广东汉族人遗传性脊髓小脑型共济失调基因突变的研究

目的 研究广东汉族人遗传性脊髓小脑型共济失调（SCA）的亚型（SCA1、SCA2、SCA3和SCA7）基因突变分布频率。方法 对临床诊断为SCA的18个家系24例SCA患者、22例散发SCA患者、45名家系“正常人”及30名非家系健康人,通过聚合酶链反应（PCR）及聚丙烯酰胺凝胶电泳（PAGE）等技术检测SCA1、2、3、7基因内CAG三核苷酸重复序列突变,并利用ABI310、377测序仪对异常等位基因片段进行DNA测序。结果 在18个SCA家系中,1个家系（5.55％）有SCA1基因突变,2个家系（11.11％）有SCA2基因突变,7个家系（38.88％）有SCA3基因突变,未发现SCA7突变,。在家系成员中检出1例症状前SCA3患者。22例散发性患者中检出SCA1、SCA2、SCA3和SCA7各1例,各占4.54％。SCA1患者CAG重复数为53～56次,正常人19～34次;SCA2患者CAG重复数为38～45次,正常人20～25次;SCA3患者CAG重复数为74～81次,正常人14～40次。SCA7患者CAG重复数为65次,正常人为9～19次。结论 提示中国人SCA主要为SCA3/MJD型,其次为SCA2和SCA1。基因分析对家族性以及散发性SCA患者的临床确诊和遗传咨询均有重要意义。     

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.     

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.     

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.     

Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado-Joseph disease (SCA3) phenotype

CONTEXT: Machado-Joseph disease (MJD/SCA3) is an autosomal dominant cerebellar ataxia of adult onset. The variability in age at onset and the complex and heterogeneous neurologic findings indicate that MJD, caused by a major gene, is modulated by modifier factors. OBJECTIVE: To study if the polymorphic CAG repeats at other loci (namely, SCA2, SCA6 and DRPLA) thus acted as modifier factors of this disease. DESIGN: Case-control. SETTING: Ambulatory care in a referral center. PATIENTS: A convenience sample of 39 unrelated, Brazilian patients with MJD. Main outcome measures: age of onset, anticipation, clinical subtypes and neurological findings. RESULTS: Fasciculations were associated with CAG repeat length of the long SCA2 allele (Mann-Whitney U-test, P < 0.03, after Bonferroni procedure). Other measures (age of onset, anticipation, clinical types and other neurological signs) were not associated with CAG repeat length of SCA2, SCA6 and DRPLA genes. CONCLUSIONS: The present results show that the CAG tract of SCA2 gene interferes with MJD phenotype. Further studies, with patients of other origins and with typing of other (CAG)n loci, are necessary.     

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     

Spinocerebellar ataxia type 6: CAG trinucleotide expansion, clinical characteristics and sperm analysis

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant spinocerebellar degeneration caused by CAG repeat expansions in the human α1A voltage-dependent calcium channel subunit gene. We analyzed 16 SCA6 patients in 14 unrelated Japanese families, and documented the clinical and molecular properties correlating with the CAG repeat expansion. Three of them were sporadic. The CAG repeat number of the expanded and normal alleles was 22.7 ± 2.0 (mean ± SD, n = 15) and 13.8 ± 2.0 (n = 15), respectively, and the repeat size of the expanded alleles correlated inversely with age at onset. The patients presented here were clinically characterized by a slowly progressive cerebellar ataxia and nystagmus. In leukocytes, the strict pattern of the peak in the expanded allele on polyacrylamide gel electrophoresis did not show the presence of cell mosaicism in SCA6, in contrast to other trinucleotide disorders. Moreover, in each patient, the number of CAG repeats in sperm was the same as in leukocytes, and the expanded alleles in sperm indicated uniform peaks as well. In our geographic area, the frequency of SCA6 was as high as MJD, in contrast to the low frequency of other autosomal dominant cerebellar ataxias. Thus, a geographic difference in the frequency of autosomal dominant spinocerebellar ataxias may be present in Japan.     

Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.     

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。     

Molecular and clinical study of spinocerebellar ataxia type 7 in Chinese kindreds

OBJECTIVE: To investigate the clinical and molecular characteristics of spinocerebellar ataxia type 7 (SCA7) in Chinese kindreds. BACKGROUND: Spinocerebellar ataxia type 7 is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. METHODS: Clinical and related examinations were performed in all affected or at-risk individuals from 4 Chinese families presenting with autosomal dominant cerebellar ataxia and decreased visual acuity. The size of the (CAG)(n) array of the SCA7 gene was detected by polymerase chain reaction, polyacrylamide gel electrophoresis, and related techniques in the 4 families and 67 healthy controls. The relationship between expanded repeat number and age of onset was statistically analyzed. RESULTS: The SCA7 mutation was identified in 2 families. Clinical study revealed that great variation occurred in the age of onset, initial symptoms, and associated signs. Meanwhile, the analysis of 11 parent-child couples demonstrated the existence of marked anticipation. Some distinct retinal changes were noted in 2 affected patients. All SCA7 patients in our series exhibited expanded CAG repeats, ranging from 44 to 85 repeats, with a strong negative correlation between repeat size and age of onset. Repeat lengths of expanded alleles showed somatic mosaicism in leukocyte DNA. There were some subtle clinical differences between the SCA7-positive and -negative cases. CONCLUSIONS: Clinical variation occurred not only among the SCA7 families but also within the same kindred. Meiotic and mitotic instability of the CAG repeat in the SCA7 gene were demonstrated, and intergenerational instability of the array was associated with the clinical phenomenon of anticipation. Arch Neurol. 2000;57:1513-1518     

Autosomal dominant cerebellar ataxia type I in Morocco: presence of the SCA1 and SCA3/MJD mutations

We searched for CAG repeat expansions at the SCA1 and SCA3/MJD loci in nine families, including 15 examined patients, with autosomal dominant cerebellar ataxia type I from Morocco. Expansion of the CAG repeat was found in one family at the SCA1 and two at the SCA3/MJD locus, demonstrating the existence of genetic heterogeneity among ADCA type I families in Morocco. Instability during transmission was observed at both loci as in other unstable mutations. The phenotypes of the SCA1 and SCA3/MJD patients were similar.     

Analysis of SCA2 and SCA3/MJD repeats in Parkinson's disease in mainland China: Genetic,clinical, and positron emission tomography findings

To investigate the prevalence and clinical feature(s) of Parkinson's disease (PD) patients with expanded (ATXN2 and MJD1) genes of spinocerebellar ataxia type 2 and 3 (SCA2 and SCA3/MJD) in a mainland Chinese population, CAG triplet repeat expansions of (SCA2 and SCA3/MJD) genes (ATXN2 and MJD1) were analyzed in a cohort of 452 PD patients, including 386 sporadic and 66 familial forms. Striatal dopamine transporter was evaluated in two SCA2 and two SCA3/MJD‐positive family members, an idiopathic PD patient and a healthy control using carbon (C11) [¹¹C]‐radiolabeled‐CFT positron emission tomography (PET). We found two patients in one familial PD (FPD) family (1.5%) and two sporadic PD patients (0.5%) with expanded CAG repeats in the ATXN2 locus, four patients in two FPD families (3%) and another three sporadic PD patients (0.8%) in the MJD1 locus. [¹¹C]‐CFT PET in detected members in SCA2 and SCA3/MJD families showed decrements of ¹¹C‐CFT uptake. These findings suggest that a mutation in SCA2 or SCA3/MJD may be one of the genetic causes of PD. © 2009 Movement Disorder Society     

Body Mass Index is Inversely Correlated with the Expanded CAG Repeat Length in SCA3/MJD Patients

Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder with no current treatment. We aimed to evaluate the body mass index (BMI) of patients with SCA3/MJD and to assess the correlations with clinical, molecular, biochemical, and neuroimaging findings. A case-control study with 46 SCA3/MJD patients and 42 healthy, non-related control individuals with similar age and sex was performed. Clinical evaluation was done with the ataxia scales SARA and NESSCA. Serum insulin, insulin-like growth factor 1 (IGF-1) and magnetic resonance imaging normalized volumetries of cerebellum and brain stem were also assessed. BMI was lower in SCA3/MJD patients when compared to controls (p?=?0.01). BMI was associated with NESSCA, expanded CAG repeat number (CAG)n, age of onset, age, disease duration, and serum insulin levels; however, in the linear regression model, (CAG)n was the only variable independently associated with BMI, in an inverse manner (R?=?-0.396, p?=?0.015). In this report, we present evidence that low BMI is not only present in SCA3/MJD, but is also directly related to the length of the expanded CAG repeats, which is the causative mutation of the disease. This association points that weight loss might be a primary disturbance of SCA3/MJD, although further detailed analyses are necessary for a better understanding of the nutritional deficit and its role in the pathophysiology of SCA3/MJD.     

Spinocerebellar ataxia type 1 in Russia

Spinocerebellar ataxia type 1 (SCA1) is one form of autosomal dominant cerebellar ataxia (ADCA) caused by trinucleotide (CAG) repeat expansion within a mutant gene. We investigated 25 patients from 15 Russian ADCA families for SCA1 mutation and found an expanded CAG repeat in 5 families. Mutant chromosomes contained 41–51 CAG repeats (mean 46.1, SD 3.1), and normal chromosomes displayed 21–27 repeat units (mean 24.7, SD 1.3). Progressive cerebellar ataxia in our series of SCA1 patients was very commonly associated with dysarthria (in all cases) and pyramidal signs (in 10 of 11 cases). In three patients from one family we found optic atrophy, which has never been described before in genetically proven cases of SCA1. We observed no specific clinical features distinguishing SCA1 from non-SCA1 patients. In contrast to the high frequency of SCA1 in our series, we found no patients with Machado-Joseph disease, another form of ADCA caused by expanded CAG repeat.     

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。     

Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation.

OBJECTIVE: Machado-Joseph disease (MJD) is an autosomal dominant cerebellar ataxia with extensive phenotypic variability originally described in families of Portuguese ancestry. Recently, the mutation causing the disease has been identified as an expanded CAG trinucleotide repeat. In this study relations between genotype and phenotype were investigated. METHODS: A series of 180 German patients with degenerative forms of ataxia were clinically and genetically examined. Patients bearing the MJD mutation were assigned to three phenotypes: phenotype 1 characterised by early onset and dystonia or pronounced rigidity associated with ataxia and spasticity. Main symptoms in phenotype 2 were ataxia and spasticity. In phenotype 3 onset was relatively late and peripheral neuropathy accompanied ataxia. Clinical and molecular data were correlated. RESULTS: An expanded CAG array was found in 42 patients from 22 families. Repeat length of CAG varied between 67 and 80 CAG motifs and showed an inverse correlation with the age of onset. For the development of phenotype 1 early onset (< 20 years) seemed more decisive than extensive repeat length. Phenotype 2 was present in all patients with more than 73 CAG motifs and onset between 20 and 40. Phenotype 3 developed in most patients with less than 73 CAG motifs and onset was regularly beyond the age of 40. Intrafamilial variability of both repeat length and phenotype was large reflecting meiotic instability of the expanded CAG repeat. CONCLUSIONS: The MJD mutation is the most frequent cause of dominantly inherited ataxia in Germany. Variations in repeat lengths substantially influence age of onset as well as phenotype but cannot explain why MJD characteristics of Portuguese families such as "bulging eyes", dystonia, and rigidity are essentially missing in German families. Despite the genotypic and phenotypic relations found in this study a reliable individual prognosis of the course of the disease is not possible at a presymptomatic stage.     

Clinical and genetic analysis of spinocerebellar ataxia in Mali

Background: Autosomal dominant cerebellar ataxia, currently denominated spinocerebellar ataxia (SCAs), represents a heterogeneous group of neurodegenerative disorders affecting the cerebellum and its connections. We describe the clinical and molecular findings in 16 patients originating from Malian families, who suffer from progressive cerebellar ataxia syndrome. Methods and results: Molecular analysis allows genetic profiles of SCA to be distinguished. In seven patients, SCA type 2 (CAG) mutation was expanded from 39 to 43 repeats. SCA type 7 (CAG) mutation was confirmed in six patients. Mutations were expanded from 49 to 59 repeats. In three patients, SCA type3 was diagnosed and CAG mutation was expanded to 73 repeats. Conclusions: Our data suggest that the most frequent types of SCA are SCA2 and SCA7. However, further studies are needed to confirm these preliminary results.     

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.     

遗传性脊髓小脑性共济失调7型的基因突变及临床特征分析

目的 研究遗传性脊髓小脑性共济失调7型（SCA7）的基因突变和临床特征。方法 对临床诊断为脊髓小脑性共济失调（SCA）的15个家系24例患者、20例散发SCA患者、41名家系“正常人”及30名非序列的突变,并利用ABI373例序仪对异常等位基因片段进行DNA测序。结果 24例SCA患者的SCA7等位基因CAG重复数目为9－18。正常人SCA7等位基因CAG重复数目为9－19。检出1例散发患者为SCA7,经基因测序证实,其异常等位基因的CAG重复数目为63。结论 CAG过度扩增是SCA7的致病原因,利用基因突变分析可进行基因诊断,提供症状前诊断及遗传咨询的依据,为基因分型奠定基础。     

Variation of CAG repeats and two intragenic polymorphisms at SCA3 locus among Machado-Joseph disease/SCA3 patients and diverse normal populations from eastern India

OBJECTIVES: MJD1/SCA3 is the most common type of spinocerebellar ataxia (SCA) worldwide. To explain the low prevalence of the disease among SCA patients from eastern India, we analysed CAG repeats and two bi-allelic intragenic markers at SCA3 locus among 412 normal individuals and 10 patients. MATERIALS AND METHODS: For CAG repeat analysis, PCR amplified fragments were run on polyacrylamide gel, transferred to a membrane, probed with (CAG)10 and detected on an autoradiograph. Bi-allelic markers were analysed using allele specific PCR amplification. RESULTS: Large normal alleles (>33 CAG repeats) were 0.015 in pooled populations. All the patients had the common haplotype C-A as observed worldwide. Frequency of C-A haplotype among large normal alleles was 0.75. CONCLUSIONS: Observed low prevalence of SCA3 could be because of the low prevalence of large normal alleles that might act as the reservoir for the expanded alleles. SCA3 mutation in Indian populations had the same origin as found worldwide.