Spinocerebellar ataxia type 17 in the Yugoslav population

OBJECTIVES: (1) Analysis of Spinocerebellar ataxia type 17 (SCA17) locus in a group of ataxic patients excluded on other known SCAs; (2) assessment of frequency distributions of SCA17 alleles in the Yugoslav population. MATERIAL AND METHODS: Study includes 115 non-related Yugoslav patients belonging to autosomal-dominant cerebellar ataxias or to sporadic idiopathic adult-onset ataxia and 115 controls. Analysis of SCA17 locus was performed using polymerase chain reaction. RESULTS: None of the analyzed patients show the presence of mutation in SCA17 locus. In the group of patients 12 different alleles in the range of 30-42 repeats were observed, while in healthy population eight alleles in the range of 30-40 repeats were detected. CONCLUSION: (1) None of 115 non-related Yugoslav ataxic patients belong to any known SCAs nor to DRPLA gene; (2) the distribution of SCA17 alleles in the Yugoslav population is consistent with the distribution in other populations and (3) the paucity of alleles with more than 39 repeats could suggest that SCA17 is very rare in the Yugoslav population.     

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.     

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.     

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.     

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.     

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.     

Autosomal dominant spinocerebellar ataxias: an Asian perspective

Autosomal dominant cerebellar ataxias, frequently referred to as spinocerebellar ataxias (SCAs) have been under intense scientific research limelight since expansions of coded CAG trinucleotide repeats were demonstrated to cause several dominantly inherited SCAs. The number of new SCA loci has expanded dramatically in recent years. At least ten genes have been identified for SCAs 1, 2, 3, 6, 7, 8, 10, 12, 17, dentatorubral-pallidoluysian atrophy (DRPLA), and six loci responsible for SCAs 4, 5, 11,13, 14, and 16 have been mapped. Genetic testing is essential for diagnosis due to the overlapping and varied phenotypic features of the different SCAs. While there is no effective treatment available, genetic counseling is important for addressing the many ethical, social, legal, and psychological issues facing SCA patients. Researchers have recently provided valuable information on the pathogenesis of the disease and hopefully a cure will be available in the near future.     

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.     

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.     

Genotypes at the APOE and SCA2 loci do not predict the course of multiple sclerosis in patients of Portuguese origin

Multiple sclerosis (MS) is a demyelinating disease that affects about one in 500 young Europeans. In order to test the previously proposed influence of the APOE and SCA2 loci on susceptibility to MS, we studied these loci in 243 Portuguese patients and 192 healthy controls and both parents of 92 patients. We did not detect any significant difference when APOE and SCA2 allele frequencies of cases and controls were compared, or when we compared cases with different forms of the disease. Disequilibrium of transmission was tested for both loci in the 92 trios, and we did not observe segregation distortion. To test the influence of the APOE epsilon4 and SCA2 22 CAGs alleles on severity of disease, we compared age at onset and progression rate between groups with and without those alleles. We did not observe an association of the epsilon4 or the 22 CAGs alleles with rate of progression in our total patient population; allele epsilon4 was associated with increased rate of progression of MS in a subset of patients with less than 10 years of the disease. However, globally in the Portuguese population, the APOE and SCA2 genes do not seem to be useful in the clinical context as prognostic markers of this disorder.     

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.     

Frequency of spinocerebellar ataxia mutations in the Kinki district of Japan

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

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

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

Genetic etiology of a Chinese ataxia cohort: Expanding the mutational spectrum of hereditary ataxias

IntroductionHereditary ataxias demonstrate a high degree of clinical and genetic heterogeneity. Understanding the genetic etiology of hereditary ataxias is crucial for genetic counseling and clinical management.MethodsThe clinical and genetic data of patients with familial or sporadic ataxias who referred to our tertiary medical center were retrospectively analyzed. Probands in this study underwent SCA repeat expansion panel firstly to screen for repeat expansion SCAs; those with negative results had NGS-targeted panels or WES testing to detect conventional mutations.ResultsA total of 223 patients were enrolled from 206 families. 5 kinds of coexisting SCA repeat expansions were observed (SCA3/SCA17, SCA3/SCA8, SCA2/SCA8, SCA3/SCA12 and SCA8/SCA12) in 12 patients from 8 families, among which SCA2/SCA8, SCA8/SCA12 and SCA3/SCA12 were reported for the first time. The coexistence of expanded SCA3 with SCA17 alleles was the most common in our study. NGS identified pathogenic/likely pathogenic variants in 12 ataxia causative genes in 13 probands. Spastic paraplegia ataxia was the most common diagnosis. Six novel mutations were detected in five ataxia-related genes.ConclusionCoexistence may not specific to a certain SCA subtype and the frequency might have been underestimated before. SCA repeat expansion panel should be considered in patients with overlapping SCA features. In addition, our study broadened the conventional mutation spectrum in ataxia-related genes. These results facilitate a better understanding of the genetic basis for hereditary ataxias.     

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

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

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.     

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。     

Absence of spinocerebellar ataxia type 3/Machado–Joseph disease within ataxic patients in the Czech population

Although spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease is the most common type of SCA worldwide, we did not identify any cases of the disease amongst SCA patients in the Czech population. It has been proposed that the prevalence of large normal alleles correlates with the frequency of various types of SCA. We have therefore attempted to resolve the absence of SCA3 in our population by investigating, within 204 normal chromosomes, the frequency and nature of CAG repeats as well as two intragenic polymorphisms. We found that large normal alleles with more than 33 CAG repeats were observed at a frequency of only 0.49%. Whereas most of the expanded alleles worldwide have the CA haplotype, this was the least common (5.4%) variant observed in our study, although it was associated with a larger mean CAG repeat length (26.9). We postulate that the absence of SCA3 in the Czech population might be explained by the lack of large normal alleles and consequently a relatively small reservoir for aberrant CAG expansions at the SCA3 locus.     

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.