The Machado-Joseph disease locus is different from the spinocerebellar ataxia locus (SCA1).

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia that has been described primarily in families of Azorean or Portuguese descent. MJD and chromosome 6p-linked spinocerebellar ataxia (SCA1) are difficult to differentiate clinically, and it has been suggested that they may be allelic variants of the same disorder. We have tested MJD families for linkage to six DNA sequence polymorphisms located on chromosome 6p, including the highly informative dinucleotide repeat, D6S89. Seventeen centimorgans telomeric to and 41 cM centromeric to D6S89, a region that includes the SCA1 locus reported to be within 3 cM of D6S89, have been excluded. These data provide conclusive evidence that MJD and SCA1 are nonallelic.     

Marked Phenotypic Heterogeneity Associated with Expansion of a CAG Repeat Sequence at the Spinocerebellar Ataxia 3/Machado-Joseph Disease Locus

The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neuro-degenerative disorders, has been mapped to chromosome 14q32.1. ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region. We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropatho-logical findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD. Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease. Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation. Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats.     

Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia.

The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat. To assess the frequency of the SCA1 and MJD trinucleotide repeat expansions among individuals diagnosed with ataxia we have collected DNA from individuals representing 311 families with adult-onset ataxia of unknown etiology and screened these samples for trinucleotide repeat expansions within the SCA1 and MJD genes. Within this group there are 149 families with dominantly inherited ataxia. Of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. Thus, together SCA1 and MJD represent 24% of the autosomal dominant ataxias in our group, and the frequency of MJD is substantially greater than that of SCA1. For the 57 patients with MJD trinucleotide repeat expansions, a strong inverse correlation between CAG repeat size and age at onset was observed (r = -.838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively.     

A Third Locus for Autosomal Dominant Cerebellar Ataxia Type 1 Maps to Chromosome 14q24.3-qter: Evidence for the Existence of a Fourth Locus

The autosomal dominant cerebellar ataxias (ADCA) type I are a group of neurological disorders that are clinically and genetically heterogeneous. Two genes implicated in the disease, SCA1 (spinal cerebellar ataxia 1) and SCA2, are already localized. We have mapped a third locus to chromosome 14q24.3-qter, by linkage analysis in a non-SCA1/non-SCA2 family and have confirmed its existence in a second such family. We suggest designating this new locus “SCA3.” Combined analysis of the two families restricted the SCA3 locus to a 15-cM interval between markers D14S67 and D14S81. The gene for Machado-Joseph disease (MJD), a clinically different form of ADCA type I, has been recently assigned to chromosome 14q24.3-q32. Although the SCA3 locus is within the MJD region, linkage analyses cannot yet demonstrate whether they result from mutations of the same gene. Linkage to all three loci (SCA1, SCA2, and SCA3) was excluded in another family, which indicates the existence of a fourth ADCA type I locus.     

Tight linkage of the gene for spinocerebellar ataxia to D6S89 on the short arm of chromosome 6 in a kindred for which close linkage to both HLA and F13A1 is excluded.

A locus for an autosomal dominant form of spinocerebellar ataxia (SCA1) has been assigned to the short arm of chromosome 6 on the basis of linkage to the major histocompatibility system (HLA). In this study of a five-generation American black family, close linkage between the disease locus and both HLA and the coagulation factor XIIIA (F13A1) locus was excluded, and lod scores for all locations of the disease locus between HLA and F13A1 were less than -1.4. These results suggest that the locus causing spinocerebellar ataxia in this family is not in this region. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is between HLA and F13A1. The maximum lod score for SCA1 and D6S89 is 4.90 at a recombination fraction of 0, both in males and in females. These data show that exclusion of close linkage to the HLA complex and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus in that family is on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89, to determine whether the locus causing the disease is SCA1.     

Mutation detection in Machado-Joseph disease using repeat expansion detection.

BACKGROUND: Several neurological disorders have recently been explained through the discovery of expanded DNA repeat sequences. Among these is Machado-Joseph disease, one of the most common spinocerebellar ataxias (MJD/SCA3), caused by a CAG repeat expansion on chromosome 14. A useful way of detecting repeat sequence mutations is offered by the repeat expansion detection method (RED), in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA. We have used RED to detect CAG expansions in families with either MJD/SCA3 or with previously uncharacterized spinocerebellar ataxia (SCA). MATERIALS AND METHODS: Five MJD/SCA3 families and one SCA family where linkage to SCA1-5 had been excluded were analyzed by RED and polymerase chain reaction (PCR). RESULTS: An expansion represented by RED products of 180-270 bp segregated with MJD/SCA3 (p < 0.00001) in five families (n = 60) and PCR products corresponding to 66-80 repeat copies were observed in all affected individuals. We also detected a 210-bp RED product segregating with disease (p < 0.01) in a non-SCA1-5 family (n = 16), suggesting involvement of a CAG expansion in the pathophysiology. PCR analysis subsequently revealed an elongated MJD/SCA3 allele in all affected family members. CONCLUSIONS: RED products detected in Machado-Joseph disease families correlated with elongated PCR products at the MJD/SCA3 locus. We demonstrate the added usefulness of RED in detecting repeat expansions in disorders where linkage is complicated by phenotyping problems in gradually developing adult-onset disorders, as in the non-SCA1-5 family examined. The RED method is informative without any knowledge of flanking sequences. This is particularly useful when studying diseases where the mutated gene is unknown. We conclude that RED is a reliable method for analyzing expanded repeat sequences in the genome.     

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.     

Confirmation of the SCA-2 locus as an alternative locus for dominantly inherited spinocerebellar ataxias and refinement of the candidate region.

The autosomal dominant spinocerebellar ataxias (SCAs) are a clinically heterogeneous group of neurodegenerative diseases. To date, two SCA loci have been identified-one locus (SCA-1) on the short arm of chromosome 6 and the second locus (SCA-2) on the long arm of chromosome 12. We have studied two large kindreds from different ethnic backgrounds, segregating an autosomal dominant form of SCA. A total of 207 living individuals, including 50 affected, were examined, and blood was collected. We performed linkage analysis using anonymous DNA markers which flank the two previously described loci. Our results demonstrate that the two kindreds, one Austrian-Canadian and one French-Canadian, are linked to SCA-2 (chromosome 12q). Multipoint linkage analysis places the SCA-2 locus within a region of approximately 16 cM between the microsatellites D12S58 and D12S84/D12S105 (odds ratio 2,371:1 in favor of this position). We show that the SCA-2 locus is not a private gene and represents an alternative SCA locus.     

Expanded CAG repeats in spinocerebellar ataxia (SCA1) segregate with distinct haplotypes in South African families

The autosomal dominant late onset spinocerebellar ataxias (SCAs) are genetically heterogeneous. Three genes, SCA1 on 6p, SCA2 on 12q and MJD1 on 14q, have been isolated for SCA1, SCA2 and Machado-Joseph disease (MJD), respectively. In these three autosomal dominant disorders the mutation is an expanded CAG repeat. Evidence for heterogeneity in families not linked to the SCA1, SCA2 and MJD loci is provided by the mapping of SCA loci to chromosomes 16q, 11cen and 3p. A total of 14 South African kindreds and 22 sporadic individuals with SCA were investigated for the expanded SCA1 and MJD repeats. None of the families nor the sporadic individuals showed expansion of the MJD repeat. Expanded SCA1 and CAG repeats were found to cosegregate with the disorder in six of the families tested and were also observed in one sporadic individual with a negative family history of SCA. The use of the microsatellite markers D6S260, D6S89 and D6S274 provided evidence that the expanded SCA1 repeats segregated with three distinct haplotypes in the six families. Use of the highly polymorphic tightly linked microsatellite markers is still important as this stage, particularly where this coincides with the possibility of a homozygous genotype with the trinucleotide repeat marker. Importantly, our molecular findings indicate: (1) an absence of MJD expanded repeats underlying SCA; (2) the major disease in this group is due to mutations in the SCA1 gene; and (3) the familial disorder in the majority population group (i.e. mixed ancestry) in the Western Cape region of South Africa is most likely to be the result of two distinct founder events. Received: 4 November 1996 / Accepted: 6 February 1997     

High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-onset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPLA; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8. We have now (1) assessed the repeat size in a group of patients with ataxia and a large number of controls, (2) examined the intergenerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alleles; large alleles accounted for only0.7% of all normal-size alleles. No expanded alleles (>/=100 CTGs) were found in controls. Expansion of the CTG tract was found in five families with ataxia; expanded alleles (all paternally transmitted) were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.     

Identification of a novel SCA locus ( SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21

We present a linkage study in a four-generation autosomal dominant cerebellar ataxia (ADCA) family of Dutch ancestry. The family shows a clinically and genetically distinct form of ADCA. This neurodegenerative disorder manifests in the family as a relatively mild ataxia syndrome with some additional characteristic symptoms. We have identified a SCA19 locus, approved by the Human Genome Nomenclature Committee that can be assigned to the chromosome region 1p21-q21. Our mutation analysis failed to identify any mutations in the known spinocerebellar ataxia ( SCA) genes and linkage analysis excluded the remaining SCA loci. We therefore performed a genome-wide scan with 350 microsatellite markers to identify the location of the disease-causing gene in this family. Multi-point analysis was performed and exclusion maps were generated. Linkage and haplotype analysis revealed linkage to an interval located on chromosome 1. The estimated minimal prevalence of ADCA in the Netherlands is about 3:100,000. To date, sixteen different SCA loci have been identified in ADCA ( SCA1-8 and SCA10-17). However, mutation analysis has been commercially available only for the SCA1, 2, 3, 6 and 7 genes. So far, a molecular analysis in these SCA genes cannot be made in about one-third of the ADCA families. Thus, the identification of this new, additional SCA19 locus will contribute to expanding the DNA diagnostic possibilities.     

Insertion of expanded CAG trinucleotide repeat motifs into a yeast artificial chromosome containing the human Machado-Joseph disease gene.

Machado-Joseph disease or spinocerebellar ataxia 3 (SCA3) is a progressive neurodegenerative disorder caused by pathological expansion of a trinucleotide repeat motif present within exon 4 of the MJD1 gene. Previous attempts to create a transgenic animal model have failed to produce a neurological deficit truly representative of the disease phenotype. This appears to be the result of inappropriate expression of the mutant protein in neuronal populations generally spared in the disease state. Introduction of a human disease gene in the context of a yeast artificial chromosome clone containing endogenous regulatory elements would enhance the potential for correct tissue/cell-specific expression at physiological levels. We report the introduction of expanded CAG repeat motifs into a 250kb yeast artificial chromosome clone spanning the MJD1 locus using two rounds of homologous recombination. Transformants exhibited both expansions and contractions of the motif with alleles ranging in size from 48 to 84 repeat units. The availability of these clones for modelling of the disease in transgenic animals should allow elucidation of the role of repeat length in the phenotypic spectrum of the disease.     

Parkinsonian phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report

Background  

Machado-Joseph disease (MJD), or spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder of late onset, which is caused by a CAG repeat expansion in the coding region of the ATXN3 gene. This disease presents clinical heterogeneity, which cannot be completely explained by the size of the repeat tract. MJD presents extrapyramidal motor signs, namely Parkinsonism, more frequently than the other subtypes of autosomal dominant cerebellar ataxias. Although Parkinsonism seems to segregate within MJD families, only a few MJD patients develop parkinsonian features and, therefore, the clinical and genetic aspects of these rare presentations remain poorly investigated. The main goal of this work was to describe two MJD patients displaying the parkinsonian triad (tremor, bradykinesia and rigidity), namely on what concerns genetic variation in Parkinson's disease (PD) associated loci (PARK2, LRRK2, PINK1, DJ-1, SNCA, MAPT, APOE, and mtDNA tRNA ^Gln T4336C).     

The hereditary spinocerebellar ataxias in Japan

In Japan, multiple system atrophy (MSA) accounts for 40% of all spinocerebellar ataxias (SCAs) and hereditary disorders account for 30%. Among the latter, autosomal dominant disorders are common and recessive ataxias are rare. Although the frequency of SCA genotypes differs between geographic regions throughout Japan, SCA6, SCA3/MJD, and DRPLA are the three major disorders, while SCA7, SCA8, SCA10, SCA12, and SCA17 are infrequent or almost undetected. SCA1 predominantly occurs in the northern part of Japan. Overall, 20-40% of dominant SCAs are due to unknown mutations. From this cluster, pure cerebellar ataxias linked with the SCA4, SCA14, and SCA16 locus have been isolated. Among the recessive SCAs, patients with AVED and EAOH have been detected. However, FRDA associated with GAA repeat expansion in the frataxin gene has not been reported so far.     

过表达 PINK1改善SCA3/MJD转基因果蝇模型的线粒体功能

脊髓小脑性共济失调3型（SCA3/MJD）,是一种因致病基因MJD1编码区内CAG异常重复扩增所致的常染色体显性遗传迟发性神经退行性疾病. 已知PINK1蛋白可通过抗氧化稳定线粒体,阻止帕金森疾病的发生,但其在SCA3/MJD中的作用尚不清楚. 本文旨在探索过表达PINK1对SCA3/MJD转基因果蝇模型的保护作用.本研究利用Mhc-Gal4启动子表达致病蛋白质片段（MJDtr-Q78）获得SCA3/MJD果蝇模型,分别运用过表达PINK1和RNA干扰PINK1研究其在SCA3/MJD果蝇模型中的功能.结果显示,疾病模型组翅膀异常率增高,线粒体呈过度融合状态,ATP值降低;PINK1 RNA干扰组翅膀异常率明显增高,线粒体呈显著过度融合状态,ATP值明显降低;PINK1过表达组翅膀异常率明显降低,线粒体清晰、完整,ATP值明显升高.本文的结果提示, 过表达PINK1对SCA3/MJD转基因果蝇模型起保护作用,而RNA干扰PINK1表达加重SCA3/MJD转基因果蝇模型病情.PINK1在SCA3/MJD果蝇模型中的功能可能通过改善细胞内线粒体功能实现.     

Familial periodic cerebellar ataxia without myokymia maps to a 19-cM region on 19p13.

Familial periodic cerebellar ataxia (FPCA) is a heterogeneous group of rare autosomal dominant disorders characterized by episodic cerebellar disturbance. A potassium-channel gene (KCNA1) has been found to be responsible for one of its subgroups, familial periodic cerebellar ataxia with myokymia (FPCA/+M; MIM 160120). A different subgroup that is not associated with myokymia (FPCA/-M; MIM 108500) was recently mapped to chromosome 19p. Here we have performed linkage analysis in two large families with FPCA/-M that also demonstrated neurodegenerative pathology of the cerebellum. Three markers in 19p13 gave significant lod scores (> 3.0), while linkage to KCNA1 and three known loci for spinocerebellar ataxia (SCA1, SCA2, and SCA3) was excluded. The highest lod score was obtained with the marker D19S413 (4.4 at recombination fraction 0), and identification of meiotic recombinants in affected individuals placed the locus between the flanking markers D19S406 and D19S226, narrowing the interval to 19 cM. A CAG trinucleotide-repeat expansion was detected in one family but did not cosegregate with the disease.     

Studies of the CAG repeat in the Machado-Joseph disease gene in Taiwan

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration characterized by cerebellar ataxia and pyramidal signs associated in varying degrees with a dystonic-rigid extrapyramidal syndrome or peripheral amyotrophy. Unstable CAG trinucleotide repeat expansion in the MJD gene on the long arm of chromosome 14 has been identified as the pathological mutation for MJD. While investigating the distribution of CAG repeat lengths of the MJD gene in Taiwan’s population, we have identified 18 MJD-affected patients and 12 at-risk individuals in seven families. In addition, we have analyzed the range of CAG repeat lengths in 96 control individuals. The CAG repeat number ranged from 13 to 44 in the controls and 72–85 in the affected and at- risk individuals. Our results indicated that the CAG repeat number was inversely correlated with the age of onset. The differences in CAG repeat length between parent and child and between siblings are greater with paternal transmission than maternal transmission. Our data show a tendency towards the phenomenon of anticipation in the MJD families but do not support unidirectional expansion of CAG repeats during transmission. We also demonstrated that PCR amplification of the CAG repeats in the MJD gene from villous DNA was possible and might prove useful as a diagnostic tool for affected families in the future. Received: 4 December 1996 / Accepted: 5 March 1997     

Mapping of a new autosomal dominant spinocerebellar ataxia to chromosome 22.

The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. The clinical symptoms include cerebellar dysfunction and associated signs from dysfunction in other parts of the nervous system. So far, five spinocerebellar ataxia (SCA) genes have been identified: SCA1, SCA2, SCA3, SCA6, and SCA7. Loci for SCA4 and SCA5 have been mapped. However, approximately one-third of SCAs have remained unassigned. We have identified a Mexican American pedigree that segregates a new form of ataxia clinically characterized by gait and limb ataxia, dysarthria, and nystagmus. Two individuals have seizures. After excluding all known genetic loci for linkage, we performed a genomewide search and identified linkage to a 15-cM region on chromosome 22q13. A maximum LOD score of 4.3 (recombination fraction 0) was obtained for D22S928 and D22S1161. This distinct form of ataxia has been designated "SCA10." Anticipation was observed in the available parent-child pairs, suggesting that trinucleotide-repeat expansion may be the mutagenic mechanism.     

Down-regulation of heat shock protein 27 in neuronal cells and non-neuronal cells expressing mutant ataxin-3

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations. Unstable CAG trinucleotide repeat expansion in the MJD gene has been identified as the pathologic mutation of MJD. In this study, human SK-N-SH neuroblastoma cells stably transfected with full-length MJD with 78 CAG repeats were established. Compared with the parental cells, cells expressing mutant ataxin-3 displayed normal morphology for over 80 generations. Less than 1% of the transfected cells contained nuclear aggregates under basal conditions, indicating that this cellular model represented an early disease stage. While t-butyl hydroperoxide (TBH) was used to assess the oxidative tolerance of cells, the results demonstrated that the transfected cells were more susceptible to low concentrations of TBH than the parental cells. Most interestingly, from 2D gel electrophoresis analysis, we identified that the expression of heat shock protein 27 (HSP27), known as a suppressor of poly(Q)-mediated cell death, dramatically decreased in SK-N-SH cells stably transfected with full-length mutant MJD. The same reduction of HSP27 was further confirmed in lymphoblastoid cells from MJD patients. Our results demonstrated that both neuronal and non-neuronal cells with expanded full-length ataxin-3 revealed reduced protein expression of HSP27. We propose that the reduction of HSP27 in the early stage of the disease plays an important role during cell death process in MJD.     

Analysis of CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci in spinocerebellar ataxia patients and distribution of CAG repeats at the SCA1, SCA2 and SCA6 loci in nine ethnic populations of eastern India

To identify various subtypes of spinocerebellar ataxias (SCAs) among 57 unrelated individuals clinically diagnosed as ataxia patients we analysed the SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci for expansion of CAG repeats. We detected CAG repeat expansion in 6 patients (10.5%) at the SCA1 locus. Ten of the 57 patients (17.5%) had CAG repeat expansion at the SCA2 locus, while four had CAG expansion at the SCA3/MJD locus (7%). At the SCA6 locus there was a single patient (1.8%) with 21 CAG repeats. We have not detected any patient with expansion in the SCA7 and DRPLA loci. To test whether the frequencies of the large normal alleles in SCA1, SCA2 and SCA6 loci can reflect some light on prevalence of the subtypes of SCAs we studied the CAG repeat variation in these loci in nine ethnic sub-populations of eastern India from which the patients originated. We report here that the frequency of large normal alleles (>31 CAG repeats) in SCA1 locus to be 0.211 of 394 chromosomes studied. We also report that the frequency of large normal alleles (>22 CAG repeats) at the SCA2 locus is 0.038 while at the SCA6 locus frequency of large normal alleles (>13 repeats) is 0.032. We discussed our data in light of the distribution of normal alleles and prevalence of SCAs in the Japanese and white populations.