。
第一部分:脊髓小脑性共济失调的系统评价
目的:
从系统评价角度主要采取定性分析方法详细了解脊髓小脑性共济失调在世界和中国的流行、分布、临床表现特点和治疗研究进展。
对象和方法:
1.中文文献取自“中国期刊全文数据库”、“中国维普数据库”,手工检索未被上述数据库收录的临床医学文献。检索策略为在“题目”中检索:脊髓小脑性共济失调OR脊髓小脑性共济失调OR MJD OR马查多-约瑟夫病。
2.外文文献取自“PUBMED”数据库,手工检索未被上述数据库收录的临床医学文献。检索检索策略为在“内容”中检索:spinocerebellar ataxia OR MJD OR Machado-Jespho disease OR Joseph disease OR Machado disease.
3.根据纳入标准和排除标准筛查后,采集研究文献报道各个国家地区的名称、研究机构名称、发表文献年限、是否开展基因诊断、家系数及基因型、家系患者病例数、性别及基因型、散发患者病例数、性别及基因型、症状前患者例数、发病年龄、性别及基因型及患者的临床表现(主要分析共济失调、构音障碍、震颤、认知功能及其他临床表现)等。
结果:
一、脊髓小脑性共济失调的研究历史
1.全世界总共有39个国家地区203家单位报道过脊髓小脑性共济失调,其中已开始开展SCA基因诊断研究的科研医疗机构有21个国家地区的100家单位。目前全世界已报道的类型有SCA1- SCA30共28个亚型(无SCA9和SCA24)。
2.中国20个省市(包括香港特别行政区和台湾地区)40家单位报道过脊髓小脑性共济失调,其中已开始开展SCA基因诊断研究的科研医疗机构25家单位。中国内地目前已报道的类型有SCA1、SCA2、MJD/SCA3、SCA6、SCA7和SCA12共6种亚型,香港特别行政区报道SCA1、SCA3和SCA6共3个亚型。台湾地区目前报道的类型有SCA1、SCA2、SCA3、SCA6、SCA7、SCA8、SCA17和SCA22共8个亚型。澳门特别行政区无SCAs相关文献。
二、脊髓小脑性共济失调的分布概况
1.世界首次报道是1861年高加索地区,而后在全世界6大洲(北美洲、南美洲、欧洲、亚洲、非洲和大洋洲)39个国家和地区人员居住地均发现了脊髓小脑性共济失调的患者。
2.中国20个省市地区报道了脊髓小脑性共济失调,主要集中在东部和南部地区。
3.世界各大洲、国家和地区脊髓小脑性共济失调亚型分布有所区别。
三、脊髓小脑性共济失调的临床特征
1.脊髓小脑性共济失调患者的性别男女比差异不明显,符合常染色体显性遗传规律。
2.脊髓小脑性共济失调大多数亚型30岁以后发病,但SCA6亚型发病年龄较晚,一般在50岁后发病。
3.脊髓小脑性共济失调患者病程比较:SCA2患者病程较长,病情进展较慢;SCA1和SCA7患者的病程较短,病情进展要快于其他3个亚型。
4.脊髓小脑性共济失调临床表现具有高度的异质性,但每个亚型具有一些自身特点引导临床医师对基因亚型的初步判定。
四、脊髓小脑性共济失调的诊断
1.中国内地总共发现482个SCAs家系,中国台湾共发现251个SCAs家系,中国香港共发现13个SCAs家系。
2.中国内地总共发现1133个SCAs患者,台湾地区总共发现601个SCAs患者,香港地区总共发现16个SCAs患者。
3.中国内地总共发现288个SCAs散发患者,台湾地区发现68名散发患者。
4.中国内地总共发现45个SCAs症状前患者,台湾地区共发现41名SCAs症状前患者患者。中国至今还未发现SCA6亚型的症状前患者。
五、脊髓小脑性共济失调的治疗
目前对遗传性脊髓小脑型共济失调治疗无显著进展,新的药物如Gabapentin、Tandospirone、Lamotrigine、Tetrahydrobiopterin、Varenicline和A型肉毒毒素主要用以改善脊髓小脑性共济失调患者的部分症状。
结论:
1.脊髓小脑性共济失调是一个世界范围的神经系统遗传疾病,遍布全球6大洲39个国家地区。SCA3是世界上发生率最高的脊髓小脑性共济失调亚型。
2.中国内地发现SCA1-3、SCA6-7、SCA12共6个亚型;中国香港发现SCA1、SCA3和SCA6共3个亚型;中国台湾发现SCA1-3、SCA6-8、SCA17、SCA22共8个亚型
3.中国内地目前报道脊髓小脑性共济失调的家系482个、家系患者1133例、散发患者288例、症状前患者45例。
4.中国台湾报道脊髓小脑性共济失调家系251个、家系患者601例、散发患者68例、症状前患者患者41例。
第二部分:三峡库区脊髓小脑性共济失调的临床特点和影像学分析
目的:
观察中国三峡库区范围内脊髓小脑性共济失调患者的临床表现特征和进行影像学分析。
对象和方法:
所有来自三峡库区范围患者就诊于第三军医大学第三附属医院神经内科。33名来自6个脊髓小脑性共济失调家系的家系患者和9名散发患者。对患者进行一般资料、临床表现、头颅MRI检查、ICARS评分分析。10名行头颅MRI检查的正常人作为MRI分析的对照。
结果:
一、三峡库区脊髓小脑性共济失调的临床表现
1.三峡库区脊髓小脑性共济失调家系患者与散发患者的发病年龄、病程无显著性区别。
2.言语不清和视力减退是部分散发脊髓小脑性共济失调患者的首发症状。
3.不区分亚型的脊髓小脑性共济失调家系患者的遗传早现不显著,但SCA3家系患
者遗传早现明显。
4.脊髓小脑性共济失调家系患者眼球震颤和肌张力异常显著高于散发患者。
二、三峡库区脊髓小脑性共济失调影像学分析
1.无论是脊髓小脑性共济失调家系患者或散发患者,小脑均出现不同程度的异常改变。散发患者桥脑、延髓异常改变比较明显。
2.家系患者第四脑室扩大较明显,家系患者和散发患者小脑都出现萎缩,尤其以散发患者更为严重。散发患者除小脑萎缩外,桥脑萎缩也比较明显,而家系患者桥脑的萎缩程度不及散发患者。
三、三峡库区脊髓小脑性共济失调危险因素分析
1.生活环境对三峡库区脊髓小脑性共济失调患病有一定影响,以农村人口居多。
2.三峡库区脊髓小脑性共济失调患者普遍受教育程度不高,以小学及以下为主。
3.三峡库区脊髓小脑性共济失调患者以汉族人口为主。
4.三峡库区范围内脊髓小脑性共济失调家系患者交通不便、婚恋范围狭窄可能是第一代患者发病的原因之一,而随着交通状况的改善、婚恋范围的扩大,脊髓小脑性共济失调家系内发病率逐代降低。
5.脊髓小脑性共济失调家系患者ICARS评分与病程呈正相关关系,而散发患者病程、所有患者的发病年龄与ICARS评分相关性不明显。
结论:
1.三峡库区脊髓小脑性共济失调患者的首发症状以行走不稳为主,部分散发患者表现言语不清和视力减退。
2.三峡库区脊髓小脑性共济失调患者均出现共济失调表现,家系患者的眼球震颤、肌张力异常发生率明显高于散发患者。
3.三峡库区脊髓小脑性共济失调患者均出现不同程度的小脑萎缩,散发患者桥脑萎缩比较明显。
4.三峡库区脊髓小脑性共济失调家系可能由于婚恋范围扩大、交通情况改善,脊髓小脑性共济失调发病率逐代降低。
5.三峡库区脊髓小脑性共济失调家系患者的病程与ICARS总评分呈正相关关系。
第三部分三峡库区脊髓小脑性共济失调的基因诊断及产前诊断
目的:
在以重庆为中心的三峡库区范围内开展脊髓小脑性共济失调的基因诊断及产前诊断,建立三峡库区脊髓小脑性共济失调患者数据库、基因库,为进一步研究三峡库区脊髓小脑性共济失调提供平台。
对象和方法:
收集13名脊髓小脑性共济失调家系患者、9名散发患者和30名家系内成员的全血基因组DNA,收集20名孕妇的羊水脱落细胞基因组DNA,采用PCR扩增的方法,建立SCA1-3,SCA6-7和SCA12的基因诊断和产前诊断的方法。
结果:
1.所采用的PCR扩增方法能够进行脊髓小脑性共济失调1-3,6-7和12的基因诊断。3%琼脂糖凝胶电泳可用于初步判定患者的基因亚型。
2.三峡库区脊髓小脑性共济失调仅发现SCA3一个亚型,包括2个家系、20名家系患者和1名散发患者。
3.三峡库区发现5名脊髓小脑性共济失调3型症状前患者。
4.孕龄16-22周,B超定位下进行羊水穿刺术提取羊水脱落细胞的基因组DNA,采用与全血基因组DNA相同的PCR扩增方法可以用于脊髓小脑性共济失调患者或症状前患者的产前诊断。
结论:
1.脊髓小脑性共济失调的基因诊断可以采用3%琼脂糖凝胶电泳初步判断。
2.三峡库区首次确诊2个脊髓小脑性共济失调3型家系,其中有20名家系患者。
3.三峡库区首次确诊1名脊髓小脑性共济失调3型散发患者。
4.三峡库区首次确诊5名脊髓小脑性共济失调3型症状前患者。
5.建立羊水脱落细胞基因组DNA用于脊髓小脑性共济失调的产前诊断方法。
全文结论:
一、脊髓小脑性共济失调发病遍布全球6大洲39个国家地区。SCA3是世界上最高发生率的脊髓小脑性共济失调亚型。中国内地发现6个亚型;中国香港3个亚型;中国台湾8个亚型。中国共报道脊髓小脑性共济失调的家系746个、家系患者1210例、散发患者356例、症状前患者86例。
二、三峡库区脊髓小脑性共济失调患者的首发症状以行走不稳为主,部分散发患者表现言语不清和视力减退。三峡库区脊髓小脑性共济失调患者头颅MRI均出现不同程度的小脑萎缩,散发患者桥脑萎缩明显。三峡库区脊髓小脑性共济失调家系患者的病程与ICARS总评分呈正相关关系。
三、脊髓小脑性共济失调的基因诊断可采用3%琼脂糖凝胶电泳进行初步判断。羊水脱落细胞基因组DNA可以用于脊髓小脑性共济失调的产前诊断。三峡库区范围内首次确诊2个脊髓小脑性共济失调3型家系、20名家系患者、1名散发患者和5名症状前患者。
Spinocerebellar ataxias (SCAs) are rare (incidence between 8 and 10 per 100,000) autosomal dominant hereditary neurological disorders with unified characteristic of progressive ataxia due to the cerebellar degeneration and its connections. Since the first identification of the gene, spinocerebellar ataxia type 1 (SCA 1), involved in dominant ataxia in 1992, twenty-eight genetically distinct subtypes (designated from SCA2 to SCA30,without SCA9 and SCA24) have been described. Because of the clinical overlap among various SCAs and the phenotypic variability of single subtypes, it is difficult to predict the SCA genotype in individual patients.
To clarify the clinical characteristics of the Three Gorge Reservoir Area, the following three parts of work were performed: (1) Systemic review about spinocerebellar ataxias, especially in China; (2)Study on clinical features and image characteristics of spinocerebellar ataxias in Three Gorge Reservoir Area; (3) Study on gene diagnosis and antenatal diagnosis of spinocerebellar ataxia patients and presymptomatic patients in Three Gorge Reservoir Area.
Part I: Systematic review about spinocerebellar ataxias
Objectives: The aim of this study was to clearify the prevalence, distribution, clinical features and therapy progress of spinocerebellar ataxias in China and other countries.
Methods:
Chinese articles: Chinese articles were researched online from CNKI full-text databases and Vip databases and were obtained by manual retrieval for other related articles out of the two main databases. Those words were formulated for the retrieval that spinocerebellar ataxia OR MJD OR Machado-Joseph disease.
Foreign languages articles: English articles were retrieved online from PUBMED, while those not included in the databases were obtained manually. Search formulas were spinocerebellar ataxia OR MJD OR Machado-Joseph disease OR Machado disease OR Joseph disease.
The following information of the enrolled articles were investigated: 1) the country or area, institutes or hospitals where the studies were performed and the publishing dates; 2) presence or absence of genetic diagnosis, genotypes, numbers of pedigrees, numbers of the familial or sporadic patients and asymptomatic patients; 3) gender, age at onset, duration and clinical features of the patients with spinocerebellar ataxia.
Results:
1. Research history of spinocerebellar ataxias
Two hundred and three research institutes or hospitals in thirty-nine countries or areas reported spinocerebellar ataxias patients. Among them, one hundred institutes or hospitals in 21 countries or areas used genetic approaches for diagnosis. In totally, there are 28 types of spinocerebellar ataxias in the world.
In China, spinocerellar ataxias cases were reported in forty research institutes or hospitals in 20 provinces. Twenty five units are able to perform a genetic diagnosis., Six types of spinocerebellar ataxias were reported in mainland including SCA1, SCA2, MJD/SCA3, SCA6, SCA7 and SCA12, 3 types were reported in Hong Kong of SCA1, SCA3 and SCA6, and 8 types in Taiwan of SCA1, SCA2, MJD/SCA3, SCA6, SCA7, SCA8, SCA17 and SCA22. However, there was no report in Macao.
2. Distribution of spinocerebellar ataxias
From the first patient reported in Caucasia Area in 1861, the cases of spinocerebellar ataxia had been reported in 39 counties or area in six continents (North America, South America, European, Asia, Africa and Oceania).
In China, patients of spinocerebellar ataxia have been diagnosed in 20 provinces or areas, distributed mainly in east and south of China.
3. Clinical characteristics of spinocerebellar ataxias
There was no significant difference on gender in family patients and sporadic patients of spinocerebellar ataxia. Many spinocerebellar ataxia onset after 30 years old, except SCA6 which often occurs after 50 years old.
Disease duration of SCA2 was longer than other types of spinocerebellar ataxias, while SCA1 and SCA7 were shorter than others with a possible faster progress.
Every subtype of spinocerebellar ataxias has some own special characters, so physicians could estimate the gene type of patient.
4. Diagnosis of spinocerebellar ataxias
There were 482 Chinese pedigrees of spinocerebellar ataxias in mainland, 13 in Hong Kong and 251 in Taiwan.
There were 1,750 patients of spinocerebellar ataxias in China. Among them, 1,133, 16 and 601 were reported in mainland, Hong Kong and Taiwan, respectively, including 288 and 68 sporadic patients in mainland and Taiwan.
There were 45 asymptomatic patients in mainland of China and 41 in Taiwan and there are no any reports of asymptomatic patients with SCA6 in China.
5. Therapy of spinocerebellar ataxias
There are no effective drugs for spinocerebellar ataxias.
Conclusions:
1. Spinocerebellar ataxias is a global disease which were reported in 6 continents including 39 countries or areas. Spinocerebellar ataxia type 3 is the main subtype in 28 types of spinocerebellar ataxias.
2. In mainland of China, there were 6 types of spinocerebellar ataxia reported which were SCA1-3, SCA6-7 and SCA12. In Hong Kong, 3 types of SCA1, SCA3 and SCA6 were observed. In Taiwan, there were 8 types of spinocerebellar ataxia reported which were SCA1-3,SCA6-8,SCA17 and SCA22.
3. In mainland of China, there were 482 pedigrees,1133 familial patients,288 sporadic patients and 45 presymptomatic patients of spinocerebellar ataxias.
4. In Taiwan, there were 251 pedigrees, 601 familial patients, 68 sporadic patients and 41 presymptomatic patients of spinocerebellar ataxias.
Part II: Clinical and imaging characteristics of spinocerebellar ataxias in Three Gorge Reservoir Area.
Objectives: To investigate the clinical and imaging characteristics of spinocerebellar ataxias patients in the Three Gorges Reservoir Area.
Methods: All the patients of spinocerebellar ataxias in the Neurology Department of the Chongqing Daping Hospital were assessed. To analysis the 33 familial patients in the 6 unrelated Chinese pedigrees and 9 sporadic patients from the Three Gorge Reservoir Area, all of them were evaluated by International Cooperative Ataxia Rating Scale (ICARS), in addition to neurological examination and brain MRI scans at our hospital,.
Results:
1. Clinical features of spinocerebellar ataxias patients in the Three Gorge Reservoir Area
There were not differences in onset age and disease duration of familial and sporadic patients in the Three Gorges Reservoir Area.
Early-onset symptoms of some sporadic patients of spinocerebellar ataxias in Three Gorge Reservoir Area were tongue trips and vision impaired.
Genetic anticipations were not clearly in all familial patients. But our 2 SCA3 pedigrees in Three Gorge Reservoir Area had significant genetic anticipation.
Nystagmus and abnormal muscle tension were common in familial patients in the Three Gorge Reservoir Area.
2. Image characters of spinocerebellar ataxias patients in the Three Gorge Reservoir Area
All familial and sporadic patients had the imaging results of cerebellum atrophy. Some sporadic patients could have pons and medulla oblongata atrophy.
Enlargement of fourth ventricle of familial patients were more significant compared to sporadic patients, whereas cerebellum and brain stem atrophy was more severe in sporadic patients.
3. Risk factors of spinocerebellar ataxia patients in the Three Gorges Reservoir Area.
Most spinocerebellar ataxia patients lived in countryside and got low education degree. Most spinocerebellar ataxia patients were Han Chinese.
Poor traffics and consanguineous marriage were potential reasons in fist generation patients. With the improvement of those factors, disease genes of spinocerebellar ataxias were gradually weakened for the genetic dilution.
Disease duration was associated with ICARS in the familial patients, but not in sporadic patients as well as the onset age.
Conclusions:
1. Onset symptom of spinocerebellar ataxias was gait instability and some sporadic patients featured of tongue trips and vision impaired in the Three Gorge Reservoir Area.
2. The rate of nystagmus and abnormal muscle tension in familial patients was higher than sporadic patients in the Three Gorge Reservoir Area.
3. The atrophy of cerebellum in head MRI of sporadic patients were more severe than those in familial patients in the Three Gorge Reservoir Area.
4. By enlarging marriage circle and improving traffic condition, the incidence of spinocerebellar ataxias in pedigrees might be gradually decreased in the Three Gorge Reservoir Area.
5. The disease duration was correlated to ICARS in familial patients of spinocerebellar ataxias in the Three Gorge Reservoir Area.
Part III: Gene diagnosis and antenatal diagnosis of spinocerebellar ataxias in the Three Gorge Reservoir Area
Objectives: To develop a method of gene diagnosis and antenatal diagnosis and to build database of spinocerebellar ataxias in the Three Gorge Reservoir Area.
Methods: Five ml whole blood was obtained from each health member and patient in the affected family, sporadic patient of spinocerebellar ataxias. In addition, 5ml amniotic fluid was collected from every of 20 normal pregnant women. Gene DNA extracting from blood cell and cast-off cell in amniotic fluid were used to perform polymerase chain reaction. It was a way of antenatal diagnosis and gene diagnosis for patients with or without symptom of spinocerebellar ataxias.
Results:
The gene types of spinocerebellar ataxias could be a preliminary determined by 3% agarose gel electrophoresis. The polymerase chain reactions were useful to perform gene diagnosis of spinocerebellar ataxias type 1-3, 6-7 and 12.
We totally observed the only type (type 3) of spinocerebellar ataxia, in the Three Gorges Reservoir Area, including 2 SCA3 pedigree, 20 familial patients and 1 sporadic patient.
In the Three Gorge Reservoir Area, 5 asymptomatic patients of spinocerebellar ataxia type 3 were diagnosed. Gene DNA extracting from cast-off cell in amniotic fluid could be used for antenatal diagnosis, the same way as the blood cell for diagnosis making in asymptomatic patients.
Conclusions:
1.3% agarose gel electrophoresis could be used for a preliminary determination of gene type in spinocerebellar ataxias type 1-3, 6-7 and 12.
2. We diagnosised 2 spinocerebellar ataxia type 3 pedigrees, including 20 familial patients, for the first time in the Three Gorge Reservoir Area.
3. We diagnosised 1 sporadic patients of spinocerebellar ataxia type 3 for the first time in the Three Gorge Reservoir Area.
4. We diagnosised 5 asymptomatic patients of spinocerebellar ataxia type 3 for the first time in the Three Gorge Reservoir Area.
5. Gene DNA extracting from cast-off cell in amniotic fluid could be used to perform antenatal diagnosis of spinocerebellar ataxia type 1-3, 6-7 and 12.
引文
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