脊髓小脑型共济失调6型患者的临床特征及基因突变分析

目的研究脊髓小脑型共济失调(SCA)6型的临床特征和基因突变频率。方法采用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术,对160个SCA家系330例患者和77例散发SCA患者进行SCA6(CAG)n的重复数分析,对异常等位基因进行测序;并对SCA6患者进行临床及MRI检查。结果检测确定4个SCA6家系6例患者SCA6(CAG)n的重复数为25和26,正常人群SCA6(CAG)n的重复数为5～17,SCA6突变频率为本组SCA家系的2.5%。SCA6患者临床仅表现为缓慢进展的小脑性共济失调,MRI显示单纯小脑萎缩。结论SCA6是中国SCA中的少见亚型,SCA6与其他SCA亚型有不同的临床及影像学特征。     

Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: Dentatorubral-pallidoluysian atrophy,machado-joseph disease,and spinocerebellar ataxia type 1

Three autosomal dominant spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and spinocerebellar ataxia type 1 (SCA1), are associated with the expansion of a CAG repeat in the respective genes. To investigate the association between CAG repeat expansion and neuropathological findings, we analyzed several brain regions from 9 cases of DRPLA, 3 cases of MJD, and 1 case of SCA1. We found that the expanded alleles were smaller in the cerebellar cortex than in other brain regions, such as the frontal cortex, in these three diseases. The discrepancy in the expanded CAG repeat length between cerebellar cortex and other tissues was most prominent in DRPLA, and especially in cases of adult-onset DRPLA. A significant correlation was found between the age at onset of DRPLA and the size of the CAG repeat expansion. Cerebella of DRPLA patients were microscopically dissected into three layers, the molecular and granularlayers and the white matter, which were analyzed separately. The lower level of CAG repeat expansion in DRPLA cerebella was representative of CAG repeat expansion in the granule cells. The microdissected samples of the granular layer of the hippocampal formation, which is densely packed with neuronal cells, revealed that the degree of CAG repeat expansion in this layer was similar to that in the cerebellum. These observations suggest that granule cells in the cerebellum and hippocampus have low levels of CAG repeat expansion, and that other types of cells exhibit a higher level of CAG repeat expansion, in spinocerebellar ataxias.     

Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan

Objective – To identify various subtypes of spinocerebellar ataxias (SCAs) among autosomal dominant cerebellar ataxia (ADCA) patients referred to our research center, SCA1, SCA2, SCA3/MJD (Machado–Joseph disease), SCA6, SCA7, SCA8 and SCA12 loci were assessed for expansion of trinucleotide repeats.
Patients and methods – A total of 211 ADCA patients, including 202 patients with dominantly inherited ataxia from 81 Taiwanese families and nine patients with sporadic ataxia, were included in this study and subjected to polymerase chain reaction (PCR) analysis. The amplified products of all loci were analyzed on both 3% agarose gels and 6% denaturing urea-polyacrylamide gels. PCR-based Southern blots were also applied for the detection of SCA7 locus.
Results – The SCA1 mutation was detected in six affected individuals from one family (1.2%) with expanded alleles of 50–53 CAG repeats. Fourteen individuals from nine families (11%) had a CAG trinucleotide repeat expansion at the SCA2 locus, while affected SCA2 alleles have 34–49 CAG repeats. The SCA3/MJD CAG trinucleotide repeat expansion in 60 affected individuals from 26 families (32%) was expanded to 71–85 CAG repeats. As for the SCA7 locus, there were two affected individuals from one family (1.2%) possessed 41 and 100 CAG repeats, respectively. However, we did not detect expansion in the SCA6, SCA8 and SCA12 loci in any patient.
Conclusions – The SCA3/MJD CAG expansion was the most frequent mutation among the SCA patients. The relative prevalence of SCA3/MJD in Taiwan was higher than that of SCA2, SCA1 and SCA7.     

Meiotic CAG repeat instability in spinocerebellar ataxia type 6: maternally transmitted elongation in a presumed sporadic case

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus. The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19. The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare. We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia. Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son. The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband. This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6.     

中国南方汉族健康人TATA结合蛋白基因三核苷酸重复变异研究

目的 研究中国大陆脊髓小脑性共济失调（spinocerebellar ataxias,SCA）17型（SCA17）的分布频率,以及南方汉族健康人群TATA结合蛋白（TATA-binding protein,TBP）基因CAG/CAA重复次数正常变异范围.方法 应用荧光聚合酶链反应（PCR）、毛细管电泳等技术,对已经排除了SCA1、2、3、6、7和齿状核-红核-苍白球路易体萎缩的67个常染色体显性遗传SCA家系的先证者、66例散发SCA患者及110名健康人进行TBP基因CAG/CAA重复次数分析.结果 南方汉族健康人群TBP基因CAG/CAA重复次数范围为26～43次,杂合频率为76.36%,共有14种等位基因.在一个散发SCA患者中发现TBP基因CAG/CAA重复次数为44次.结论 SCA17在中国内地为罕见的SCA亚型,南方汉族健康人群TBP基因常见的CAG/CAA重复次数为34和35次.     

Spinocerebellar ataxia 3 and machado-joseph disease: Clinical,molecular, and neuropathological features

Patients with spinocerebellar ataxia 3 (SCA3) and Machado-Joseph disease (MJD) carry an expanded CAG repeat in the MJDl gene. One hundred twenty families of different geographic origin with autosomal dominant cerebellar ataxia (ADCA) type I were tested. Thirty-four families (126 patients) carried an expanded CAG repeat. The expanded and the normal allele did not overlap and the repeat was unstable during transmission, with variation in the size of the CAG length ranging from ?8 to +5 and a mean expansion of 0.86 repeats without differences according to the parental sex. There was a combined effect of the number of CAG repeats of the expanded and normal allele on the age at onset, which accounted for 70% of its variability. The length of the CAG repeat influenced the frequency of clinical signs associated with cerebellar ataxia, such as abnormal tendon reflexes or decreased vibration sense, whereas the interindividual variation of supranuclear ophthalmoplegia, sphincter and swallowing difficulties, and amyotrophy was mostly determined by different disease durations. We compared the clinical profile of 91 SCA3/MJD patients with 51 SCAl and 32 SCA2 patients. There were striking differences between the SCA3/MJD and SCA2 but not with SCAl groups of patients. Despite their clinical similarities, distinct neuropathological features were observed in 2 SCA3/MJD and SCAl patients.     

Spinocerebellar ataxia type 6: CAG repeat expansion in α1a voltage-dependent calcium channel gene and clinical variations in japanese population

Autosomal dominant spinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneous group of neurodegenerative disorders. Recently, mild CAG repeat expansion in the α_1A voltage-dependent calcium channel gene has been found to be associated with a type of autosomal dominant SCA (SCA6). We analyzed 98 Japanese families with autosomal dominant SCAs, for whom CAG repeat expansions of the SCA1, SCA2, Machado-Joseph disease/SCA3, and dentatorubral-pallidoluysian atrophy genes were excluded, and 5 apparently sporadic cases of cortical cerebellar atrophy. The diagnosis of SCA6 was confirmed in 30 families (31%) comprising 47 affected individuals and 1 sporadic case. The size of expanded CAG repeats ranged from 21 to 26 repeat units and was found to be correlated inversely with age at onset. We identified 2 SCA6 patients homozygous for expanded CAG repeats, whose ages at onset were earlier than the 95% lower confidence level, suggesting the presence of a gene dosage effect of expanded CAG repeat. Ataxia is the most common initial symptom found in 45 of the 48 patients. Patients with a prolonged disease course showed other accompanying clinical features including dystonic postures, involuntary movements, and abnormalities in tendon reflexes.     

SCA2 trinucleotide expansion in German SCA patients

Autosomal dominant spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders which lead to progressive cerebellar ataxia. A gene responsible for SCA type 2 has been mapped to human chromosome 12 and the disease causing mutation has been identified as an unstable and expanded (CAG)_n trinucleotide repeat. We investigated the (CAG)_n repeat length of the SCA2 gene in 842 patients with sporadic ataxia and in 96 German families with dominantly inherited SCA which do not harbor the SCA1 or MJD1/SCA3 mutation, respectively. The SCA2 (CAG)_n expansion was identified in 71 patients from 54 families. The (CAG)_n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)_n repeat lengths with the age of onset in 41 patients revealed an inverse correlation. Two hundred and forty-one apparently healthy octogenerians carried alleles between 16 and 31 repeats. One 50-year old, healthy individual had 34 repeats; she had transmitted an expanded allele to her child. The small difference between ‘normal’ and disease alleles makes it necessary to define the extreme values of their ranges. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany. Received December 30, 1996; Revised and Accepted January 31, 1997     

Neuropathological and molecular studies of spinocerebellar ataxia type 6 (SCA6)

SCA6 is an autosomal dominant spinocerebellar ataxia (SCA) caused by a small CAG repeat expansion of the gene encoding an α-1a-voltage-dependent Ca channel gene subunit on chromosome 19p13. A Japanese woman with SCA6, with a 7-year history of progressive pure cerebellar ataxia, died of malignant lymphoma. Systematic neuropathological examination showed that neuronal degeneration was confined to the cerebellar Purkinje cells and, to a lesser degree, the granular cells, without any involvement of other central nervous system structures. Such pathological selectivity correlates with the localized expression of the responsible gene, and coincides with the neurological manifestation. These findings might contribute to establishing the phenotype of the SCA6 via comparison with other dominant ataxias. Received: 7 July 1997 / Revised, accepted: 14 August 1997     

Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12.

Spinocerebellar ataxia 12 (SCA12) is a recently identified form of autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5' untranslated region of the gene PPP2R2B. We analyzed 77 Indian families with autosomal dominant cerebellar ataxia phenotype and confirmed the diagnosis of SCA12 in 5 families, which included a total of 6 patients and 21 family members. The sizes of the expanded alleles ranged from 55 to 69 CAG repeats, and the sizes of the normal alleles ranged from 7 to 31 repeats. We believe our study is the first to demonstrate that SCA12 may not be as rare in some populations as previously thought.     

Identification of five Spinocerebellar Ataxia Type 2 pedigrees in patients with autosomal dominant cerebellar ataxia in Taiwan

OBJECTIVES: The autosomal dominant cerebellar ataxias (ADCAs) are a group of genetically diverse neurological conditions linked by progressive deterioration in balance and coordination. Spinocerebellar Ataxia Type 2 (SCA2) is one of the ADCAs and also belongs to a special group caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. We aimed to investigate the frequency of SCA2 mutation in the ataxia patients referred to the clinic. MATERIALS AND METHODS: We screened 58 families with inherent cerebellar ataxia and 57 normal individuals by the use of radioactive genomic polymerase chain reaction (PCR) method. A simple non-radioactive PCR for rapid detection of the expanded SCA2 alleles via agarose gel electrophoresis was also employed. RESULTS: Eight SCA2 affected patients and 1 at-risk individual in 5 unrelated SCA2 families were identified. The CAG repeats of normal alleles in the sample studied range in size from 16 to 30 repeat units, while those of SCA2 chromosomes are expanded to 34 to 49 repeat units. Our results also showed that unlike SCA 1 and SCA3/MJD, the size distribution of the normal alleles showed few polymorphisms, with the 22 repeat allele accounting for 90.1%. Homozygosity in normal individuals was 80.2%. No overlap in ataxin-2 allele size between normal and expanded chromosomes was observed. CONCLUSION: This is the first report of the SCA2 gene distributions in the population of Taiwan. The SCA2 mutation accounts for 8.6% of ADCA type I families referred to us, intermediate between SCA1(1.7%) and SCA3/MJD (24%) of the ADCA type I families in our collection.     

脊髓小脑性共济失调6型的分子遗传学诊断及临床特点

目的 研究脊髓小脑性共济失调6型(SCA6)的基因诊断方法及临床特点。方法 对临床诊断为脊髓小脑性共济失调(SCA)的36个家系43例患者及38例散发患者，应用聚合酶链反应对SCA6基因含有CAG三核苷酸重复片段进行扩增，并对异常等位基因片段进行DNA测序，计算CAG重复次数；对2例SCA6患者临床资料进行分析。结果 正常人的SCA6等位基因CAG重复数目为10～13。本组检出家族性患者1例，散发患者1例，其异常等位基因内CAG重复数目分别为25、24。患者临床基本特征为缓慢进展的小脑性共济失调、眼震、构音障碍。结论 致病基因内CAG三核苷酸重复异常扩增是SCA6的确诊依据。SCA6的临床表现与其他SCA亚型无明显差别。     

Cerebellar ataxia in the eastern and southern parts of Norway

Introduction –  The relative frequencies of different ataxias vary among different ethnic and geographic groups. The aim of this study was to examine patients with cerebellar ataxia and find the occurrence of autosomal dominant and recessive cerebellar ataxias in the population of the southern and eastern parts of Norway and estimate its prevalence.
Materials and methods –  Probands were systematically tested for spinocerebellar ataxia 1, 2, 3, 6 and Friedreich's ataxia. A total of 94 patients with ataxia were assessed.
Results –  We registered 60 patients from 39 unrelated families with hereditary ataxias. One family with SCA2 (two patients), one family with Friedreich's ataxia (two patients), two patients heterozygote for Friedreich's ataxia and one metabolic ataxia were identified.
Conclusions –  We have few Friedreich's ataxia and SCA 1,2,3 and 6 in our population. Prevalence in Oslo County was estimated at 2.2/100,000 for autosomal recessive and 3.0/100,000 for autosomal dominant ataxia, respectively.     

Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Italy.

BACKGROUND: The spinocerebellar ataxias (SCAs) are clinically heterogeneous disorders caused by triplet repeat expansions in the sequence of specific disease genes. Spinocerebellar ataxia type 8 (SCA8), originally described in a family characterized by pure cerebellar ataxia with slow disease progression, presents with expansion of combined CTA/CTG repeats. OBJECTIVE: To perform SCA8 repeat expansion analysis in a heterogeneous group of ataxic patients, to determine the prevalence of this mutation in our patients and establish the frequency of expanded CTA/CTG repeats in a large group of control subjects. PATIENTS: One hundred sixty-seven patients affected by sporadic, autosomal dominant and recessive hereditary ataxia were clinically examined and analyzed for SCA8 expansion. We further studied 161 control subjects and 125 patients with psychiatric disorders. RESULTS: We found abnormally expanded CTA/CTG repeats in 5 ataxic patients, 3 of them characterized by pure cerebellar ataxia. One patient had vitamin E deficiency and 1 patient with a sporadic case was affected by gluten ataxia. No evidence of expanded alleles was found in healthy control subjects and in patients with psychiatric disorders. CONCLUSIONS: Our data support the evidence that CTG expansions may be linked to SCA8, since the pathogenic expansions have been found only among patients with genetically unidentified forms of hereditary and sporadic ataxia. Patients carrying expanded alleles present peculiar phenotypic features, thus suggesting that unknown additional factors could probably predispose to the disease.     

Clinical, neuropathological, and molecular study in two families with spinocerebellar ataxia type 6 (SCA6)

To clarify the clinical, neuropathological, and molecular characteristics of spinocerebellar ataxia type 6 (SCA6), two unrelated Japanese families with SCA6 were studied. A clinical feature of the two families was late onset "pure" cerebellar ataxia. Pathologically, three SCA6 brains consistently showed Purkinje cell dominant cortical cerebellar degeneration. Morphometric analysis showed that loss of the cerebellar granule cells and inferior olivary neurons were very mild compared with the severity of Purkinje cell loss. There was no obvious ubiquitin immunoreactive nuclear inclusions. All affected patients had identical expanded alleles, and the expansion was also homogeneously distributed throughout the brain without mosaicism. The present study showed that SCA6 is characterised by Purkinje cell dominant cortical cerebellar degeneration, highly stable transmission of the CAG repeat expansion, and lack of ubiquitin immunoreactive nuclear inclusions.     

Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17)

Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late-onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17. To estimate the frequency of SCA17 among white SCA patients and to define the phenotypic variability, we determined the frequency of SCA17 in a large sample of 1,318 SCA patients. In total, 15 patients in four autosomal dominant SCA families had CAG/CAA repeat expansions in the TBP gene ranging from 45 to 54 repeats. The clinical features of our SCA17 patients differ from other SCA types by manifesting with psychiatric abnormalities and dementia. The neuropathology of SCA17 can be classified as a "pure cerebellar" or "cerebello-olivary" form of ataxia. However, intranuclear neuronal inclusion bodies with immunoreactivity to anti-TBP and antipolyglutamine were much more widely distributed throughout the brain gray matter than in other SCAs. Based on clinical and genetic data, we conclude that SCA17 is rare among white SCA patients. SCA17 should be considered in sporadic and familial cases of ataxia with accompanying psychiatric symptoms and dementia.     

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。     

Typische Antizipation bei spinozerebellärer Ataxie Typ 7

Spinocerebellar ataxia type 7 (SCA7) belongs to the category of autosomal dominant cerebellar ataxias (ADCA). The clinical picture is characterised by progressive ataxia and macular degeneration. Other common signs are slow saccades, external ophthalmoplegia, and pyramidal tract signs. The disease is caused by the expansion of an unstable CAG trinucleotide repeat in the gene for ataxin 7 on chromosome 3. SCA7 is a rare disorder. The first case in Germany was described only recently. We report two additional patients, father and son, with the molecular genetic diagnosis of SCA7. The father carries a trinucleotide expansion of 42 CAG repeats, the son 51. Normal alleles range from 7 to 35 CAG repeats. Both patients show the typical picture with progressive ataxia and macular degeneration. We found a pronounced anticipation (earlier disease onset in subsequent generations), which is highly characteristic of CAG repeat disorders.     

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.