Extended haplotype with rs41524547-G defines the ancestral origin of SCA10.

Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35 kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia-a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.

ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850-4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.

Mechanistic and Therapeutic Insights into Ataxic Disorders with Pentanucleotide Expansions.

Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from Alu elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms complex secondary and tertiary structures that can give rise to RNA-mediated toxicity, including protein sequestration, pentapeptide synthesis, and mRNA dysregulation. Since several of these diseases have recently been discovered, our understanding of their pathological mechanisms is limited, and their therapeutic interventions underexplored. This review aims to highlight new in vitro and in vivo insights into these incurable diseases.

Balance and physical functioning in Spinocerebellar ataxias 3 and 10.

OBJECTIVES: Limitations of functional capacity and balance are common features of the natural history of spinocerebellar ataxias (SCA). However, their onset and progression patterns differ according to subtype. The aim of our study was to compare physical functionality and balance parameters in SCA10 and SCA3 patients, correlating with clinical variables. MATERIALS & METHODS: Cross-sectional study evaluating ninety-five SCA patients (60 with SCA3 and 35 with SCA10) with validated scales for functional independence, balance and the severity of signs and symptoms. RESULTS: The groups were similar in terms of age and gender, and results were adjusted for age at symptom onset. The SCA10 patients had better results for balance and functional independence (p < 0.007). They also had lower scores for disease severity (p < 0.0002) and the subitems gait (p < 0.0005), posture (p < 0.0021) and sitting balance (p < 0.0008). Symptom progression in both groups was similar for patients with a disease duration of up to ten years, but there was a more marked decline in SCA3 patients after this period. CONCLUSIONS: We have shown that disease progression as assessed by balance and physical functioning is slower in SCA10 patients than SCA3 patients, particularly after 10 years of disease. These findings are important as they can help to characterize the disease, assisting in the development of new therapies and rehabilitation programs.

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.

Is fatigue an important finding in patients with spinocerebellar ataxia type 10 (SCA10)?

Spinocerebellar ataxia type 10 (SCA10) is a rare dominantly inherited neurodegenerative disorder characterized by cerebellar ataxia, dysarthria, ocular dysmetria, and seizures in some populations. Fatigue has been described in SCA1, SCA3, but has not been objectively investigated in SCA10. Our aim is to investigate the presence and related causal factors of fatigue among SCA10 patients. Twenty-eight patients with SCA10 and matched healthy controls were included and assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Modified Fatigue Impact Scale (MFIS), Beck Inventory Depression (BDI) and Epworth Sleepiness Scale (ESS). Fatigue was evidenced in 32% of SCA10 versus 3.6% for the control group (p = 0.005). The following independent variables were not significant predictors for MFIS-BR: duration of disease, SARA and BSS. Age at onset of disease (r = -0.307, p = 0.021) and EDS (r = -0.347, p = 0.014) were mild to moderate predictors of fatigue. Similar to other SCAs, fatigue is common in SCA10 patients, suggesting a possible role of a common topographic degenerative pattern in its pathophysiology.

Spinocerebellar ataxia type 10 (SCA10): Mutation analysis and common haplotype based inference suggest its rarity in Indian population.

Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant cerebellar ataxia caused by nucleotide ATTCT expansion in ATXN10 gene. SCA10 has been reported in patients of cerebellar ataxia from Amerindian/Latin America and in East Asian ancestry. A common founder has been ascribed to the origin of ATTCT repeat expansion mutation in both the population. Here we present our investigation of the SCA10 pentanucleotide repeat expansion in 461 SCA patients of the Indian population. The analysis of multi-ethnic at-risk haplotype C-(ATTCT)n-GGC was performed using genotype data of various ethnic population included in the 1000 Genomes Project (KGP) to infer the prevalence of at-risk haplotype in the Indian populations. Unsurprisingly, none of the patient's DNA samples with (ATTCT)n expansion was observed in pathological range, however, the observed normal range of (ATTCT)n was 8-22 repeats, suggesting very rare or absence of the occurrence of SCA10 in Indian SCA patients. The at-risk haplotype, CGGC was found to be the most prevalent haplotype across different populations and no segregation of CGGC haplotype with large normal or small normal ATTCT repeats length was observed. However, on extended haplotype analysis, some lineage of CGGC with a flanking divergence at 5' end was observed specifically in the American or East Asian population but not in other population in KGP dataset. Together, these evidence points towards the absence of SCA10 in Indian population and haplotype-based analysis also suggests its occurrence to be rare in South Asian, European and African population. Further investigations are required to establish the present finding. SIGNIFICANCE: The implications of the findings of this study are 1.) For the diagnostic work-up of SCAs in the Indian population and to decide upon inclusion of SCA10 in panel based genetic investigations even for Indians living abroad. 2.) The haplotype based inference of its presumptive prevalence through the estimation of at-risk haplotype using population genetics approach (South-Asians as the background) allowed us to estimate the possible absence of SCA10 in Indian population. SCA10 is a rare autosomal dominant cerebellar ataxia mostly reported among SCA patients from Latin America and recently described in East Asia population. The genetic study of SCA10 performed in the unrelated Indian spinocerebellar ataxia patients with heterogeneous ethnicity confirmed its absence from the Indian population and that conforms to population genetic based inference of its rarity or absence. 3.) This approach may be adopted for the screening of other subtypes of SCAs, i.e. other rare SCAs e.g. SCA31, SCA36, and SCA37.

Extensive cerebellar and thalamic degeneration in spinocerebellar ataxia type 10.

INTRODUCTION: Spinocerebellar ataxia type 10 (SCA10) is a hereditary neurodegenerative disorder caused by repeat expansions in the ATXN10 gene. Patients present with cerebellar ataxia frequently accompanied by seizures. Even though loss of cerebellar Purkinje neurons has been described, its brain degeneration pattern is unknown. Our aim was to characterize the gray and white matter degeneration patterns in SCA10 patients and the association with clinical features. METHODS: We enrolled 18 patients with molecular diagnosis of SCA10 and 18 healthy individuals matched for age and sex. All participants underwent brain MRI including high-resolution anatomical and diffusion images. Whole-brain Tract-Based Spatial Statistics (TBSS) and Voxel-Based Morphometry (VBM) were performed to identify white and grey matter degeneration respectively. A second analysis in the cerebellum identified the unbiased pattern of degeneration. Motor impairment was assessed using the SARA Scale. RESULTS: TBSS analysis in the patient group revealed white matter atrophy exclusively in the cerebellum. VBM analysis showed extensive grey matter degeneration in the cerebellum, brainstem, thalamus, and putamen. Significant associations between cerebellar degeneration and SARA scores were found. Additionally, degeneration in thalamic GM and WM in the cerebellar lobule VI were significantly associated with the presence of seizures. CONCLUSION: The results show that besides cerebellum and brainstem, brain degeneration in SCA10 includes predominantly the putamen and thalamus; involvement of the latter is strongly associated with seizures. Analysis of the unbiased degeneration pattern in the cerebellum suggests lobules VIIIb, IX, and X as the primary cerebellar targets of the disease, which expands to the anterior lobe in later stages.

Clinical and Genetic Evaluation of Spinocerebellar Ataxia Type 10 in 16 Brazilian Families.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder in which patients have a slowly progressive cerebellar ataxia, with dysarthria, dysphagia, and epilepsy. The aims of this study were to characterize the phenotypic expression of SCA10 and to examine its genotype-phenotype relationships. Ninety-one Brazilian patients with SCA10 from 16 families were selected. Clinical and epidemiological data were assessed by a standardized protocol, and severity of disease was measured by the Scale for the Assessment and Rating of Ataxia (SARA). The mean age of onset of symptoms was 34.8 ± 9.4 years. Sixty-two (68.2%) patients presented exclusively with pure cerebellar ataxia. Only 6 (6.6%) of the patients presented with epilepsy. Patients with epilepsy had a mean age of onset of symptoms lower than that of patients without epilepsy (23.5 ± 15.5 years vs 35.4 ± 8.7 years, p = 0.021, respectively). All cases of intention tremor were in women from one family. This family also had the lowest mean age of onset of symptoms, and a higher percentage of SCA10 cases in women. There was a positive correlation between duration of disease and severity of ataxia (rho = 0.272, p = 0.016), as quantified by SARA. We did not find a statistically significant correlation between age of onset of symptoms and expansion size (r = - 0.163, p = 0.185). The most common clinical presentation of SCA10 was pure cerebellar ataxia. Our data suggest that patients with epilepsy may have a lower age of onset of symptoms than those who do not have epilepsy. These findings and the description of a family with intention tremor in women with earlier onset of symptoms draw further attention to the phenotypic variability of SCA10.

Spinocerebellar ataxias in Southern Brazil: Genotypic and phenotypic evaluation of 213 families.

OBJECTIVES: To describe and correlate the genotype and phenotype of patients diagnosed with SCAs in southern of Brazil. PATIENTS AND METHODS: Data were collected from the records of our ataxia outpatient clinic. We included 460 patients from 213 families, who were divided into four groups: SCA3, SCA10, Other SCAs and Undetermined. RESULTS: The most frequent type was SCA3 (45.7%), followed by SCA10 (18.3%), SCA2 (6.5%), SCA1 (4.3%), SCA7 (1.8%), and SCA6 (0.65%). The Undetermined group represented 22.8% of all patients. We observed a high frequency of SCA10 when compared to data from other studies, which can be explained by a founder effect in our region. Statistically significant differences were found for several symptoms when comparing SCA groups, especially lid retraction (p < 0.001), ophthalmoplegia (p < 0.001), visual loss (p < 0.001) and slow saccades (p < 0.001) which may help clinically differentiate SCAs and allow neurologists to request the right confirmatory genetic test and define prognosis. Also, the prevalence of epilepsy in SCA10 patients was lower than usual (4.8%), suggesting a genetic variation of the disease. CONCLUSION: Although SCA3 remains the most common, we observed a high frequency of SCA10 in our region. In addition, some symptoms and signs might help differentiate the SCAs.

Sleep disorders in spinocerebellar ataxia type 10.

As sleep disturbances have been reported in spinocerebellar ataxias (SCAs), including types SCA1, SCA2, SCA3, SCA6 and SCA13, identification and management of these disturbances can help minimise their impact on SCA patients' overall body functions and quality of life. To our knowledge, there are no studies that investigate sleep disturbances in SCA10. Therefore, the aim of this study was to assess sleep disturbances in patients with SCA10. Twenty-three SCA10 patients and 23 healthy controls were recruited. Patients were evaluated in terms of their demographic and clinical data, including disease severity (Scale for the Assessment and Rating of Ataxia, SARA) and excessive daytime sleepiness (Epworth Sleepiness Scale, ESS), and underwent polysomnography. SCA10 patients had longer rapid eye movement (REM) sleep (p = .04) and more REM arousals than controls (p< .0001). There was a correlation of REM sleep onset with the age of onset of symptoms (r = .459), and with disease duration (r = -.4305). There also was correlation between the respiratory disturbance index (RDI) and SARA (r = -.4013), and a strong indirect correlation between arousal index and age at onset of symptoms (r = -.5756). In conclusion, SCA10 patients had sleep abnormalities that included more REM arousals and higher RDI than controls. Our SCA10 patients had sleep disorders related to shorter disease duration and lower severity of ataxia, in a pattern similar to that of other neurodegenerative diseases.

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.

A Comparative Optical Coherence Tomography Study of Spinocerebellar Ataxia Types 3 and 10.

SCA3 presents with a CAG expansion at 14q24.3-q32 while SCA10 shows an ATTCT expansion at 22q13-qter. SCA10 seems to be less aggressive than SCA3. For an in vivo, noninvasive approach of the correlation between central nervous system and clinical evolution, we can use optic coherence tomography (OCT) to measure retinal nerve fiber (RNFL) and ganglion cell layer (GCL) thickness. To describe OCT findings in SCA10, correlate it with expansion size and disease severity and compare with those of SCA3. We analyzed ten individuals with SCA3 and nine with SCA10 recruited from the neurology service of Hospital de Clínicas of Paraná-Brazil. They were submitted to OCT and clinical evaluation using SARA score. Expansion size, demographic data, time from disease onset, and age of onset were collected. We found no correlation between size of expansion, SARA, and RNFL or GCL thickness in SCA10. RNFL seemed to be thicker in SCA10 (p > 0.05). GCL thickness, SARA, median age, and time from disease onset did not differ between groups. SCA10 individuals had an earlier disease onset. In SCA3, there was a negative correlation between SARA and RNFL thickness in nasal area. To the best of our knowledge, this is the first paper assessing retinal changes by OCT in individuals with SCA10. The lack of correlation between disease progression, age, and time since onset supports the anatomopathological findings which suggest SCA10 is less aggressive than other SCAs. The findings in SCA3 are in accordance with the literature.

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-10 with paranoid schizophrenia.

Spino-cerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder that is characterized by cerebellar ataxia, seizures and nystagmus with a fragmented pursuit. Schizophrenia has been reported with SCAs 1 and 2 yet in SCA 10, psychiatric manifestations are uncommon. We report a Hispanic family involving a father and his four children with SCA10 genetic mutation. Two of his children, a 20-year-old female and a 23-year-old male, presented with gradually progressive spino-cerebellar ataxia and paranoid schizophrenia. Neurological examination revealed ocular dysmetria, dysdiadokinesia, impaired finger-to-nose exam, gait ataxia and hyperreflexia in both the cases. Additionally, they had a history of psychosis with destructive behavior, depression and paranoid delusions with auditory hallucinations. Serology and CSF studies were unremarkable and MRI brain revealed cerebellar volume loss. Ultimately, a test for ATAXIN-10 mutation was positive thus confirming the diagnosis of SCA10 in father and his four children. We now endeavor to investigate the association between schizophrenia and SCA10.

Spinocerebellar ataxias: genotype-phenotype correlations in 104 Brazilian families

OBJECTIVE: Spinocerebellar ataxias are neurodegenerative disorders involving the cerebellum and its connections. There are more than 30 distinct subtypes, 16 of which are associated with an identified gene. The aim of the current study was to evaluate a large group of patients from 104 Brazilian families with spinocerebellar ataxias. METHODS: We studied 150 patients from 104 families with spinocerebellar ataxias who had received molecular genetic testing for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, and dentatorubral-pallidoluysian atrophy. A statistical analysis of the results was performed using basic descriptive statistics and the correlation coefficient (r), Student's t-test, chi-square test, and Yates' correction. The statistical significance level was established for p-values <0.05. RESULTS: The results show that the most common subtype was spinocerebellar ataxia 3, which was followed by spinocerebellar ataxia 10. Moreover, the comparison between patients with spinocerebellar ataxia 3, spinocerebellar ataxia 10, and other types of spinocerebellar ataxia revealed distinct clinical features for each type. In patients with spinocerebellar ataxia 3, the phenotype was highly pleomorphic, although the most common signs of disease included cerebellar ataxia (CA), ophthalmoplegia, diplopia, eyelid retraction, facial fasciculation, pyramidal signs, and peripheral neuropathy. In patients with spinocerebellar ataxia 10, the phenotype was also rather distinct and consisted of pure cerebellar ataxia and abnormal saccadic eye movement as well as ocular dysmetria. Patients with spinocerebellar ataxias 2 and 7 presented highly suggestive features of cerebellar ataxia, including slow saccadic ocular movements and areflexia in spinocerebellar ataxia 2 and visual loss in spinocerebellar ataxia 7. CONCLUSIONS: Spinocerebellar ataxia 3 was the most common subtype examined, followed by spinocerebellar ataxia 10. Patients with spinocerebellar ataxia 2 and 7 demonstrated highly suggestive features, whereas the phenotype of spinocerebellar ataxia 3 patients was highly pleomorphic and spinocerebellar ataxia 10 patients exhibited pure cerebellar ataxia. Epilepsy was absent in all of the patients with spinocerebellar ataxia 10 in this series.