中国汉族人群SCA1、2、3、6、7、8、10、12、17亚型和齿状核-红核-苍白球-路易体萎缩亚型频率分布

目的 研究中国汉族人群中脊髓小脑性共济失调(SCAs)不同基因亚型的频率分布.方法 运用聚合酶链反应、变性聚丙烯酰胺凝胶电泳、Southern blot、T载体克隆重组DNA技术结合直接测序等技术对559例临床诊断为SCA的患者(363例常染色体显性遗传先证者,196例散发患者)进行了SCA1、SCA2、SCA3/MJD、SCA6、SCA7、SCA8、SCA10、SCA12、SCA17和齿状核-红核-苍白球-路易体萎缩(DRPLA)致病基因多核苷酸病理重复突变检测分析.结果 在363个常染色体显性遗传的SCA(AD-SCA)家系中,发现有15个SCA1家系(4.13%),26个SCA2家系(7.16%),187个SCA3/MJD家系(51.52%),6个SCA6家系(1.65%),7个SCA7家系(1.93%),1个SCA12家系(0.28%)和1个SCA17家系(0.28%),120个SCA家系未明确基因分型(33.06%);在196例散发SCA患者中,发现有2例SCAI患者(1.02%),3例SCA2患者(1.53%),15例SCA3/MJD患者(7.65%),3例SCA6患者(1.53%),173例SCA患者未明确基因分型(88.27%);未发现SCA8、SCA10和DRPLA型患者.结论 在中国汉族人群中SCA3/MJD为最常见的SCA亚型,其次为SCA2、SCA1、SCA7和SCA6,SCA12和SCA17比较少见,SCA8、SCA10和DRPLA罕见,SCA17亚型为国内首次报道.部分AD-SCA家系存在其他致病基因的作用,大部分散发SCA患者除遗传因素外还存在其他致病因素.     

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.     

Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families

BACKGROUND: Autosomal dominant cerebellar ataxias are a clinical and genetically heterogeneous group of progressive neurodegenerative diseases, at present associated with 22 loci (spinocerebellar ataxia [SCA] 1-SCA8, SCA10-SCA19, SCA21, SCA22, fibroblast growth factor 14 [FGF14]-SCA, and dentatorubral-pallidoluysian atrophy [DRPLA]). The relevant gene has been identified in 12 cases (SCA1-3, SCA6-8, SCA10, SCA12, FGF14, and DRPLA), and in all but the recently identified SCA14, SCA17, PRKCG and FGF14 genes, the defect consists of the expansion of a short nucleotide repeat. OBJECTIVES: To investigate the relative prevalence of SCA1-3, SCA6-8, SCA10, SCA12, and SCA17 gene expansions in Italian families with hereditary ataxia, specifically to verify the occurrence of SCA10, SCA12, and SCA17 in Italy; and to analyze samples from probands with negative test results at the initial screening by means of the repeat expansion detection technique to identify CAG/CTG expansions in novel loci.Patients Two hundred twenty-five unrelated Italian index cases with hereditary ataxia, most (n = 183) of whom presented with a clear dominantly transmitted trait. RESULTS: We found that SCA1 and SCA2 gene mutations accounted for most cases (21% and 24%, respectively). We found SCA3, SCA6, SCA7, SCA8, and SCA17 to be very rare (approximately 1% each), and no case of SCA10 or SCA12 was identified. Half of the index cases (113/225) were negative for expansions in the known SCA genes. Repeat expansion detection analysis performed on 111 of these cases showed a CAG/CTG repeat expansion of at least 50 triplets in 22 (20%). Twenty-one of 22 expansions could be attributed to length variation at 2 polymorphic loci (expanded repeat domain CAG/CTG 1 [ERDA1] or CTG repeat on chromosome 18q21.1 [CTG18.1]). In 1 patient, the expansion was assigned to the DRPLA gene. CONCLUSIONS: The distribution of SCA1-3 and SCA6-7 gene mutations is peculiar in Italy. We found a relatively high frequency of SCA1 and SCA2 gene expansions; SCA3, SCA6, and SCA7 mutations were rare, compared with other European countries. No SCA10 or SCA12 and only a few SCA8 (2/225) and SCA17 (2/225) families were detected. In patients negative for defects in known SCA genes, repeat expansion detection data strongly suggest that, at least in our population, CAG/CTG expansions in novel genes should be considered an unlikely cause of the SCA phenotype.     

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.     

Frequency analysis and clinical characterization of different types of spinocerebellar ataxia in Serbian patients.

The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ethnic groups, presumably due to a founder effect. We investigated the relative prevalence of SCA1-3, 6-8, 12, 17; dentate-rubro-pallidoluysian atrophy; and Friedreich's ataxia (FRDA) in Serbian patients with adult-onset (>20 years of age) hereditary and sporadic SCAs, and compared clinical features of patients with genetically confirmed SCAs. A total of 108 patients from 54 families (38 apparently dominant [ADCA] and 16 apparently recessive) with adult-onset hereditary ataxia and 75 apparently sporadic patients were assessed. Of 38 families with ADCA, 13 (34%) were positive for an expansion in an SCA1 and 5 families (13%) for an expansion in an SCA2 allele. In 20 families (53%), no expansions have been identified in any of the analyzed genes. Gaze palsy, spasticity, and hyperreflexia were significantly more common in SCA1, whereas slow saccades, hypotonia, hyporeflexia, and dystonia prevailed in SCA2 patients. Among the 16 families with an apparently recessive mode of ataxia inheritance, 4 (25%) were identified as having the FRDA mutation. Ataxia-causing mutations were identified in 8 (10.6%) of patients with apparently sporadic adult-onset ataxia.     

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.     

Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families

Two hundred and forty-eight patients from 116 Italian families with dominant ataxia were studied for CAG expansion within SCA1, 2, 3, 6, 7 (spinocerebellar ataxia) and DRPLA (dentatorubropallidoluysian atrophy) genes. Fifty-six percent of the families originated from Southern, 19% from Central and 25% from Northern Italy. SCA2 was the commonest mutation, accounting for 47% of the families, followed by SCA1 (24%), SCA6 (2%), SCA7 (2%) and DRPLA (1%). No SCA3 family was found. Twenty-four percent of the families carried a still unidentified mutation. When occurrence of mutations was evaluated according to the geographic origin, SCA1 was the commonest in Northern (72%), whereas SCA2 was prevalent (63%) in Southern Italy. The number of CAG repeats in SCA1 normal alleles was higher in Northern than in Central-Southern Italy.     

Dentatorubro-Pallidoluysian Atrophy (DRPLA) among 700 Families with Ataxia in Brazil

Dentatorubro-pallidoluysian atrophy (DRPLA) is a spinocerebellar ataxia (SCA) very rare in non-Asian populations. To date, DRPLA was undetected in the general Brazilian population. Adult-onset ataxic patients have been recruited from several Brazilian neurology and neurogenetics centers. CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17 and DRPLA associated genes, and ATTCT expansions at SCA10 gene were studied. A single DRPLA case detected is reported. Proband was a 69-year-old Brazilian woman of mixed ancestry, with a late-onset pure ataxia: her alleles at the associated gene, ATN1, presented 14/52 CAG repeats. History of gait ataxia and dementia was observed in two out of six siblings but was absent in her parents. This was the single DRPLA diagnosis obtained from 700 Brazilian unrelated cases with adult-onset ataxia, 487 of them with clear autosomal dominant inheritance. DRPLA accounted for 0.14% of all adult-onset ataxia cases and for 0.2% of families with autosomal dominant inheritance. Normal CAG repeats at ATN1 had a median (range) of 14 (5–20) repeats in other 410 Brazilian chromosomes. DRPLA is quite rare in Brazilian SCA families, which is consistent with the lack of large normal alleles in our population.     

Adult onset spinocerebellar ataxia in a Canadian movement disorders clinic

BACKGROUND: The spinocerebellar ataxias (SCAs) are a genetically and clinically heterogeneous group of neurodegenerative disorders. Relative frequencies vary within different ethnic groups and geographical locations. OBJECTIVES: 1) To determine the frequencies of hereditary and sporadic adult onset SCAs in the Movement Disorders population; 2) to assess if the fragile X mental retardation gene 1 (FMR1) premutation is found in this population. METHODS: A retrospective chart review of individuals with a diagnosis of adult onset SCA was carried out. Testing for SCA types 1, 2, 3, 6, 7, and 8, Dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich ataxia and the FMR1 expansion was performed. RESULTS: A total of 69 patients in 60 families were identified. Twenty-one (35%) of the families displayed autosomal dominant and two (3.3%) showed autosomal recessive (AR) pattern of inheritance. A positive but undefined family history was noted in nine (15%). The disorder appeared sporadic in 26 patients (43.3%). In the AD families, the most common mutation was SCA3 (23.8%) followed by SCA2 (14.3%) and SCA6 (14.3%). The SCA1 and SCA8 were each identified in 4.8%. FA was found in a pseudodominant pedigree, and one autosomal recessive pedigree. One sporadic patient had a positive test (SCA3).Dentatorubral-pallidoluysian atrophy and FMR1 testing was negative. CONCLUSION: A positive family history was present in 53.3% of our adult onset SCA patients. A specific genetic diagnosis could be given in 61.9% of dominant pedigrees with SCA3 being the most common mutation, followed by SCA2 and SCA6. The yield in sporadic cases was low. The fragile X premutation was not found to be responsible for SCA.     

The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population

OBJECTIVES: Frequency and distribution of dominant ataxias caused by dynamic mutations may vary in different populations, which has been explained on the basis of relative frequency of predisposing normal alleles. The aim of the study was to evaluate the occurrence of spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA) in Finland, and to investigate the role of predisposing normal alleles in a genetically homogenous population. MATERIAL AND METHODS: Mutation analyses for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA and frataxin genes were performed for 251 unrelated Finnish patients who presented with progressive ataxia disorder. RESULTS: Expansions of SCA1, SCA2, SCA6, SCA7, SCA8, and SCA17 genes were detected in 2, 1, 1, 7, 22, and 1 patients, respectively. Altogether, 39 and 7% of dominant and sporadic SCA patients, respectively, harboured expansions at some of the investigated loci. Normal variation, collected from 477 to 502 chromosomes at each disease loci, revealed that Finns were different from the Japanese but largely similar to other Caucasians. CONCLUSIONS: Lack of SCA3 and excess of SCA8 are characteristic to the Finnish population. Homozygosity for the SCA8 expansion increases penetrance. Frequencies of large normal alleles at the SCA loci predict poorly prevalence of the respective diseases in Finland. Prioritization in DNA testing, based on ethnic origin and geographical location, is recommendable in Finland, and analogous approach may be applied to other countries as well.     

The occurrence of spinocerebellar ataxias caused by dynamic mutations in Polish patients

Background and purposeAutosomal dominant spinocerebellar ataxias (SCAs) belong to a group of neurodegenerative disorders usually of adult age at onset. Predominant clinical features are progressive ataxia, dysarthria, as well as pyramidal signs and polyneuropathy. Molecular analysis allows particular types of SCA to be distinguished. Genetic tests are applied in 10 types of SCA resulting from dynamic mutations: SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, SCA17 and DRPLA.Material and methodsDNA samples from 1598 patients with ataxia symptoms were analysed to establish the number of CAG/CTG repeats in respective genes excluding SCA10.ResultsWe diagnosed 224 cases of SCA1 (120 families) and 49 cases of SCA2 (23 families). Moreover, presymptomatic testing was done in 85 individuals from SCA1 families and for 21 cases from SCA2 families. An increased number of CTG repeats in the SCA8 gene was observed in 14 families and in 3 families a rare type of SCA, SCA17, was detected.ConclusionsOur data suggest that frequencies of some types of SCA in Poland are different from those in other European countries, with irregular distribution within the country. The most frequent types are SCA1 and SCA2. A striking feature of the Polish population is the lack of SCA3 – the most frequent type in Western Europe.     

Multiplex families with multiple system atrophy

BACKGROUND: Multiple system atrophy (MSA) has been considered a sporadic disease, without patterns of inheritance. OBJECTIVE: To describe the clinical features of 4 multiplex families with MSA, including clinical genetic aspects. DESIGN: Clinical and genetic study. SETTING: Four departments of neurology in Japan. Patients Eight patients in 4 families with parkinsonism, cerebellar ataxia, and autonomic failure with age at onset ranging from 58 to 72 years. Two siblings in each family were affected with these conditions. MAIN OUTCOME MEASURES: Clinical evaluation was performed according to criteria by Gilman et al. Trinucleotide repeat expansion in the responsible genes for the spinocerebellar ataxia (SCA) series and for dentatorubral-pallidoluysian atrophy (DRPLA) was evaluated by polymerase chain reaction. Direct sequence analysis of coding regions in the alpha-synuclein gene was performed. RESULTS: Consanguineous marriage was observed in 1 of 4 families. Among 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The most frequent phenotype was MSA with predominant parkinsonism, observed in 5 patients. Six patients showed pontine atrophy with cross sign or slitlike signal change at the posterolateral putaminal margin or both on brain magnetic resonance imaging. Possibilities of hereditary ataxias, including SCA1 (ataxin 1, ATXN1), SCA2 (ATXN2), Machado-Joseph disease/SCA3 (ATXN1), SCA6 (ATXN1), SCA7 (ATXN7), SCA12 (protein phosphatase 2, regulatory subunit B, beta isoform; PP2R2B), SCA17 (TATA box binding protein, TBP) and DRPLA (atrophin 1; ATN1), were excluded, and no mutations in the alpha-synuclein gene were found. CONCLUSIONS: Findings in these multiplex families suggest the presence of familial MSA with autosomal recessive inheritance and a genetic predisposition to MSA. Molecular genetic approaches focusing on familial MSA are expected to provide clues to the pathogenesis of MSA.     

Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus

BACKGROUND: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. OBJECTIVE: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. PATIENTS AND METHODS: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. RESULTS: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. CONCLUSIONS: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.     

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.     

High prevalence of spinocerebellar ataxia type 1 (SCA1) in an isolated region of Japan

Autosomal dominant cerebeller ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders that differ in both the clinical manifestations and modes of inheritance. At present, eight different genes causing ADCAs have been found: spinocerebeller ataxia type 1 (SCA1), SCA2, SCA3/Machado-Joseph disease (MJD), SCA6, SCA7, SCA8, SCA12 and dentatorubropallidoluysian atrophy (DRPLA). The relative prevalence of each mutation varies according to race and native place. We studied 117 unrelated ADCA families that originated from the Tohoku District in the northernmost part of Honshu Island in Japan (mainly Miyagi Prefecture in the central part of Tohoku District). The SCA1 mutation was the most frequent among the known disorders (24.8% of all such families). The relative prevalence of SCA1 in the Tohoku District is very high compared with the values already reported from other regions in the world. Because the population of this area had seldom moved, the alleles with SCA1 mutations (including alleles with an intermediate CAG repeat number) are assumed to have been present in this area for a long time.     

Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6.

BACKGROUND: Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders. The mutational basis for most of these disorders is an expanded CAG repeat sequence within the coding regions of the genes involved. The prevalence of SCA in the ethnic Chinese on Taiwan remains unclear. Moreover, there has been no report of SCA type 6 (SCA6) among Chinese people. OBJECTIVES: To characterize the prevalence of SCA in the ethnic Chinese on Taiwan, and to specifically characterize Chinese patients with SCA6 in terms of clinical and molecular features. PATIENTS AND METHODS: Using a molecular approach, we investigated SCA in 74 Taiwanese families with dominantly inherited ataxias and in 49 Taiwanese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 12 patients from 8 families and in 2 sporadic cases. Furthermore, the intragenic polymorphic marker D19S1150 was amplified by polymerase chain reaction to analyze for linkage disequilibrium. RESULTS: Machado-Joseph disease-SCA3 was the most common type of autosomal dominant SCA in the Taiwanese cohort, accounting for 35 cases (47.3%), followed by SCA6 (8 [10.8%]), SCA2 (8 [10.8%]), SCA1 (4 [5.4%]), SCA7 (2 [2.7%]), dentatorubropallidoluysian atrophy (1 [1.4%]), and SCA8 (0%). The genes responsible for 16 (21.6%) of Taiwanese dominantly inherited SCA cases remain to be determined. Among the 49 patients with sporadic ataxias in the present series, 2 (4.1%) were found to harbor SCA6 mutations. In the families with SCA6, we found significant anticipation in the absence of genetic instability on transmission, indicating that some other mechanism might account for the anticipation. The same frequent allele of the intragenic DNA marker (D19S1150) was shared by 7 of 10 Taiwanese families with SCA6. CONCLUSIONS: Although SCA6 has, so far, not been reported in mainland Chinese, we found a geographic cluster of families with SCA6 on Taiwan. Genotyping studies suggest a founder effect in the Taiwanese patients with SCA6.     

Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India

Objective: Spinocerebellar ataxia type 2 (SCA2) has been reported as the commonest dominant hereditary ataxia in India. However, India is an ethnically and religiously diverse population. Previous studies have not clearly indicated exact ethnic and religious origins, and must therefore be interpreted with caution. The purpose of this study was to determine the prevalence of different SCA mutations in a relatively homogeneous population from eastern India.

Methods: We identified 28 families with autosomal dominant cerebellar ataxia from eastern India. Each underwent full clinical evaluation and were analysed for the presence of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and SCA17 mutations. In addition, haplotype analysis was carried out in seven of the 16 families with SCA2.

Results: Seven patients from four (14%) families were positive for an expansion in SCA1 and 26 patients from 16 (57%) families were positive for an expansion in SCA2. No mutations were detected in the remaining eight families (29%). Most of the SCA1 and SCA2 families were Hindu from the state of Bihar. Five out of 26 SCA2 patients in this study did not have slow saccades. In addition, four of seven SCA1 patients had slow saccades. We found an association between the SCA2 CAG repeat expansion and the 285 base pair (bp) allele of microsatellite marker D12S1672, and also data supportive of the association between the expansion and the 225 bp allele of D12S1333, which has been previously described.

Conclusions: We conclude that (1) although slow ocular saccades are highly suggestive of SCA2, that they are not universal, nor are they exclusive to this disorder and (2) SCA2 is likely to be the commonest dominant ataxia in eastern India, with further evidence for a founder effect.

     

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