n-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway.

Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule n-butylidenephthalide (n-BP). n-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the n-BP treatment may be effective in treating SCA3 disease. n-BP treatment led to the depletion of mutant ATXN3 with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, n-BP treated animal and HEK-293GFP-ATXN3-84Q cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the n-BP-induced elimination of aggregates. Collectively, n-BP shows promising results for the treatment of SCA3.

Neurodegenerative phosphoprotein signaling landscape in models of SCA3.

Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disorder resulting from an aberrant expansion of a polyglutamine stretch in the ataxin-3 protein and subsequent neuronal death. The underlying intracellular signaling pathways are currently unknown. We applied the Reverse-phase Protein MicroArray (RPMA) technology to assess the levels of 50 signaling proteins (in phosphorylated and total forms) using three in vitro and in vivo models expressing expanded ataxin-3: (i) human embryonic kidney (HEK293T) cells stably transfected with human ataxin-3 constructs, (ii) mouse embryonic fibroblasts (MEF) from SCA3 transgenic mice, and (iii) whole brains from SCA3 transgenic mice. All three models demonstrated a high degree of similarity sharing a subset of phosphorylated proteins involved in the PI3K/AKT/GSK3/mTOR pathway. Expanded ataxin-3 strongly interfered (by stimulation or suppression) with normal ataxin-3 signaling consistent with the pathogenic role of the polyglutamine expansion. In comparison with normal ataxin-3, expanded ataxin-3 caused a pro-survival stimulation of the ERK pathway along with reduced pro-apoptotic and transcriptional responses.

Which Factors in Spinocerebellar Ataxia Type 3 Patients Are Associated with Restless Legs Syndrome/Willis-Ekbom Disease?

There is evidence of a higher prevalence of restless legs syndrome/Willis-Ekbom disease (RLS/WED) in individuals with spinocerebellar ataxia type 3 (SCA3), although the factors underlying this association remain unknown. The present study aimed to determine the prevalence of RLS/WED in SCA3 patients and to investigate which factors of SCA3 patients are associated with presence of RLS/WED. From February to August of 2006, we carried out clinical interviews in 40 controls and 40 SCA3 patients, diagnosed and followed up at Faculty of Medicine of Ribeirão Preto, University of São Paulo. Twenty-seven SCA3 patients were submitted to a detailed clinical protocol, electroneuromyography, blood work up, polysomnography (PSG), suggested immobilization test (SIT), and magnetic resonance image (MRI). RLS/WED was found in 27.5% of SCA3 patients and 2.5% of normal controls (p = 0.003). The factors related to RLS/WED in SCA3 patients were female gender, age at start of the symptoms of ataxia after 30 years, presence of peripheral neuropathy, and documented iron deficiency. Among SCA3 patients, those with RLS showed higher values of maximal discomfort level and discomfort level sum compared to non-RLS individuals on SIT. There is a relation between RLS/WED and SCA3, which seems to be resultant of different factors whose identification could improve the quality of assistance to those patients as well as to promote a better comprehension of the pathophysiology of both RLS/WED and SCA3.

Static and Dynamic Ocular Motor Abnormalities as Potential Biomarkers in Spinocerebellar Ataxia Type 3.

While dynamic ocular motor abnormalities (e.g., gaze-evoked nystagmus (GEN), low optokinetic nystagmus (OKN), pursuit and vestibulo-ocular reflex (VOR) gains, and dysmetric saccades) have been shown to be potential biomarkers in spinocerebellar ataxia type 3 (SCA3), the value of static abnormalities (e.g., convergent [esodeviation] and divergent strabismus [exodeviation]) is unknown. Moreover, studies on dynamic abnormalities in SCA3 usually do not take into account the existence of potential abduction-adduction asymmetries in patients with degenerative ataxia. Thirty-eight patients with genetically confirmed SCA3 (24 females; mean age ± SD, 49.8± 12.2 years) and 22 healthy controls (12 females, p = 0.589; mean age ± SD, 50.7± 12.5 years, p = 0.651) underwent clinical and video-oculographic assessment. A p value < 0.002 (between- and within-group analyses) and < 0.001 (correlation analysis) was considered significant. Patients showed larger esodeviation at distance (p < 0.001), became more esodeviated in lateral gaze (p < 0.001), and their near exodeviation correlated with scale for the assessment and rating of ataxia (SARA) score (p = 0.004). Pursuit, OKN, and VOR gains were lower in patients, both for their adducting and abducting components (p < 0.001). Saccades showed higher velocities (p < 0.001), abducting saccades showed lower amplitude (p < 0.001), and adducting saccades tended to show greater vertical bias (p = 0.018) in patients. Abducting saccades showed relatively lower velocity (p < 0.001) and lower amplitude (p = 0.015) than abducting saccades within patients. All dynamic ocular motor abnormalities except saccades correlated with SARA score, CAG repeat number, and/or disease duration (p < 0.001). Static and dynamic ocular motor abnormalities are potential biomarkers in SCA3. SCA3 studies using saccades should take into account the existence of potential abduction-adduction asymmetries.

Gray matter atrophy patterns within the cerebellum-neostriatum-cortical network in SCA3.

OBJECTIVE: To investigate the spatial patterns and the probable sequences of gray matter atrophy in spinocerebellar ataxia type 3 (SCA3). METHODS: A total of 47 patients with SCA3 and 49 age- and sex-matched healthy controls participated in the study. High-resolution T1-weighted MRI were examined in all participants. We used the causal network of structural covariance (CasCN) to identify the sequence of gray matter atrophy patterns. This was achieved by applying Granger causality analysis to a gray matter atrophy staging scheme performed by voxel-based morphometry from the network level. RESULTS: Participants in the premanifest stage of the disease showed the presence of focal gray matter atrophy in the vermis. As the disease duration increased, there was progressive gray matter atrophy in the cerebellar, neostriatum, frontal lobe, and parietal lobe. The patients with SCA3 also showed proximal and distal cortical atrophy sequences exerting from the vermis to the regions mainly located in the cerebellum-neostriatum-cortical network. CONCLUSION: Our results, although preliminary in nature, indicate that the gray matter atrophy in SCA3 lies and extends to involve more regions according to distinct anatomical patterns, mainly in the cerebellum-neostriatum-cortical network. These findings advance our understanding on the natural history of structural damage in SCA3, while confirming known clinical features. This could provide unique insight into the ordered sequential process of regional brain atrophy that targets a particular network.

Genotype-phenotype correlation in 667 Chinese families with spinocerebellar ataxia type 3.

INTRODUCTION: Due to diverse symptoms of spinocerebellar ataxia type 3 (SCA3) and the high prevalence of SCA3 in China, a more in-depth study of Chinese SCA3 patients in a large cohort is well merited. METHODS: During the last 10 years, 730 patients and 133 premanifest individuals from 667 SCA3 families genetically confirmed to have SCA3 were enrolled from three leading academic hospitals in China. The clinical profile and genotype-phenotype correlation were analyzed. RESULTS: A quadratic equation best explained the relationship between the logarithmically transformed age at onset (AAO) and expanded CAG repeats (expCAGs) (r2 = 0.634, p < 0.001). The expCAG and AAO in Asian populations and western populations were compared with the Chinese population. SCA3 individuals had shorter normal CAG repeats (norCAGs) than healthy controls (Mann-Whitney, p < 0.0001). Most (92.1%) SCA3 patients had gait-ataxia onset. Their AAO and expCAGs were not significantly different from SCA3 patients with non-gait-ataxia onset. Limb ataxia and pyramidal impairment occurred less in patients with disease duration >10 years. Intriguingly, onset after parturition happened in 10 female patients with the AAO of 26.7 ± 4.3 years and the expCAG of 77.4 ± 1.4 repeats. Five out of 12 patients with subtype V and larger expCAGs (78.8 ± 4.8 repeats) suffered from spastic gait initially, and 10 out of 12 showed no limb ataxia. Nystagmus happened most frequently (10.5%) in premanifest individuals. CONCLUSION: We demonstrated the genotype-phenotype correlation in the largest cohort of SCA3 individuals to date, and interestingly found some new phenomena in Chinese SCA3 individuals.

Association of serum neurofilament light and disease severity in patients with spinocerebellar ataxia type 3.

OBJECTIVE: To investigate serum neurofilament light protein (sNfL) levels in patients with spinocerebellar ataxia type 3 (SCA3) and to determine whether they are associated with disease severity. METHODS: This cross-sectional study enrolled 185 healthy controls and 235 ATXN3 mutation carriers (17 asymptomatic stage, 20 preclinical stage, and 198 ataxic stage). We measured sNfL levels with the single molecule array (Simoa) platform. Clinical disease severity was assessed using the Scale of Assessment and Rating of Ataxia (SARA) and the Inventory of Nonataxia Signs (INAS). In a subgroup of 50 ataxic stage patients, we further evaluated the gray matter volume and the integrity of white matter fibers by MRI. RESULTS: sNfL concentrations were elevated in asymptomatic, preclinical, and ataxic ATXN3 mutation carriers compared to controls (12.18 [10.20-13.92], 21.84 [18.37-23.45], 36.06 [30.04-45.90], and 8.24 [5.92-10.84] pg/mL, median [interquartile range], respectively, p < 0.001). sNfL correlated with SARA (r = 0.406, 95% confidence interval [CI] 0.284-0.515, p < 0.0001) and INAS (r = 0.375, 95% CI 0.250-0.487, p < 0.0001), and remained significant after adjustment for age and CAG repeats. In addition, we observed negative correlations of the sNfL with gray matter volume in the left precentral gyrus and the left paracentral lobule as well as with the mean diffusivity in widespread white matter tracts. CONCLUSION: Our results demonstrate that sNfL levels are increased in SCA3 and are associated with clinical disease severity, which supports sNfL as a biomarker for disease severity in SCA3. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with SCA3, sNfL elevations are associated with clinical disease severity.

Quantitative assessment of postural instability in spinocerebellar ataxia type 3 patients.

OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is one of the most common hereditary neurodegenerative diseases, with balance instability as main symptom. Balance quantification is crucial for evaluating the efficacy of therapeutic interventions. However, balance evaluation in SCA3 is often subject to bias. Here, we aimed to quantitatively evaluate postural instability and investigate the relationship between postural instability and clinical characteristics in SCA3 patients. METHODS: Sixty-two SCA3 patients and 62 normal controls were recruited, and their postural balance was measured using a posturographic platform. Principal component analysis was performed as data reduction to identify postural instability factors. Multivariable linear regression was used to investigate potential risk factors for postural instability and to explore whether postural instability predicts the severity and progression of ataxia in SCA3 patients. RESULTS: We found SCA3 patients experience postural instability characterized by significant impairment in static and dynamic stability. The condition without visual feedback was the most sensitive measure in differentiating SCA3 from controls. Regression analyses revealed that ataxia severity predicted both static (P = 0.014) and dynamic stability (P = 0.001). Likewise, along with expanded CAG repeats (P < 0.001), both static (P < 0.001) and dynamic stability (P < 0.001) predicted ataxia severity, but not ataxia progression. INTERPRETATION: Our findings demonstrate the validity of using the Pro-kin system for assessing postural instability in SCA3 patients. This type of quantitative assessment of balance dysfunction can contribute to clinical trials and balance rehabilitation in SCA3 patients.

Growth hormone rescue cerebellar degeneration in SCA3 transgenic mice.

Spinocerebellar ataxia type 3 (SCA3) is a fatal neurodegenerative disease for which no identified effective treatment or prevention methods exist. However, low-dose growth hormone (GH) therapy, as a potential off-label use, may deter the progress of SCA3. SCA3 15Q and SCA3 84Q transgenic mice harboring a YAC transgene that expresses the human ATXN3 gene with a pathogenic expanded 15 CAG repeat and 84 CAG repeat motif, respectively, were recruited. SCA3 15Q transgenic mice were considered as the healthy control group, whereas low-dose GH- and PBS-treated SCA3 84Q transgenic mice were considered as the study and sham groups, respectively. The SCA3 84Q transgenic mice were administered intraperitoneal injections of GH or PBS weekly from the postnatal age of 9 months-18 months. After 9 months of GH treatment in the SCA3 84Q transgenic mice, all locomotor functions including rotarod test, behavior box analysis were restored. The GH-treated SCA3 84Q transgenic mice revealed more preserved Purkinje cells/cerebellar cortex and less ataxin-3 aggregation, DNA oxidative, cell apoptosis compared with the PBS-treated SCA3 84Q transgenic mice. GH therapy may be one of the potential off-labeled using in the alleviation of SCA3 progression.

Trehalose in Machado-Joseph Disease: Safety, Tolerability, and Efficacy.

Machado-Joseph disease (MJD) is relatively prevalent among the Yemenite Jewish subpopulation living in Israel. Currently, there is no treatment able to modify the disease progression. Trehalose is a disaccharide with protein-stabilizing and autophagy-enhancing properties. In animal models of MJD, trehalose showed reduction of cerebellar lesion size and improved motor function. This study was designed to be a proof-of-concept, phase 2 study lasting 6 to 12 months, to determine the safety, tolerability, and efficacy of weekly IV administration of 15 g or 30 g 10% trehalose solution in 14 MJD patients. Primary endpoints were safety and tolerability, which were assessed by various clinical and laboratory tests. Secondary endpoints were changes in the Scale for Assessment and Rating of Ataxia (SARA) score, Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), time to do 9-hole peg test (9HPT), time to do 8-meter walk (8MW), and quality of life assessed by the World Health Organization Quality-of-Life Questionnaire-BREF (WHOQoL-BREF). Trehalose was well tolerated, and no serious drug-related adverse events were noted. The average SARA score, NESSCA, and time to do 9HPT and 8MW and the WHOQoL-BREF for all patients remained stable at 6 months. Six patients received treatment for as long as 12 months and continued to remain stable on all the above tests. IV trehalose seems to be safe in humans and probably effective to stabilize neurological impairment in MJD.

The impact of ethnicity on the clinical presentations of spinocerebellar ataxia type 3.

BACKGROUND: For a variety of sporadic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, it is well-established that ethnicity does affect the disease phenotypes. However, how ethnicity contributes to the clinical symptoms and disease progressions in monogenetic disorders, such as spinocerebellar ataxia type 3 (SCA3), remains less studied. METHODS: We used multivariable linear and logistical regression models in 257 molecularly-confirmed SCA3 patients (66 Caucasians, 43 African Americans, and 148 Asians [composed of 131 Chinese and 17 Asian Americans]) to explore the influence of ethnicity on age at onset (AAO), ataxia severity, and non-ataxia symptoms (i.e. depression, tremor, and dystonia). RESULTS: We found that Asians had significantly later AAO, compared to Caucasians (ß = 4.75, p = 0.000) and to African Americans (ß = 6.64, p = 0.000) after adjusting for the pathological CAG repeat numbers in ATXN3. African Americans exhibited the most severe ataxia as compared to Caucasians (ß = 3.81, p = 0.004) and Asians (ß = 4.39, p = 0.001) after taking into consideration of the pathological CAG repeat numbers in ATXN3 and disease duration. Caucasians had a higher prevalence of depression than African Americans (ß = 1.23, p = 0.040). Ethnicity had no influence on tremor or dystonia. CONCLUSIONS: Ethnicity plays an important role in clinical presentations of SCA3 patients, which could merit further clinical studies and public health consideration. These results highlight the role of ethnicity in monogenetic, neurodegenerative disorders.

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.

Childhood-Onset Spinocerebellar Ataxia 3: Tongue Dystonia as an Early Manifestation.

Background: Dystonia is a relatively common feature of spinocerebellar ataxia 3 (SCA3). Childhood onset of SCA3 is rare and typically associated with either relatively large, or homozygous, CAG repeat expansions. Case report: We describe a 10-year-old girl with SCA3, who presented with tongue dystonia in addition to limb dystonia and gait ataxia due to a heterozygous expansion of 84 repeats in ATXN3. Discussion: Diagnosis of the SCAs can be challenging, and even more so in children. Tongue dystonia has not previously been documented in SCA3.

What is the best way to keep walking and moving around for individuals with Machado-Joseph disease? A scoping review through the lens of Aboriginal families with Machado-Joseph disease in the Top End of Australia.

OBJECTIVES: Machado-Joseph disease (MJD) is the most common spinocerebellar ataxia worldwide. Prevalence is highest in affected remote Aboriginal communities of the Top End of Australia. Aboriginal families with MJD from Groote Eylandt believe 'staying strong on the inside and outside' works best to keep them walking and moving around, in accordance with six key domains that form the 'Staying Strong' Framework. The aim of this current study was to review the literature to: (1) map the range of interventions/strategies that have been explored to promote walking and moving around (functional mobility) for individuals with MJD and; (2) align these interventions to the 'Staying Strong' Framework described by Aboriginal families with MJD. DESIGN: Scoping review. DATA SOURCES: Searches were conducted in July 2018 in MEDLINE, EMBASE, CINAHL, PsychINFO and Cochrane Databases. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Peer-reviewed studies that (1) included adolescents/adults with MJD, (2) explored the effects of any intervention on mobility and (3) included a measure of mobility, function and/or ataxia were included in the review. RESULTS: Thirty studies were included. Few studies involved participants with MJD alone (12/30). Most studies explored interventions that aligned with two 'Staying Strong' Framework domains, 'exercising your body' (n=13) and 'searching for good medicine' (n=17). Few studies aligned with the domains having 'something important to do' (n=2) or 'keeping yourself happy' (n=2). No studies aligned with the domains 'going country' or 'families helping each other'. CONCLUSIONS: Evidence for interventions to promote mobility that align with the 'Staying Strong' Framework were focused on staying strong on the outside (physically) with little reflection on staying strong on the inside (emotionally, mentally and spiritually). Findings suggest future research is required to investigate the benefits of lifestyle activity programmes that address both physical and psychosocial well-being for families with MJD.

Generation of an induced pluripotent stem cell line (XHCSUi001-A) from urine cells of a patient with spinocerebellar ataxia type 3.

The induced pluripotent stem cell (iPSC) line XHCSUi001-A generated from urine cells of a female spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) patient by using the integration-free methods. The induced XHCSUi001-A retained the disease-causing ATXN3 mutation, expressed pluripotency markers, exhibited a normal karyotype and retained the ability to differentiate into the three germ layers in-vitro and in-vivo. This newly induced iPSC line could be a potential tool for researching the disease-specific mechanisms and drug screening of SCA3/MJD.

Differential toxicity of ataxin-3 isoforms in Drosophila models of Spinocerebellar Ataxia Type 3.

The most commonly inherited dominant ataxia, Spinocerebellar Ataxia Type 3 (SCA3), is caused by a CAG repeat expansion that encodes an abnormally long polyglutamine (polyQ) repeat in the disease protein ataxin-3, a deubiquitinase. Two major full-length isoforms of ataxin-3 exist, both of which contain the same N-terminal portion and polyQ repeat, but differ in their C-termini; one (denoted here as isoform 1) contains a motif that binds ataxin-3's substrate, ubiquitin, whereas the other (denoted here as isoform 2) has a hydrophobic tail. Most SCA3 studies have focused on isoform 1, the predominant version in mammalian brain, yet both isoforms are present in brain and a better understanding of their relative pathogenicity in vivo is needed. We took advantage of the fruit fly, Drosophila melanogaster to model SCA3 and to examine the toxicity of each ataxin-3 isoform. Our assays reveal isoform 1 to be markedly more toxic than isoform 2 in all fly tissues. Reduced toxicity from isoform 2 is due to much lower protein levels as a result of its expedited degradation. Additional studies indicate that isoform 1 is more aggregation-prone than isoform 2 and that the C-terminus of isoform 2 is critical for its enhanced proteasomal degradation. According to our results, although both full-length, pathogenic ataxin-3 isoforms are toxic, isoform 1 is likely the primary contributor to SCA3 due to its presence at higher levels. Isoform 2, as a result of rapid degradation that is dictated by its tail, is unlikely to be a key player in this disease. Our findings provide new insight into the biology of this ataxia and the cellular processing of the underlying disease protein.

Prediction of Survival With Long-Term Disease Progression in Most Common Spinocerebellar Ataxia.

BACKGROUND: Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. OBJECTIVE: To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. METHODS: Four hundred sixty-two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. RESULTS: Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18-1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12-1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19-1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11-1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: "severe" (n = 13; 12%), "intermediate" (n = 31; 29%), and "moderate" (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. CONCLUSION: Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. © 2019 International Parkinson and Movement Disorder Society.

Estimation of skeletal muscle mass in patients with spinocerebellar ataxia type 3 and 10.

BACKGROUND: Neurodegenerative diseases may progress to a level in which patients present spontaneous weight loss, resulting in increased falls and functional disabilities when the disease is associated with muscle mass depletion. OBJECTIVE: Evaluate the muscle compartment in patients presenting spinocerebellar ataxia (SCA) type 3 and 10. METHODS: Forty-six patients presenting SCA type 3 and 10 were assessed and 76 volunteers were selected to the control group. In order to evaluate the muscle compartment, muscle mass anthropometric measurements were assessed and total skeletal muscle mass calculated through a predictive equation. RESULTS: Women with SCA3 presented greater weight loss and muscle mass reduction compared to those with SCA10 and the control group. Among the predictive measurements, calf muscle circumference showed a more significant correlation with total skeletal muscle mass (p = 0.718). CONCLUSION: Patients presenting both types of ataxia did not show severe depletion in their nutritional status; however, those with SCA3 displayed greater weight loss and muscle mass reduction compared to the SCA10 group.

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.

Age at onset prediction in spinocerebellar ataxia type 3 changes according to population of origin.

BACKGROUND AND PURPOSE: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the length of CAG repeat expansions in ATXN3 shows an inverse correlation with age at onset (AO). Recently, a formula for predicting AO based on CAG expansion was developed for European carriers. We tested this formula in SCA3/MJD carriers from distinct origins and developed population-specific models to predict AO. METHODS: This was a parametric survival modelling study. RESULTS: The European formula (EF) was tested in 739 independent SCA3/MJD carriers from South Brazil, Taiwan and the Portuguese Azorean islands, and it largely underestimated AO in South Brazilian and Taiwanese test cohorts. This finding challenged the universal use of the EF, leading us to develop and validate population-specific models for AO prediction. Using validation cohorts, we showed that Brazilian and Taiwanese formulas largely outperformed the EF in a population-specific manner. Inversely, the EF was more accurate at predicting AO among Portuguese Azorean patients. Hence, specific prediction models were required for each SCA3/MJD ethnic group. CONCLUSIONS: Our data strongly support the existence of as yet unknown factors that modulate AO in SCA3/MJD in a population-dependent manner, independent of CAG expansion length. The generated models are made available to the scientific community as they can be useful for future studies on SCA3/MJD carriers from distinct geographical origins.