Spinocerebellar ataxias in Asia: Prevalence, phenotypes and management.

This paper reviews and summarizes three main aspects of spinocerebellar ataxias (SCA) in the Asian population. First, epidemiological studies were comprehensively reviewed. Overall, the most common subtypes include SCA1, SCA2, SCA3, and SCA6, but there are large differences in the relative prevalence of these and other SCA subtypes between Asian countries. Some subtypes such as SCA12 and SCA31 are rather specific to certain Asian populations. Second, we summarized distinctive phenotypic manifestations of SCA patients of Asian origin, for example a frequent co-occurrence of parkinsonism in some SCA subtypes. Lastly, we have conducted an exploratory survey study to map SCA-specific expertise, resources, and management in various Asian countries. This showed large differences in accessibility, genetic testing facilities, and treatment options between lower and higher income Asian countries. Currently, many Asian SCA patients remain without a final genetic diagnosis. Lack of prevalence data on SCA, lack of patient registries, and insufficient access to genetic testing facilities hamper a wider understanding of these diseases in several (particularly lower income) Asian countries.

SCA2 in the Indian population: Unified haplotype and variable phenotypic patterns in a large case series.

BACKGROUND: Spinocerebellar ataxia-2 is one of the most prevalent SCA type across the world and one of the commonest in India. We aimed to characterize SCA2 patients both clinically and genetically (ATXN2-CAG repeats and its haplotypic background). METHODS: A total of 436 SCA2 patients were recruited consecutively comprising individuals of multiple ethnicities and two large multigenerational families. A detailed clinical evaluation and genetic analysis for CAG repeat length estimation and two marker based haplotype analysis [rs695871 and rs695872 located 177 bp and 106 bp upstream of CAG sequence in Exon 1 of ATXN2] was performed. RESULTS: Generalized limb ataxia and slow saccades were prevalent features in majority of our patients, while hyporeflexia and extrapyramidal features were less commonly observed manifestations. Slow ocular saccades, upper limb ataxia and tremor showed significant associations with age of onset, CAG repeat length and disease duration. We observed a 100% association of C-C haplotype with the expanded ATXN2 repeats. CONCLUSION: This study represents the largest study of SCA2 Indian patients that highlights the clinico-genetic manifestations and haplotype analysis. A significant proportion of patients have not shown the characteristic slow saccades and hyporeflexia thus indicating the influences of other factors in modulation of the disease which warrants further investigations. The observation of CC haplotype in all our SCA2 patients indicates a common origin across all Indian sub populations and that also indicate a common global founder event in the past.

Founder Effects of Spinocerebellar Ataxias in the American Continents and the Caribbean.

Spinocerebellar ataxias (SCAs) comprise a heterogeneous group of autosomal dominant disorders. The relative frequency of the different SCA subtypes varies broadly among different geographical and ethnic groups as result of genetic drifts. This review aims to provide an update regarding SCA founders in the American continents and the Caribbean as well as to discuss characteristics of these populations. Clusters of SCAs were detected in Eastern regions of Cuba for SCA2, in South Brazil for SCA3/MJD, and in Southeast regions of Mexico for SCA7. Prevalence rates were obtained and reached 154 (municipality of Báguano, Cuba), 166 (General Câmara, Brazil), and 423 (Tlaltetela, Mexico) patients/100,000 for SCA2, SCA3/MJD, and SCA7, respectively. In contrast, the scattered families with spinocerebellar ataxia type 10 (SCA10) reported all over North and South Americas have been associated to a common Native American ancestry that may have risen in East Asia and migrated to Americas 10,000 to 20,000 years ago. The comprehensive review showed that for each of these SCAs corresponded at least the development of one study group with a large production of scientific evidence often generalizable to all carriers of these conditions. Clusters of SCA populations in the American continents and the Caribbean provide unusual opportunity to gain insights into clinical and genetic characteristics of these disorders. Furthermore, the presence of large populations of patients living close to study centers can favor the development of meaningful clinical trials, which will impact on therapies and on quality of life of SCA carriers worldwide.

Haplotype Study in SCA10 Families Provides Further Evidence for a Common Ancestral Origin of the Mutation.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and epilepsy. The disease is caused by a pentanucleotide ATTCT expansion in intron 9 of the ATXN10 gene on chromosome 22q13.3. SCA10 has shown a geographical distribution throughout America with a likely degree of Amerindian ancestry from different countries so far. Currently available data suggest that SCA10 mutation might have spread out early during the peopling of the Americas. However, the ancestral origin of SCA10 mutation remains under speculation. Samples of SCA10 patients from two Latin American countries were analysed, being 16 families from Brazil (29 patients) and 21 families from Peru (27 patients) as well as 49 healthy individuals from Indigenous Quechua population and 51 healthy Brazilian individuals. Four polymorphic markers spanning a region of 5.2 cM harbouring the ATTCT expansion were used to define the haplotypes, which were genotyped by different approaches. Our data have shown that 19-CGGC-14 shared haplotype was found in 47% of Brazilian and in 63% of Peruvian families. Frequencies from both groups are not statistically different from Quechua controls (57%), but they are statistically different from Brazilian controls (12%) (p < 0.001). The most frequent expanded haplotype in Quechuas, 19-15-CGGC-14-10, is found in 50% of Brazilian and in 65% of Peruvian patients with SCA10. These findings bring valuable evidence that ATTCT expansion may have arisen in a Native American chromosome.

Spinocerebellar ataxia type-7: Report of a family in Northwest Nigeria.

Spinocerebellar ataxia type-7 (SCA7) is a cytosine-adenine-guanine (CAG) repeat polyglutamine disorder characterized by progressive degeneration of the cerebellum, brainstem, spinal cord, and retina. Clinical features include progressive ataxia, visual loss, pyramidal weakness, sensory impairment, and dementia. Among the autosomal dominant cerebellar ataxias, SCA7 is relatively common in Scandinavia and South Africa but rare worldwide and is not previously reported in Nigeria. In this study, we describe a family in Katsina State, Northwest Nigeria, with nine individuals across three generations affected by the SCA7 phenotype. Analysis of DNA from proband and two affected relatives revealed 39 CAG repeat expansions in one allele of ataxin-7 in each.

Genetic and clinical analysis of spinocerebellar ataxia type 36 in Mainland China.

Spinocerebellar ataxia type 36 (SCA36) is a new SCA subtype recently reported in Japanese and Spanish pedigrees. To assess the frequency and clinical characteristics of SCA36 in patients from Mainland China, we combined the repeat-primed polymerase chain reaction method and Southern blot analysis to detect the GGCCTG hexanucleotide repeats of NOP56 in 364 probands with SCA, 126 probands with hereditary spastic paraplegia and 99 probands with amyotrophic lateral sclerosis (ALS). Systematic and targeted clinical evaluations and investigations were conducted in the SCA36 patients. As a result, eight autosomal dominant spinocerebellar ataxia (ADCA) pedigrees (a total of 13 patients) and one sporadic SCA (S-SCA) patient were identified as SCA36 in the SCA cohort, accounting for approximately 1.60% of the cases in the ADCA group and 0.32% of those in the S-SCA group in Mainland China. The characteristics include late onset and slow progression accompanied by acoustic impairments and 'possible' ALS phenotype in patients from Mainland China.

Spinocerebellar ataxia type 10 in the South of Brazil: the Amerindian-Belgian connection / Ataxia espinocerebelar tipo 10 no sul do Brasil: a conexão Ameríndia-Belga

Spinocerebellar ataxia type 10 (SCA10) is a rare form of autosomal dominant ataxia found predominantly in patients from Latin America with Amerindian ancestry. The authors report the history of SCA10 families from the south of Brazil (the states of Paraná and Santa Catarina), emphasizing the Belgian-Amerindian connection.

A ataxia espinocerebellar tipo 10 (AEC10) é uma forma rara de ataxia cerebelar autossômica dominante, encontrada predominantemente em pacientes da América Latina, de origem Ameríndia. Os autores relatam a história de famílias com AEC10 do sul do Brasil (estados do Paraná e Santa Catarina), enfatizando a conexão Ameríndia-Belga.

Spinocerebellar ataxia type 10 in the South of Brazil: the Amerindian-Belgian connection.

Spinocerebellar ataxia type 10 (SCA10) is a rare form of autosomal dominant ataxia found predominantly in patients from Latin America with Amerindian ancestry. The authors report the history of SCA10 families from the south of Brazil (the states of Paraná and Santa Catarina), emphasizing the Belgian-Amerindian connection.

Evidence for a common founder effect amongst South African and Zambian individuals with Spinocerebellar ataxia type 7.

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by the expansion of a CAG repeat within the ataxin 7 gene, leading to a pathogenic polyglutamine tract within the ataxin 7 protein. SCA7 patients suffer from progressive cerebellar ataxia and macular degeneration. SCA7 is considered to be rare, although founder effects have been reported in South Africa, Scandinavia and Mexico. The South African SCA7-associated haplotype has not been investigated in any other populations, and there have been limited reports of SCA7 patients from other African countries. Here, we describe the first two ethnic Zambian families with confirmed SCA7. Haplotype analysis showed that the South African SCA7 haplotype alleles were significantly associated with the pathogenic expansion in affected Zambian individuals, providing strong evidence for a shared founder effect between South African and Zambian SCA7 patients.

Spinocerebellar ataxia type 10 in Peru: the missing link in the Amerindian origin of the disease.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia with a variable presentation of epileptic seizures, which is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in ATXN10 on 22q13.3. Herein, we report the first description of SCA10 in a Peruvian family, supporting the Amerindian origin of SCA10 and the Panamerican geographical distribution of the disease in North, Central and South America. Moreover, the presence of an interruption motif in the SCA10 expansion along with epileptic seizures in this family supports the correlation between the two, as seen in other families. Finally, this is the first SCA10 patient ever observed outside of America, specifically in Italy. Since this patient is a Peruvian immigrant of Amerindian ancestry, our case report highlights the growing need for awareness amongst clinicians of seemingly geographically restricted rare diseases.

Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes.

Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.

Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia.

IMPORTANCE: The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described. OBJECTIVE: To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTS: A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. MAIN OUTCOMES AND MEASURES: Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. RESULTS: We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. CONCLUSIONS AND RELEVANCE: We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome ß-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

Founder effect and ancestral origin of the spinocerebellar ataxia type 7 (SCA7) mutation in Mexican families.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disease characterized by progressive cerebellar ataxia and macular degeneration causing progressive blindness. It accounts for 1 to 11.6 % of spinocerebellar ataxias (SCAs) cases worldwide and for 7.4 % of SCA7 cases in Mexico. We identified a cluster of SCA7 families who resided in a circumscribed area of Veracruz and investigated whether the high incidence of the disease in this region was due to a founder effect. A total of 181 individuals from 20 families were studied. Four microsatellite markers and one SNP flanking the ATNX7 gene were genotyped and the ancestral origin and local ancestry analysis of the SCA7 mutation were evaluated. Ninety individuals from 19 families had the SCA7 mutation; all were found to share a common haplotype, suggesting that the mutation in these families originated from a common ancestor. Ancestral origin and local ancestry analysis of SCA7 showed that the chromosomal segment containing the mutation was of European origin. We here present evidence strongly suggesting that the high frequency of SCA7 in Veracruz is due to a founder effect and that the mutation is most likely of European origin with greatest resemblance to the Finnish population.

Diversity of ARSACS mutations in French-Canadians.

BACKGROUND: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. METHODS: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. RESULTS: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. CONCLUSIONS: The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

Investigation of SCA10 in the Cypriot population: further exclusion of SCA dynamic repeat mutations.

Autosomal dominant cerebellar ataxias (ADCAs) encompass a heterogeneous group of rare diseases that affect the cerebellum and its connections. The most common forms have been associated with dynamic mutations while some rarer forms with conventional mutations. Studies in different populations revealed differences in their relative frequencies both within and between the studied populations, showing that the frequencies are depended on ethnic and geographical factors. Previous investigation of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in the Cypriot population, revealed no pathogenic expansion in the Cypriot SCA patients. We hereby present our recent investigation of the SCA10 pentanucleotide repeat expansion. Forty-two ascertained Cypriot sporadic ataxia patients, the index case from 1 ADCA and 14 ARCA families and a cohort of normal population individuals were included in the study. All our patients have normal range ATXN10 gene ATTCT repeat numbers (10-19). In the normal population group, repeat lengths ranged from 11 to 20 with the 14 repeats allele being the most frequent. Therefore, all currently established dynamic repeat SCA mutations are absent from the Cypriot population, indicating distinct genetic causes.

Inherited polyglutamine spinocerebellar ataxias in South Africa.

OBJECTIVE: To determine the frequency and distribution of polyglutamine spinocerebellar ataxias (SCAs) from referrals over a 24-year period to the National Health Laboratory Service (NHLS) in South Africa (SA). METHODS: Paper-based clinical reports in the University of Cape Town laboratory and the NHLS electronic patient record database spanning a 24-year period were mined for information regarding the molecular diagnosis, ethnicity and CAG repeat length for individuals referred for molecular genetic testing for the polyglutamine SCAs. RESULTS: SCA1 and 7 are the most frequent types of polyglutamine SCA in the SA patient population, followed by SCA2, 3 and 6. SCA1 is the most common type in the coloured, white and Indian populations, whereas the majority of indigenous black African patients are affected with SCA7 and 2. Of individuals tested, 22% were found to be positive for one of the polyglutamine SCAs. CONCLUSION: Although trends in the frequency and distribution of the polyglutamine SCAs in SA have not changed significantly since our previous study in 2003, they differ remarkably from those reported elsewhere, and reflect the unique genetic and demographic background of SA. The provision of accurate and complete patient information and family history is crucial to the diagnostic process, to enable comprehensive epidemiological studies and assist in developing therapeutic and patient management strategies.

Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis.

OBJECTIVE: To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS. DESIGN: Case-control study. SETTING: France and Quebec, Canada. PARTICIPANTS: A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin. RESULTS: We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases. CONCLUSIONS: Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.

[Polynucleotide repeat expansion of nine spinocerebellar ataxia subtypes and dentatorubral-pallidoluysian atrophy in healthy Chinese Han population].

OBJECTIVE: To assist the establishment of platform and provide the reference standard for mutation detection in spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7, 8, 10, 12, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) in Chinese Han population. METHODS: The nucleotide repeat numbers of the 9 SCA subtypes and DRPLA were detected using fluorescence-PCR and capillary gel electrophoresis technique in 300 healthy Chinese Han individuals. RESULTS: Among the 300 healthy controls, the range of the CAG trinucleotide repeat number was 17 to 35 in SCA1, 14-28 in SCA2, 13-41 in SCA3/MJD, 4-16 in SCA6, 5-17 in SCA7, 5-21 in SCA12, 23-41 in SCA17, and 12-33 in DRPLA; and the range of CTA/CTG trinucleotide repeat number on SCA8 locus was 12-43 and the range of ATTCT pentanucleotide repeat number on SCA10 locus was 9-32. Of which, the 12 CTA/CTG repeats of SCA8, 9 ATTCT repeats of SCA10, 23 CAG repeats of SCA17 were the shortest normal repeat number, while the 41 CAG repeats of SCA3/MJD, 32 CAG repeats of SCA10 were the largest normal number that have not been reported. CONCLUSION: The normal ranges of polynucleotide repeats of different subtypes of SCA vary with geographical areas and ethnicities. It might be associated with the genetic and ethnic backgrounds. This is the first normal reference standard of polynucleotide repeat number of these ten SCA subtypes in Chinese Han.

[Simulation of the distribution of spinocerebellar ataxia type 1 in Yakut populations: model parameters and results of simulation].

Demographic and clinical genetic parameters used for simulation modeling of the prevalence of spinocerebellar ataxia type 1 (SCA1) in Yakut populations are described. Demographic parameters of simulated populations and the clinical genetic characteristics of carriers of the SCA1 mutant allele in them have been compared with actual data on Abyisky and Ust-Aldansky uluses of the Republic of Sakha (Yakutia). The results of a series of simulation experiments (without migration or spontaneous mutagenesis) agree with the conclusion that the high prevalence of rate of spinocerebellar ataxia type 1 in Yakut populations may be maintained because of their specific demographic structure. Prediction of the disease prevalence has shown that it will take about 1290 years for natural selection to eliminate the mutation from the population. If medical genetic counseling (MGC) is offered to 1% of the carriers of the mutation, this period will be reduced to 200 years.