中国大陆南方汉族正常人群齿状核红核苍白球路易体萎缩基因三核苷酸重复变异研究

目的研究中国大陆南方正常人群齿状核红核苍白球路易体萎缩(DRPLA)基因(以CAG)n正常变异范围,以及DRPLA基因(CAG)n扩展突变在中国大陆脊髓小脑型共济失调(SCA)患者中的分布。方法应用荧光PCR,毛细管电泳等技术,对67个已经排除了SCA1、SCA2、SCA3、SCA6、SCA7的常染色体显性遗传SCA家系的先证者和66个散发SCA患者以及94个南方正常汉族人进行DRPLA基因CAG重复次数分析。结果未发现DRPLA基因(CAG)n扩展突变；DRPLA基因(CAG)n正常变异范围为5～21个拷贝,15个拷贝最多见,杂合频率为89．13%,共14种等位基因。结论DRPLA在中国大陆为罕见的SCA亚型,DRPLA基因(CAG)n正常变异范围存在地区和种族差异,中国大陆DRPLA发病率低可能同正常国人较大重复次数的等位基因少见有关。     

宁夏地区回、汉族脊髓小脑共济失调家系SCA3/MJD基因突变研究

目的通过对宁夏地区临床诊断为脊髓小脑共济失调的3个家系(2个汉族家系、1个回族家系)进行SCA3/MJD基因检测,探讨脊髓小脑共济失调的发病机制与临床特点,以为临床应用提供依据。方法对3家系受试者进行神经系统检查和系谱调查,部分行头部MRI和肌电图检查,以及SCA3/MJD基因胞嘧啶-腺嘌呤-鸟嘌呤(CAG)重复数目检测。结果3家系中共计8例脊髓小脑共济失调患者(汉族家系1中6例、汉族家系2中1例和回族家系中1例),符合常染色体显性遗传特点,以共济失调与构音障碍为主要表现,其次为眼外肌麻痹、眼球震颤、慢眼动、锥体束征等。其中汉族家系1和回族家系明确诊断为SCA3/MJD家系,两家系中7例患者(汉族家系1中6例、回族家系中1例)及2例临床表型正常亲属(两家系中各1例)检测出SCA3/MJD异常等位基因,其CAG重复数目为66～81次。汉族家系2中1例患者及汉族家系1中4例临床表型正常亲属SCA3/MJD基因CAG重复数目为20～33次。正常等位基因与异常等位基因CAG重复数目差异有统计学意义(t=5.309,P=0.000)。结论宁夏地区回、汉族脊髓小脑共济失调患者中存在SCA3/MJD基因型,基因检测分析有利于明确诊断脊髓小脑共济失调且能够检出症状前患者。     

遗传性共济失调:基因型与临床表型研究进展

本文从临床特征、家系来源、遗传方式、基因定位和克隆等角度综述了遗传性共济失调,包括SCA1、SCA2、SCA3/MJD、SCA4、SCA5、SCA7、EA、DRPLA、AVED、FRDA、AT、IOSCA的基因型与临床表型研究进展,显示了共济失调极大的遗传异质性。致病基因的研究将为该病的基因诊断和基因型分型提供理论依据。     

遗传性痉挛性截瘫患者MJD1基因的突变分析

目的探讨中国汉族人群中遗传性痉挛性截瘫(Hereditary Spastic Paraplegia,HSP或SPG)患者的MJD1基因突变特点,进一步探索HSP和遗传性脊髓小脑性共济失调(Spinocerebellar Ataxia,SCA)的遗传和临床异质性。方法应用聚合酶链反应、8%变性聚丙烯酰胺凝胶电泳和DNA T载体连接测序等方法对78例临床诊断为HSP的患者进行MJD1基因突变分析。结果在18个HSP家系中检出SCA3/MJD1家系2个,占11.1%,该2例家系均为常染色体显性遗传,2例家系先证者在临床上符合HSP的诊断标准,突变的MJD1等位基因CAG三核苷酸异常重复次数分别为65和69次,散发的HSP病例未发现MJD1等位基因的异常。结论HSP和SCA都具有明显的临床和遗传异质性,其表型在临床上有相互交叉现象,部分SCA3/MJD1患者临床上可为典型的痉挛性截瘫特征而无任何明显的共济失调表现。对临床表现为HSP的患者,尤其是有明显阳性家族史的患者进行MJD1基因诊断可以弥补HSP临床诊断的不足。     

宁夏地区脊髓小脑性共济失调家系基因突变特征的研究

目的研究宁夏地区脊髓小脑性共济失调(SCA)患者基因突变的特征。方法用聚合酶链反应(PCR)、毛细管凝胶电泳(CGE)及DNA测序方法对1个临床诊断为SCAs的宁夏籍家系中6例SCA患者和4名亲属进行SCA3/Machado-Joseph disease(MJD)基因三核苷酸CAG重复序列检测。结果此家系中6例患者及1名表型正常的家系成员检测出异常SCA3/MJD等位基因,CAG重复数为66～81次;确诊为SCA3/MJD。其余3名家系成员CAG重复数正常(22～33次)。结论宁夏地区SCAs患者有SCA3/MJD亚型。提示基因检测对SCAs患者的明确诊断及分型有重要意义。     

遗传性脊髓小脑型共济失调7型临床特征及基因突变分析

目的分析中国汉族人群ATXN7基因突变,探讨遗传性脊髓小脑型共济失调7型（SCA7）患者临床特征。方法运用聚合酶链反应、变性聚丙烯酰胺凝胶电泳和毛细管电泳方法对521例临床诊断为SCA的患者（337例常染色体显性遗传先证者,184例散发患者）及258名健康对照人群进行ATXN7基因CAG三核苷酸重复突变分析,并对有ATXN7基因异常的7个家系进行临床总结。结果337例常染色体显性遗传先证者中发现7个ATXN7基因CAG三核苷酸异常重复扩增突变（2.08%）,其异常重复次数范围为38～71次;184例散发患者未发现CAG三核苷酸异常重复扩增突变。258名健康对照者中共发现13种等位基因,CAG重复次数范围为5～17次,平均10.23次,以10次CAG三核苷酸重复最常见。7个SCA7家系临床主要表现为共济失调、视力下降、眼底病变,同时可合并其他多种少见临床症状,在父系遗传时存在明显的遗传早现现象。结论SCA7多呈常染色体显性遗传,散发病例罕见,临床表现复杂,进行ATXN7基因突变分析有助于临床诊断。     

脊髓小脑共济失调2型、3型患者10例基因突变与临床表型分析

目的探讨脊髓小脑共济失调（SCA）2型、3型患者的基因突变特点及临床表型。方法总结4个SCAs家系的9例患者和1例散发患者的临床表现，对全部患者、43名家系成员及60名健康对照，采用PCR、荧光PCR、毛细管电泳等技术检测分析SCA2、3基因内CAG三核苷酸重复序列的长度及拷贝数。结果3个家系中的6例患者、1例散发患者存在SCA3／MJD（CAG）n扩展突变，CAG重复数为68—75次；1个家系的3例患者存在SCA2（CAG）n扩展突变，CAG重复数为39—41次。两型患者的临床表现有重叠之处，但在发病年龄、病程进展、神经系统受累部位等方面有明显差异。结论SCA3／MJD型与SCA2型在临床表现上存在一定差异性，有助于鉴别和分型，但基因检测是明确诊断的惟一方法。     

遗传性痉挛性截瘫spastin、atlastin和paraplegin基因突变分析

目的探讨遗传性痉挛性截瘫(HSP)spastin、atlastin和parap legin基因的突变特点。方法应用聚合酶链反应-单链构象多态性(PCR-SSCP)结合DNA序列分析方法对24个常染色体显性遗传HSP家系和14例散发患者进行spastin基因和atlastin基因突变分析;对12个常染色体隐性遗传HSP家系和14例散发患者进行parap legin基因突变分析。结果在5个不同的常染色体显性遗传HSP家系中发现4个spastin基因新突变(1223 insCTCA、1258T→A,1293A→G和1668delCTA),在2例散发患者中发现2个spastin基因多态(IVS1-31C→G和IVS2-47A→G);在常染色体显性遗传HSP家系和散发患者中未发现atlastin基因突变或多态;在常染色体隐性遗传HSP家系和散发患者中未发现致病突变,仅在2例散发患者中发现2个parap legin基因多态(2063G→A及2066G→A)。结论我国遗传性痉挛性截瘫患者中spastin基因突变较常见,atlastin和parap legin基因的突变率可能较低。     

齿状核红核苍白球丘脑底核萎缩1例家系报道及文献复习

目的探讨中国汉族人群齿状核红核苍白球丘脑底核萎缩(DRPLA)患者的临床表现及基因突变特点。方法收集以共济失调伴不自主动作为主要表现的常染色体显性遗传家族史一家系的临床资料。应用重复引物多聚酶链反应(TP-PCR)和毛细管电泳技术对脊髓小脑性共济失调1、2、3、6、7、12、1 7亚型相关基因、亨廷顿病相关HTT基因和DRPLA相关ATN1基因的动态突变进行检测,发现异常扩增进一步用PCR及Sanger测序法验证。结合文献复习回顾分析中国DRPLA家系的临床和基因特点。结果该家系先证者检出ATN1基因5号外显子上CAG三核苷酸重复序列异常扩增,扩增数为9/59。ATNl CAG三核苷酸重复序列异常扩增数48次,可确诊为DRPLA。文献报道DRPLA家系16例,患者临床表现均较典型,异常扩增重复数为54~71次,平均(62.3±4.20)次。结论中国DRPLA病例报道较少,临床应对疑似病例进行基因筛查,提高诊断率。     

痉挛性截瘫并共济失调表型的家系基因分析

以该院门诊收治的5例具有痉挛性截瘫合并共济失调表型的家系先证者为研究对象,运用高通量测序芯片结合毛细管电泳技术对这些家系先证者进行致病基因动态突变检测。发现了一个家系先证者携带有ATXN3/MJD1基因CAG重复84次,其妹妹CAG重复82次,其父CAG重复73次,该家系拟诊为遗传性脊髓小脑共济失调3型(SCA3/MJD)家系,并具有明显的临床异质性及遗传早现现象。建议对于兼有痉挛性截瘫及小脑性共济失调表型的患者,特别是具有显性遗传家族史的患者,应进行SCA3致病基因的动态突变检测,同时对家系内表型正常的成员应仔细查体,以防漏诊。     

Frequency of spinocerebellar ataxia mutations in the Kinki district of Japan

OBJECTIVES: To determine the frequencies of spinocerebellar ataxias (SCAs) in the Kinki district, the western part of the main island of Japan. MATERIAL AND METHODS: One hundred and forty-three families with dominantly inherited ataxia and 220 patients with apparently sporadic cerebellar ataxia were examined for the SCA1, SCA2, SCA3/Machado-Joseph disease (MJD), SCA6, SCA7, SCA8, SCA12 and dentatorubral-pallidoluysian atrophy (DRPLA) mutations. RESULTS: Among the dominant families, SCA1 accounted for 3%, SCA2 for 4%, SCA3/MJD for 24%, SCA6 for 31% and DRPLA for 12%. Neither SCA7 nor SCA12 mutations were detected. Among the apparently sporadic patients, 15% were found to have expanded triplet repeats. Of these, the SCA6 mutation was most frequently detected. CONCLUSION: SCA6 is the most common SCA in the Kinki district of Japan. Comparison of our results with those from other regions of Japan and different countries shows geographic and ethnic variation in the frequency of SCAs.     

Frequency of SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds

OBJECTIVE: To assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, and DRPLA (dentatorubropallidoluysian atrophy) CAG trinucleotide repeat expansions [(CAG)n] among persons diagnosed with hereditary SCA from Chinese families. PATIENTS AND METHODS: Spinocerebellar ataxia type 1, SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA (CAG)n mutation were detected with the polymerase chain reaction, highly denaturing polyacrylamide gel electrophoresis, and silver staining technique in 167 patients with autosomal dominant SCA from 85 Chinese families and 37 patients with sporadic SCA. RESULTS: Spinocerebellar ataxia type 1 (CAG)n mutation in 7 patients from 4 kindreds (4.70%) was expanded to 53 to 62 repeats. Spinocerebellar ataxia type 2 (CAG)n mutation in 12 patients from 5 kindreds (5.88%) was expanded to 42 to 47 repeats. Spinocerebellar ataxia type 3/Machado-Joseph disease (CAG)n mutation in 83 patients from 41 kindreds (48.23%) was expanded to 68 to 83 repeats. Sixty-five patients from 35 kindreds (41.19%) and 37 patients with sporadic SCA did not test positive for SCA1, SCA2, SCA3/MJD, SCA6, SCA7, or DRPLA. There was a predictable inverse relationship between the number of CAG repeats and the age at onset for SCA3/MJD and SCA2. Clinically, dementia and hyporeflexia were more frequent in patients with SCA2, while spasticity, hyperreflexia, and Babinski signs were more frequent in patients with SCA3/ MJD, and those might be helpful in clinical work to primarily distinguish patients with SCA3/MJD and SCA2 from others with different types of SCA. CONCLUSIONS: The frequency of SCA3/MJD is substantially higher than that of SCA1 and SCA2 in patients with autosomal dominant SCA from Chinese kindreds, who are non-Portuguese. Clinical expressions of the various types of SCAs overlap one another; therefore, for clinical study it is important to make a gene diagnosis and genetic classification for patients with SCA.     

A survey of spinocerebellar ataxia in South Brazil – 66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease–causing mutations

Background The autosomal dominant spinocerebellar ataxias (SCAs) are a clinical and genetically heterogeneous group of debilitating, neurodegenerative diseases, related to fourteen different loci– SCAs 1, 2, 4, 5, 6, 7, 8, 10, 11, 12, 13 and 14, Machado-Joseph disease (MJD/SCA 3), and DRPLA. Objectives (1) to verify the frequency of SCA1, SCA2, MJD, DRPLA, SCA6, SCA7 and SCA8 in a series of new SCA patients from South Brazil and (2) to compare their molecular and clinical characteristics with other patients previously described. Methods sixty-six cases were included in the present study: 52 were familial and 14 sporadic. Molecular analysis of the trinucleotide repeat loci were performed according to methods in the literature. Results 92 % of families with autosomal dominant inheritance segregated the MJD1 mutation, 2 % of families segregated the SCA7 mutation and 6 % remained undiagnosed. Among 14 isolated cases, one showed the SCA8 mutation. Clinical and molecular findings were similar to those already described in the literature, but revealed (1) one SCA7 patient with eyelid retraction, a sign usually related to MJD; and (2) one sporadic case of SCA8. Conclusions The proportion of MJD cases was very high, probably reflecting an Azorean founder effect. The estimated frequency of affected individuals with MJD, in our region, was 1.8 / 100,000, and of SCAs other than MJD, 0.2/100,000. Received: 13 February 2001, Received in revised form: 6 April 2001, Accepted: 9 April 2001     

Hereditary ataxias in Akita prefecture]

To provide a genetic survey of hereditary ataxia, we performed PCR screening of SCA1, SCA2, MJD1 (SCA 3), SCA6, DRPLA, with 71 patients in 61 families living in Akita prefecture (1,205,571 population in 1997) in Japan. Of 71 patients in 61 families, 18 MJD1, 14 SCA6, 5 DRPLA, 1 SCA1 and 1 SCA2 patients were detected. Eighty percent of autosomal dominant inherited spinocerebellar degeneration (AD-SCD) including 7 spoladic patients genetically diagnosed as AD-SCD was MJD1 (45.7%) and SCA6 (34.3%). These suggest the prevalence rate of hereditary ataxias in Akita prefecture; 1.5 and 1.2/100,000 of MJD1 and SCA6, respectively. Only one patient of SCA1 was detected, which was frequently reported in Hokkaido and Tohoku area in Japan.     

Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal

Background and purpose:  The relative frequency of the different autosomal dominant cerebellar ataxia (ADCA) varies widely amongst different geographic locations. Here we describe a series of 45 ADCA families from Portugal.
Methods:  Patients with progressive cerebellar dysfunction of autosomal dominant transmission underwent a clinical examination protocol and genetic testing for spinocerebellar ataxia (SCA)1 to Machado-Joseph disease (MJD)/SCA3, SCA6, SCA7, SCA10, SCA12, SCA17 and dentatorubral-pallidoluysian atrophy (DRPLA). We registered the clinical characteristics and frequency of each type of ataxia.
Results:  MJD/SCA3 was the most frequent ADCA (26 families, 57.8% of all families), followed by DRPLA (5 families, 11.2%), SCA7 (2 families, 4.4%), SCA2 and SCA1 (1 family each, 2.2% each); 10 families (22.2%) had no molecular diagnosis. SCA1 and SCA7 patients had African ancestry. DRPLA patients had Portuguese ancestry and were characterized by prominent anticipation and a variable combination of epilepsy, extra-pyramidal symptoms and dementia. Ophtalmoparesis, slow saccades and retinopathy were most distinctive of SCA3, SCA2 and SCA7 cases, respectively.
Conclusions:  MJD/SCA3 was the most common ADCA in this group of families. The high frequency of DRPLA and presence of SCA1 and SCA7 cases was unexpected. The presence of these rarer ADCA types probably reflects migration phenomena, posing a challenge for differential diagnosis.     

Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia

The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified.     

CAG repeat expansions in patients with sporadic cerebellar ataxia

CAG repeat expansions cause spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6 and dentatorubral-pallidoluysian atrophy (DRPLA). So far these expansions have been examined mainly in ataxia patients with a family history. However, some sporadic cases with SCA have recently been reported. To elucidate the frequency and characteristics of sporadic SCAs, we screened 85 Japanese ataxia patients without a family history for the SCA1, SCA2, SCA3, SCA6 and DRPLA mutations. As a result, 19 patients (22%) were found to have expanded CAG repeats. Among sporadic SCAs, the SCA6 mutation was most frequently observed. The sporadic SCA6 patients had smaller CAG repeats and a later age of onset than SCA6 patients with an established family history. We also identified one father-child pair in which intermediate sized CAG repeats expanded into the SCA2 disease range during transmission. These findings suggest that patients with ataxia even without a family history should be examined for a CAG repeat expansion.     

Spinocerebellar Ataxias in Brazil—Frequencies and Modulating Effects of Related Genes

This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2 (7.8 %), 20 SCA7 (5.6 %), 15 SCA1 (4.2 %), 12 SCA10 (3.3 %), 5 SCA6 (1.4 %), and 65 families without a molecular diagnosis (18.1 %). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7 % of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p?<?0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented.