Correction: The Role of the Mammalian DNA End-processing Enzyme Polynucleotide Kinase 3'-Phosphatase in Spinocerebellar Ataxia Type 3 Pathogenesis.

[This corrects the article DOI: 10.1371/journal.pgen.1004749.].

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.

The Cerebellar Cognitive Affective/Schmahmann Syndrome Scale in Spinocerebellar Ataxias.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3.

OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.

Synaptic Loss in Spinocerebellar Ataxia Type 3 Revealed by SV2A Positron Emission Tomography.

BACKGROUND: Severe reduced synaptic density was observed in spinocerebellar ataxia (SCA) in postmortem neuropathology, but in vivo assessment of synaptic loss remains challenging. OBJECTIVE SPINOCEREBELLAR ATAXIA TYPE 3: The objective of this study was to assess in vivo synaptic loss and its clinical correlates in spinocerebellar ataxia type 3 (SCA3) patients by synaptic vesicle glycoprotein 2A (SV2A)-positron emission tomography (PET) imaging. METHODS: We recruited 74 SCA3 individuals including preataxic and ataxic stages and divided into two cohorts. All participants received SV2A-PET imaging using 18 F-SynVesT-1 for synaptic density assessment. Specifically, cohort 1 received standard PET procedure and quantified neurofilament light chain (NfL), and cohort 2 received simplified PET procedure for exploratory purpose. Bivariate correlation was performed between synaptic loss and clinical as well as genetic assessments. RESULTS: In cohort 1, significant reductions of synaptic density were observed in cerebellum and brainstem in SCA3 ataxia stage compared to preataxic stage and controls. Vermis was found significantly involved in preataxic stage compared to controls. Receiver operating characteristic (ROC) curves highlighted SV2A of vermis, pons, and medulla differentiating preataxic stage from ataxic stage, and SV2A combined with NfL improved the performance. Synaptic density was significantly negatively correlated with disease severity in cerebellum and brainstem (International Co-operative Ataxia Rating Scale: ρ ranging from -0.467 to -0.667, P ≤ 0.002; Scale of Assessment and Rating of Ataxia: ρ ranging from -0.465 to -0.586, P ≤ 0.002). SV2A reduction tendency of cerebellum and brainstem identified in cohort 1 was observed in cohort 2 with simplified PET procedure. CONCLUSIONS: We first identified in vivo synaptic loss was related to disease severity of SCA3, suggesting SV2A PET could be a promising clinical biomarker for disease progression of SCA3. © 2023 International Parkinson and Movement Disorder Society.

SCAview: an Intuitive Visual Approach to the Integrative Analysis of Clinical Data in Spinocerebellar Ataxias.

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge.

The S-Factor, a New Measure of Disease Severity in Spinocerebellar Ataxia: Findings and Implications.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by CAG (encoding glutamine) repeat expansion in the Ataxin-3 (ATXN3) gene. We have shown previously that ATXN3-depleted or pathogenic ATXN3-expressing cells abrogate polynucleotide kinase 3'-phosphatase (PNKP) activity. Here, we report that ATXN3 associates with RNA polymerase II (RNAP II) and the classical nonhomologous end-joining (C-NHEJ) proteins, including PNKP, along with nascent RNAs under physiological conditions. Notably, ATXN3 depletion significantly decreased global transcription, repair of transcribed genes, and error-free double-strand break repair of a 3'-phosphate-containing terminally gapped, linearized reporter plasmid. The missing sequence at the terminal break site was restored in the recircularized plasmid in control cells by using the endogenous homologous transcript as a template, indicating ATXN3's role in PNKP-mediated error-free C-NHEJ. Furthermore, brain extracts from SCA3 patients and mice show significantly lower PNKP activity, elevated p53BP1 level, more abundant strand-breaks in the transcribed genes, and degradation of RNAP II relative to controls. A similar RNAP II degradation is also evident in mutant ATXN3-expressing Drosophila larval brains and eyes. Importantly, SCA3 phenotype in Drosophila was completely amenable to PNKP complementation. Hence, salvaging PNKP's activity can be a promising therapeutic strategy for SCA3.

SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F.

Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the in vivo accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.

Blood Neurofilament Light Chain in Genetic Ataxia: A Meta-Analysis.

BACKGROUND: No comprehensive meta-analysis has ever been performed to assess the value of neurofilament light chain (NfL) as a biomarker in genetic ataxia. OBJECTIVE: We conducted a meta-analysis to summarize NfL concentration and evaluate its utility as a biomarker in genetic ataxia. METHODS: Studies were included if they reported NfL concentration of genetic ataxia. We used log (mean ± SD) NfL to describe mean raw value of NfL. The effect size of NfL between genetic ataxia and healthy controls (HC) was expressed by mean difference. Correlation between NfL and disease severity was calculated. RESULTS: We identified 11 studies of 624 HC and 1006 patients, here referred to as spinocerebellar ataxia (SCA1, 2, 3, 6, and 7), Friedreich ataxia (FRDA), and ataxia telangiectasia (A-T). The concentration of blood NfL (bNfL) elevated with proximity to expected onset, and progressively increased from asymptomatic to preclinical to clinical stage in SCA3. Compared with HC, bNfL levels were significantly higher in SCA1, 2, 3, and 7, FRDA, as well as A-T, and the difference increased with the advancing disease in SCA3. bNfL levels correlated with disease severity in SCA3. There was a significant correlation between bNfL and longitudinal progression in SCA3. Additionally, bNfL increased with age in HC, yet this is probably masked by higher disease-related effects on bNfL in genetic ataxia. CONCLUSIONS: bNfL can be used as a potential biomarker to predict disease onset, severity, and progression of genetic ataxia. Reference-value setting of bNfL should be divided according to age. © 2021 International Parkinson and Movement Disorder Society.

Brief assessment of cognitive function in myotonic dystrophy: Multicenter longitudinal study using computer-assisted evaluation.

INTRODUCTION/AIMS: Myotonic dystrophy type 1 (DM1) is known to affect cognitive function, but the best methods to assess central nervous system involvement in multicenter studies have not been determined. In this study our primary aim was to evaluate the potential of computerized cognitive tests to assess cognition in DM1. METHODS: We conducted a prospective, longitudinal, observational study of 113 adults with DM1 at six sites. Psychomotor speed, attention, working memory, and executive functioning were assessed at baseline, 3 months, and 12 months using computerized cognitive tests. Results were compared with assessments of muscle function and patient reported outcomes (PROs), including the Myotonic Dystrophy Health Index (MDHI) and the 5-dimension EuroQol (EQ-5D-5L) questionnaire. RESULTS: Based on intraclass correlation coefficients, computerized cognitive tests had moderate to good reliability for psychomotor speed (0.76), attention (0.82), working memory speed (0.79), working memory accuracy (0.65), and executive functioning (0.87). Performance at baseline was lowest for working memory accuracy (P < .0001). Executive function performance improved from baseline to 3 months (P < .0001), without further changes over 1 year. There was a moderate correlation between poorer executive function and larger CTG repeat size (r = -0.433). There were some weak associations between PROs and cognitive performance. DISCUSSION: Computerized tests of cognition are feasible in multicenter studies of DM1. Poor performance was exhibited in working memory, which may be a useful variable in clinical trials. Learning effects may have contributed to the improvement in executive functioning. The relationship between PROs and cognitive impairment in DM1 requires further study.

Biallelic Intronic AAGGG Expansion of RFC1 is Related to Multiple System Atrophy.

OBJECTIVE: A recessive biallelic repeat expansion, (AAGGG)exp , in the RFC1 gene has been reported to be a frequent cause of late-onset ataxia. For cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), the recessive biallelic (AAGGG)exp genotype was present in ~92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA), which shares a spectrum of symptoms with CANVAS. METHODS: In this study, we screened the pathogenic (AAGGG)exp repeat and 5 other PNRs in 104 Chinese sporadic adult-onset ataxia of unknown aetiology (SAOA) patients, 282 MSA patients, and 203 unaffected individuals. Multiple molecular genetic tests were used, including long-range polymerase chain reaction (PCR), repeat-primed PCR (RP-PCR), Sanger sequencing, and Southern blot. Comprehensive clinical assessments were conducted, including neurological examination, neuroimaging, nerve electrophysiology, and examination of vestibular function. RESULTS: We identified biallelic (AAGGG)exp in 1 SAOA patient and 3 MSA patients. Additionally, 1 MSA patient had the (AAGGG)exp /(AAAGG)exp genotype with uncertain pathogenicity. We also described the carrier frequency for different PNRs in our cohorts. Furthermore, we summarized the distinct phenotypes of affected patients, suggesting that biallelic (AAGGG)exp in RFC1 could be associated with MSA and should be screened routinely in the MSA diagnostic workflow. INTERPRETATION: Our results expanded the clinical phenotypic spectrum of RFC1-related disorders and raised the possibility that MSA might share the same genetic background as CANVAS, which is crucial for re-evaluating the current CANVAS and MSA diagnostic criteria. ANN NEUROL 2020;88:1132-1143.

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.

Intron retention induced by microsatellite expansions as a disease biomarker.

Expansions of simple sequence repeats, or microsatellites, have been linked to ∼30 neurological-neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we test the hypothesis that these GC-rich intronic microsatellite expansions selectively trigger host intron retention (IR). Using DM2, FECD, and C9-ALS/FTD as examples, we demonstrate that retention is readily detectable in affected tissues and peripheral blood lymphocytes and conclude that IR screening constitutes a rapid and inexpensive biomarker for intronic repeat expansion disease.

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.

Body composition in Spinocerebellar ataxia type 3 and 10 patients: Comparative study with control group.

Background: Spinocerebellar ataxias (SCAs) are a group of neurodegenerative genetic diseases characterized by movement disorders that can affect nutritional status and body composition. This study sought to assess body composition in SCA3 and SCA10 patients. Methods: Anthropometric assessments and bioelectric impedance analysis were performed in 46 SCA3 and SCA10 patients and 76 controls of both genders. Results: Of the patients, 69.6% had SCA3 and 58.7% were women. SCA3 patients had significantly lower percentages of body fat (%BF) than controls (15.0 ± 6.1 vs. 20.6 ± 7.1; p=0.014) and (22.4 ± 6.9 vs. 30.1 ± 6.0; p<0.001), respectively. Among the women, there was a statistically significant difference in %BF between SCA3 and SCA10 patients (22.4 ± 6.9 vs. 32.4 ± 4.9; p<0.001). Male and female SCA3 patients had significantly lower fat-free mass (FFM) than controls [50.6 kg (46.9-54.7) vs. 58.6 kg (52.6-63.9); p=0.001] and [38.2 kg (35.1-42.6) vs. 42.8 kg (39.7-46.1); p=0.004], respectively. Male SCA10 patients also had lower FFM than controls [51.2 kg (47.1-55.4) vs. (52.6-63.9); p=0.008]. Female SCA10 patients had significantly higher FFM than controls and SCA3 patients [45.0 kg (43.3-45.6) vs. 42.8 kg (39.7-46.1); p=0.004] and [45.0 kg (43.3-45.6) vs. 38.2 kg (35.1-42.6); p=0.004], respectively. There was moderate correlation (-0.42) between disease duration and muscle mass (MM), and weak (-0.38) between SARA (Scale for the Assessment and Rating of Ataxia) and MM in SCA3. In SCA10, there was no significant correlation between these variables. Conclusion: Female SCA3 patients had more body composition changes than female SCA10 patients, mainly in relation to FFM. SCA3 and SCA10 patients need nutritional follow-up to minimize body compartment changes.

Intravenously Administered Novel Liposomes, DCL64, Deliver Oligonucleotides to Cerebellar Purkinje Cells.

Cerebellar Purkinje cells (PCs) show conspicuous damages in many ataxic disorders. Targeted delivery of short nucleic acids, such as antisense oligonucleotides, to PCs may be a potential treatment for ataxic disorders, especially spinocerebellar ataxias (SCAs), which are mostly caused by a gain of toxic function of the mutant RNA or protein. However, oligonucleotides do not cross the blood-brain barrier (BBB), necessitating direct delivery into the central nervous system (CNS) through intra-thecal, intra-cisternal, intra-cerebral ventricular, or stereotactic parenchymal administration. We have developed a novel liposome (100 to 200 nm in diameter) formulation, DCL64, composed of dipalmitoyl-phosphatidylcholine, cholesterol, and poloxamer L64, which incorporates oligonucleotides efficiently (≥ 70%). Confocal microscopy showed that DCL64 was selectively taken up by brain microvascular endothelial cells by interacting with low-density lipoprotein receptor (LDLr) family members on cell surface, but not with other types of lipid receptors such as caveolin or scavenger receptor class B type 1. LDLr family members are implicated in brain microvascular endothelial cell endocytosis/transcytosis, and are abundantly localized on cerebellar PCs. Intravenous administration of DCL64 in normal mice showed distribution of oligonucleotides to the brain, preferentially in PCs. Mice that received DCL64 showed no adverse effect on hematological, hepatic, and renal functions in blood tests, and no histopathological abnormalities in major organs. These studies suggest that DCL64 delivers oligonucleotides to PCs across the BBB via intravenous injection with no detectable adverse effects. This property potentially makes DCL64 particularly attractive as a delivery vehicle in treatments of SCAs.

Olfactory Function in SCA10.

Although the main clinical manifestations of spinocerebellar ataxias (SCAs) result from damage of the cerebellum, other systems may also be involved. Olfactory deficits have been reported in other types of ataxias, especially in SCA3; however, there are no studies on olfactory deficits in SCA type 10 (SCA10). To analyze olfactory function of SCA10 patients compared with that of SCA3, Parkinson's, and healthy controls. Olfactory identification was tested in three groups of 30 patients (SCA10, SCA3, and Parkinson's disease (PD)) and 44 healthy controls using the Sniffin' Sticks (SS16) test. Mean SS16 score was 11.9 ± 2.9 for the SCA10 group, 12.3 ± 1.9 for the SCA3 group, 6.6 ± 2.8 for the PD group, and 12.1 ± 2.0 for the control group. Mean SS16 score for the SCA10 group was not significantly different from the scores for the SCA3 and control groups but was significantly higher than the score for the PD group (p < 0.001) when adjusted for age, gender, and history of smoking. There was no association between SS16 scores and disease duration in the SCA10 or SCA3 groups or number of repeat expansions. SS16 and Mini Mental State Examination scores were correlated in the three groups: SCA10 group (r = 0.59, p = 0.001), SCA3 group (r = 0.50, p = 0.005), and control group (r = 0.40, p = 0.007). We found no significant olfactory deficits in SCA10 in this large series.

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.

Tremor in the Degenerative Cerebellum: Towards the Understanding of Brain Circuitry for Tremor.

Cerebellar degenerative pathology has been identified in tremor patients; however, how the degenerative pathology could contribute to tremor remains unclear. If the cerebellar degenerative pathology can directly drive tremor, one would hypothesize that tremor is likely to occur in the diseases of cerebellar ataxia and follows the disease progression in such disorders. To further test this hypothesis, we studied the occurrence of tremor in different disease stages of classical cerebellar degenerative disorders: spinocerebellar ataxias (SCAs). We further separately analyzed postural tremor and rest tremor, two forms of tremor that both involve the cerebellum. We also explored tremor in different subtypes of SCAs. We found that 18.1% of SCA patients have tremor. Interestingly, SCA patients with tremor have worse ataxia than those without tremor. When stratifying patients into mild, moderate, and severe disease stages according to the severity of ataxia, moderate and severe SCA patients more commonly have tremor than those with mild ataxia, the effect most prominently observed in postural tremor of SCA3 and SCA6 patients. Finally, tremor can independently contribute to worse functional status in SCA2 patients, even after adjusting for ataxia severity. Tremor is more likely to occur in the severe stage of cerebellar degeneration when compared to mild stages. Our results partially support the cerebellar degenerative model of tremor.