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The functional Scale for the Assessment and Rating of Ataxia (f-SARA) assesses Gait, Stance, Sitting, and Speech. It was developed as a potentially clinically meaningful measure of spinocerebellar ataxia (SCA) progression for clinical trial use. Here, we evaluated content validity of the f-SARA. Qualitative interviews were conducted among individuals with SCA1 (n = 1) and SCA3 (n = 6) and healthcare professionals (HCPs) with SCA expertise (USA, n = 5; Europe, n = 3). Interviews evaluated symptoms and signs of SCA and relevance of f-SARA concepts for SCA. HCP cognitive debriefing was conducted. Interviews were recorded, transcribed, coded, and analyzed by ATLAS.TI software. Individuals with SCA1 and 3 reported 85 symptoms, signs, and impacts of SCA. All indicated difficulties with walking, stance, balance, speech, fatigue, emotions, and work. All individuals with SCA1 and 3 considered Gait, Stance, and Speech relevant f-SARA concepts; 3 considered Sitting relevant (42.9%). All HCPs considered Gait and Speech relevant; 5 (62.5%) indicated Stance was relevant. Sitting was considered a late-stage disease indicator. Most HCPs suggested inclusion of appendicular items would enhance clinical relevance. Cognitive debriefing supported clarity and comprehension of f-SARA. Maintaining current abilities on f-SARA items for 1 year was considered meaningful for most individuals with SCA1 and 3. All HCPs considered meaningful changes as stability in f-SARA score over 1-2 years, 1-2-point change in total f-SARA score, and deviation from natural history. These results support content validity of f-SARA for assessing SCA disease progression in clinical trials.

Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763). PLS regression selected items based on their ability to detect clinical decline, with optimized weights based on the items degree of progression. Following model validation, SCACOMS was leveraged to examine disease progression and treatment effects in a 48-week SCA clinical trial cohort (NCT03701399). Items from the Clinical Global Impression-Global Improvement Scale (CGI-I), the Friedreich Ataxia Rating Scale (FARS) - functional stage, and the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) were objectively selected with weightings based on their sensitivity to clinical decline. The resulting SCACOMS exhibited improved sensitivity to disease progression and greater treatment effects (compared to the original scales from which they were derived) in a 48-week clinical trial of a novel therapeutic agent. The trial analyses also provided a SCACOMS-derived estimate of the temporal delay in SCA disease progression. SCACOMS is a useful composite measure, effectively capturing disease progression and highlighting treatment effects in patients with SCA. SCACOMS will be a powerful tool in future studies given its sensitivity to clinical decline and ability to detect a meaningful clinical impact of disease-modifying treatments.

INTRODUCTION: Traditional methods for assessing movement quality rely on subjective standardized scales and clinical expertise. This limitation creates challenges for assessing patients with spinocerebellar ataxia (SCA), in whom changes in mobility can be subtle and varied. We hypothesized that a machine learning analytic system might complement traditional clinician-rated measures of gait. Our objective was to use a video-based assessment of gait dispersion to compare the effects of troriluzole with placebo on gait quality in adults with SCA. METHODS: Participants with SCA underwent gait assessment in a phase 3, double-blind, placebo-controlled trial of troriluzole (NCT03701399). Videos were processed through a deep learning pose extraction algorithm, followed by the estimation of a novel gait stability measure, the Pose Dispersion Index, quantifying the frame-by-frame symmetry, balance, and stability during natural and tandem walk tasks. The effects of troriluzole treatment were assessed in mixed linear models, participant-level grouping, and treatment group-by-visit week interaction adjusted for age, sex, baseline modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA), and time since diagnosis. RESULTS: From 218 randomized participants, 67 and 56 participants had interpretable videos of a tandem and natural walk attempt, respectively. At Week 48, individuals assigned to troriluzole exhibited significant (p = 0.010) improvement in tandem walk Pose Dispersion Index versus placebo {adjusted interaction coefficient: 0.584 [95% confidence interval (CI) 0.137 to 1.031]}. A similar, nonsignificant trend was observed in the natural walk assessment [coefficient: 1.198 (95% CI - 1.067 to 3.462)]. Further, lower baseline Pose Dispersion Index during the natural walk was significantly (p = 0.041) associated with a higher risk of subsequent falls [adjusted Poisson coefficient: - 0.356 [95% CI - 0.697 to - 0.014)]. CONCLUSION: Using this novel approach, troriluzole-treated subjects demonstrated improvement in gait as compared to placebo for the tandem walk. Machine learning applied to video-captured gait parameters can complement clinician-reported motor assessment in adults with SCA. The Pose Dispersion Index may enhance assessment in future research. TRIAL REGISTRATION-CLINICALTRIALS. GOV IDENTIFIER: NCT03701399.

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.

Background: Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2. Methods: Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis. Results: Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death. Conclusion: In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in exon 10 of ATXN3. Extra-cerebellar manifestations, including external ophthalmoplegia, dystonia, Parkinsonism, and peripheral neuropathy, are predominantly present in SCA3 cases. Here, we report a case of SCA3 presenting with a split hand and minipolymyoclonus. Case presentation: A 73-year-old female patient presented with a 5-year history of ataxic gait. Neurological examination revealed cerebellar ataxia and minipolymyoclonus in the digits on both sides and muscle atrophy in the right hand, consistent with the split hand pattern. Electrodiagnostic studies demonstrated decreased amplitude of compound muscle action potentials and neurogenic motor unit potentials, indicating lower motor neuron involvement. Conclusions: Our patient's case indicated a split hand and minipolymyoclonus in SCA3. Clinicians should consider these extra-cerebellar manifestations in patients with SCA3. Although neither split hand nor minipolymyoclonus are likely to directly result in a specific etiological diagnosis, a common pathophysiological mechanism for both may be lower motor neuron involvement. This extracerebellar manifestation contributes to narrowing down the diagnostic possibilities for cases presenting with progressive cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no cure, nor effective treatment strategy.Our aim was to investigate the safety and efficacy of high‐dose ganglioside GM1 (ganglioside‐monosialic acid) pulse treatment in patients with SCA3.Patients were randomly allocated to receive either high‐dose GM1 (400 mg on the first day followed by 200 mg/day), low‐dose GM1 (40 mg/day), or placebo (normal saline) for 4 weeks. The primary outcome, assessed by measuring the change in the Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline to 12 weeks post‐treatment, is central to evaluating treatment efficacy. Secondary outcomes included changes in the International Cooperative Ataxia Rating Scale (ICARS) score, Barthel Index of Activities of Daily Living (ADL), and plasma and cerebrospinal fluid (CSF) GABA levels. Safety was assessed in all treated patients.A total of 48 patients with SCA3 were enrolled in this study. After 12 weeks, data from 43 patients were included in the efficacy analysis (intention‐to‐treat analysis). The least‐squares mean change in the SARA score from baseline to 12 weeks post‐treatment was −3.80 (standard error [SE], 0.39; 95% confidence interval [CI], −4.58 to −3.02) in the high‐dose GM1 group, 0.34 (SE, 0.40; 95% CI, −0.46 to 1.13) in the low‐dose GM1 group, and 0.73 (SE, 0.40; 95% CI, −0.07 to 1.52) in the placebo group, respectively. Secondary outcomes showed improvements in the ICARS score, Barthel Index of ADL, and plasma and CSF GABA levels in the high‐dose GM1 group compared to the low‐dose GM1 and placebo groups. All treatments were well‐tolerated and safe.High‐dose GM1 treatment significantly ameliorated ataxic symptoms in patients with SCA3. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias. Editor's summary: Spinocerebellar ataxias (SCAs) are neurodegenerative diseases affecting coordination and movement. Purkinje cells (PCs) are especially vulnerable in SCAs, but their low abundance makes cell type–specific transcriptomic profiling difficult. Using a PC enrichment protocol for snRNA-seq, Bartelt et al. discovered that genes contributing to zebrin-II PC subtype identity were dysregulated in the SCA7-266Q mouse model. Immunohistochemistry revealed a loss of zebrin-II striping in the cerebella of SCA7-266Q mice and mouse models of other SCA subtypes. snRNA-seq on postmortem cerebellar tissue from patients with SCA7 demonstrated zebrin-II dysregulation in molecular layer interneurons. These results suggest that dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across SCAs. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 6 (SCA6) is a polyglutamine disorder caused by the expansion of CAG repeats in the gene encoding voltage‐gated calcium channel subunit alpha1 A (CACNA1A). The clinical features of SCA6 include slowly progressive cerebellar ataxia and downbeat positioning nystagmus. The clinical significance of 19 CAG repeats is unclear. We report a case with 19/11 CAG repeats in CACNA1A determined by direct sequencing. The case presented with DPN, which is one of the most important symptoms of SCA6, but did not present with ataxia. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia type 21 (SCA21) is a rare inherited neurological disorder characterized by motor, cognitive, and behavioral disturbances, caused by autosomal dominant TMEM240 variants. Objectives: To identify the genetic cause of a dystonic tremor with autosomal dominant inheritance. Methods: Six subjects of a multi‐generational French family affected by tremor and dystonia were studied. Each patient underwent a comprehensive clinical assessment and a whole‐exome sequencing analysis. Results: All six subjects presented with early‐onset prominent hand dystonic tremor and multifocal/generalized dystonia, secondarily developing mild cerebellar ataxia. The younger generation showed more pronounced cognitive and behavioral impairment. The known pathogenic TMEM240 c.509C>T (p.P170L) variant was found in heterozygosis in all subjects. Conclusions: Dystonic tremor can represent the core clinical feature of SCA21, even in absence of overt cerebellar ataxia. Therefore, TMEM240 pathogenic variants should be considered disease‐causing in subjects displaying dystonic tremor, variably associated with ataxia, parkinsonism, neurodevelopmental disorders, and cognitive impairment. [ABSTRACT FROM AUTHOR]

The document delves into multiple studies on Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration, focusing on topics such as disease diagnosis, patient stratification, and understanding disease mechanisms. It discusses the importance of biomarkers, autonomic nervous function, and astrocyte pathology in ALS research and clinical trials. Additionally, the research explores genetic risk factors, respiratory impairments, and the impact of genetic polymorphisms on survival in ALS and FTD patients, aiming to improve prognosis and management of these neurodegenerative diseases. [Extracted from the article]

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is caused by the expansion of a genetically unstable polyglutamine-encoding CAG repeat in ATXN3. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease onset and slowing the rate of somatic expansion has been proposed as a therapeutic strategy. Here, we utilised high-throughput ultra-deep MiSeq amplicon sequencing to precisely define the number and sequence of the ATXN3 repeat, the genotype of an adjacent single nucleotide variant and quantify somatic expansion in blood and buccal swab DNA of a cohort of individuals with SCA3 from the Azores islands (Portugal). We revealed systematic mis-sizing of the ATXN3 repeat and high levels of inaccuracy of the traditional fragment length analysis that have important implications for attempts to identify modifiers of clinical and molecular phenotypes. Quantification of somatic expansion in blood DNA and multivariate regression revealed the expected effects of age at sampling and CAG repeat length, although the effect of repeat length was surprisingly modest with much stronger associations with age. We also observed an association of the downstream rs12895357 single nucleotide variant with the rate of somatic expansion, and a higher level of somatic expansion in buccal swab DNA compared to blood. These data suggest that the ATXN3 locus in SCA3 patients in blood or buccal swab DNA might serve as a good biomarker for clinical trials testing suppressors of somatic expansion with peripheral exposure. [ABSTRACT FROM AUTHOR]

Background & Objective: Autosomal recessive cerebellar ataxias (ARCA) are rare heterogenous neurodegenerative disorders characterized by degeneration of the cerebellum and spinal cord with an early onset before the age of 20 years. PMPCA (MIM: 613036), is a key enzyme in mitochondrial protein processing which is critical for cell survival and growth. Our objective was to investigate Peptidase, Mitochondrial Processing Subunit Alpha (PMPCA) mutations linked with Spinocerebellar ataxia, autosomal recessive 2 (SCAR2). Method: In the current study, Whole Exome Sequencing (WES) was done followed by Sanger sequencing for the validation of the WES results. Results: WES results identified a novel homozygous variant, NM_015160.2: c.802C>T p.(Arg268Trp) in PMPCA gene. Mutation in this gene leads to progressive cerebellar ataxia with fine motor skills difficulties, intentional tremors, slow slurred speech and learning difficulties in a 12-year-old Saudi patient. WES results were further validated by Sanger sequencing technique. Conclusions: Identified phenotype in our case was similar as previously described for SCAR2 related conditions. To our knowledge, this is the first reported mutation in PMPCA gene leading to SCAR2 in Saudi Arabia. These findings will enrich the scarce literature, further provide a new insight on the role of PMPCA gene-related disorders leading to SCAR2 and expand the disease concept. In addition, this will help to establish a database for the disease and its causative factors will further help in controlling diseases resulting from consanguinity in Saudi population. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS. [ABSTRACT FROM AUTHOR]

The fragile X premutation is a public health concern worldwide. Implementing a comprehensive screening program for FMR1 premutation alleles could empower individuals and families with information, supporting informed health decisions and potentially reducing the incidence of fragile X syndrome (FXS). This study aimed to determine the prevalence of FMR1 premutations in the Thai population. We screened 369 female blood donors and 449 males with tremor and/or ataxia who tested negative for spinocerebellar ataxia (SCA) types 1, 2, and 3 for FMR1 CGG repeat expansions. Among the female blood donors, 0.27% (1/369) had a premutation allele, and 1.08% (4/369) had intermediate alleles. One female with a premutation carrier had 89 CGG repeats with one AGG interruption. In the male cohort, no premutations or full mutations were found; however, intermediate alleles were identified in 0.67% (3/449) of the males. This study provides the evidence of fragile X premutation screening in the Thai population. These findings contribute to the understanding of FMR1 premutation prevalence in Thailand and should encourage wider discussions on the feasibility for a national fragile X carrier screening program in Thailand to reduce the burden of fragile X-associated disorders. [ABSTRACT FROM AUTHOR]

Potassium channel mutations play an important role in neurological diseases, such as spinocerebellar ataxia (SCA). SCA is a heterogeneous autosomal-dominant neurodegenerative disorder with multiple sub-entities, such as SCA13, which is characterized by mutations in the voltage-gated potassium channel Kv3.3 (KCNC3). In this study, we present a rare and atypical case of SCA13 with a predominant episodic central rotational vertigo, while the patient suffered only from mild progressive cerebellar symptoms, such as dysarthria, ataxia of gait and stand, and recently a cognitive impairment. In this patient, we identified a heterozygous variant in KCNC3 (c.2023G > A, p.Glu675Lys) by next-generation sequencing. This Kv3.3E675K variant was studied using voltage-clamp recordings in Xenopus oocytes. While typical SCA13 variants are dominant-negative, show shifts in the voltage-dependence of activation or an altered TBK1 regulation, the Kv3.3E675K variant caused only a reduction in current amplitude and a more pronounced cumulative inactivation. Thus, the differences to phenotypes observed in patients with classical SCA13 mutations may be related to the mechanism of the observed Kv3.3 loss-of-function. Treatment of our patient with riluzole, a drug that is known to also activate potassium channels, turned out to be partly beneficial. Strikingly, we found that the Kv3.3 and Kv3.3E675K inactivation and the frequency-dependent cumulative inactivation was antagonized by increased extracellular potassium levels. Thus, and most importantly, carefully elevated plasma potassium levels in the physiological range, or novel drugs attenuating Kv3.3 inactivation might provide novel therapeutic approaches to rescue potassium currents of SCA13 variants per se. In addition, our findings broaden the phenotypic spectrum of Kv3.3 variants, expanding it to atypical phenotypes of Kv3.3-associated neurological disorders. [ABSTRACT FROM AUTHOR]

Background: Although genetic interventions are on the horizon for some polyglutamine expansion diseases, such as subtypes of spinocerebellar ataxia (SCA) and Huntington's disease (HD), the patients' preferences regarding these new therapies are unclear. This study aims to get insight into what extent different characteristics of genetic interventions affect the preferences of patients with SCA and HD with regard to these interventions. Methods: Manifest and premanifest patients with SCA or HD were recruited online by platforms of patient associations. The respondents conducted a questionnaire that included a discrete choice experiment (DCE). The experimental design included 24 choice sets, but these were divided into three blocks of eight to reduce the number of tasks per respondent. Each choice set included two alternative treatments and consisted of four attributes (mode and frequency of administration, chance of a beneficial effect, risks, and follow-up), each with three or four different levels. The forced choice-elicitation format was used. Data were analyzed by using a multinominal logistic regression model. Results: Responses of 216 participants were collected. The mode and frequency of administration of a genetic intervention, as well as the chance of a beneficial effect both influence the choice for a genetic intervention. Respondents less prefer repeated lumbar punctures compared to a single operation. As expected, a higher beneficial effect of treatment was preferred. Risks and follow-up did not influence the choice for a genetic intervention. Conclusions: The results can be used for the design and implementation of future genetic interventional trials as well as of patient-centered care pathways for rare movement disorders such as SCA and HD. [ABSTRACT FROM AUTHOR]

The "Supplementary Material" from the journal "Frontiers in Cellular Neuroscience" offers additional figures and tables concerning mutations in the KCNC3 gene linked to the Kv3.3 channel. The data includes information on voltage-dependent activation and inactivation, as well as the exploration of drugs to regulate Kv3.3 currents. Tables detail mutations in the KCNC3 gene and genes analyzed in a clinical exome approach. The material delves into the activation kinetics, deactivation kinetics, and inactivation accumulation of wild-type Kv3.3 and Kv3.3E675K potassium channels, revealing minimal differences between the two in most cases. The research seeks to elucidate the functional variances between the wild-type and mutant potassium channels. [Extracted from the article]

Introduction: Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by abnormal CAG repeat expansion in the PPP2R2B gene. This disease is classically characterized by action tremor, dysarthria, ataxia, and hyperreflexia. There are limited reports regarding the non-motor symptoms in patients with SCA 12. We investigated the frequency and factors associated with the selected non-motor symptoms in patients with SCA 12. Methods: Genetically diagnosed (CAG repeats > 43) and symptomatic cases of SCA 12 were included in the study. Motor severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and The Essential Tremor Rating Assessment Scale (TETRAS). Non-motor symptoms such as depression, autonomic function, and cognition were assessed using the Hamilton Depression Rating Scale (HAM-D), the Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT), and the Montreal Cognitive Assessment (MoCA), respectively. Results: The mean age of the cohort with 34 SCA12 patients was 64.87 years (standard deviation 6.844). In this study, 21 patients (61.76%) had either mild or moderate cognitive impairment, almost equally frequent in early and advanced cases. Similarly a number of patients demonstrated evidence of moderate and severe depression. The SARA score was strongly associated with theMoCA score, and CAG repeat length could independently predict the MoCA score in this cohort. Autonomic symptoms were commonly present, with the majority of the patients experiencing urinary symptoms. Discussion: Non-motor symptoms are common in SCA12 patients, even in the early stages of the condition. Timely detection and treatment of these symptoms may improve the therapeutic outcome and quality of life for SCA12 patients. The diverse symptoms of SCA12 perhaps indicate a widespread neurodegeneration beyond the cerebellum or its direct connections. [ABSTRACT FROM AUTHOR]

Currently, routine diagnostics for spinocerebellar ataxia (SCA) look for polyQ repeat expansions and conventional variations affecting the proteins encoded by known SCA genes. However, ~40% of the patients still remain without a genetic diagnosis after routine tests. Increasing evidence suggests that variations in the enhancer regions of genes involved in neurodegenerative disorders can also cause disease. Since the enhancers of SCA genes are not yet known, it remains to be determined whether variations in these regions are a cause of SCA. In this pilot project, we aimed to identify the enhancers of the SCA genes ATXN1, ATXN3, TBP and ITPR1 in the human cerebellum using 4C-seq, publicly available datasets, reciprocal 4C-seq, and luciferase assays. We then screened these enhancers for copy number variants (CNVs) in a cohort of genetically undiagnosed SCA patients. We identified two active enhancers for each of the four SCA genes. CNV analysis did not reveal any CNVs in the enhancers of the four SCA genes in the genetically undiagnosed SCA patients. However, in one patient, we noted a CNV deletion with an unknown clinical significance near one of the ITPR1 enhancers. These results not only reveal elements involved in SCA gene regulation but can also lead to the discovery of novel SCA-causing genetic variants. As enhancer variations are being increasingly recognized as a cause of brain disorders, screening the enhancers of ATXN1, ATXN3, TBP and ITPR1 for variations other than CNVs and identifying and screening enhancers of other SCA genes might elucidate the genetic cause in undiagnosed patients. [ABSTRACT FROM AUTHOR]

Objectives: Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials. Methods: We performed a prospective 1‐year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient‐reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1‐year progression and evaluated the potential predictive value of several baseline markers on 1‐year disease progression. Results: At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non‐ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA). Longer disease duration, longer non‐expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1‐year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N‐acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase. Interpretation: Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024;96:774–787 [ABSTRACT FROM AUTHOR]

Background/Objectives: Degenerative cerebellar ataxias (DCA) present a group of complex neurological disorders primarily affecting the cerebellum and its pathways. Classic manifestations include motor symptoms of cerebellar ataxia. However, emerging evidence suggests that the cerebellum also plays a crucial role in various cognitive and emotional processes. The objective was to assess the psychiatric profile of a heterogeneous group of patients with degenerative cerebellar ataxia. Methods: Our sample comprised 107 participants diagnosed with cerebellar degenerative ataxia. All patients were clinically evaluated using SARA, INAS, and different neuropsychiatric scales (ACE-R, HAMA, HAMD, AS, and GAF). Results: The majority of patients had autosomal dominant ataxia (38.3%) followed by sporadic ataxia (32.7%) with an average age at the moment of diagnosis of 35.3 ± 16.23 years, while the mean duration of disease at the study beginning was 12.1 ± 9.9 years. Psychiatric disorders were present in 40 patients (37.4%), with dysthymia (14.2%), major depressive disorder (9.4%), and MDD with melancholic features (7.6%). The presence of MDD with melancholic features was statistically significantly correlated with a lower ACE-R total score (r = −0.223; p = 0.022), while dysthymia was statistically significantly associated with a shorter duration of the disease (r = −0.226; p = 0.020) and older age (r = 0.197; p = 0.043). Statistically significant differences were observed between MSA-C patients and those with sporadic ataxia (HDRS p < 0.001, HARS p < 0.001, Apathy Scale p = 0.003, and GAF p = 0.004). Conclusions: Based on our findings, we can conclude that the degree of motor deficit has a significant impact on the development of psychiatric disorders, including depression, anxiety, and apathy. However, it is not the only factor, and the impact also depends on the type of DCA. [ABSTRACT FROM AUTHOR]

Given the high morbidity related to the progression of gait deficits in spinocerebellar ataxias (SCA), there is a growing interest in identifying biomarkers that can guide early diagnosis and rehabilitation. Spatiotemporal parameter (STP) gait analysis using inertial measurement units (IMUs) has been increasingly studied in this context. This study evaluated STP profiles in SCA types 3 and 10, compared them to controls, and correlated them with clinical scales. IMU portable sensors were used to measure STPs under four gait conditions: self-selected pace (SSP), fast pace (FP), fast pace checking-boxes (FPCB), and fast pace with serial seven subtractions (FPS7). Compared to healthy subjects, both SCA groups had higher values for step time, variability, and swing time, with lower values for gait speed, cadence, and step length. We also found a reduction in speed gain capacity in both SCA groups compared to controls and an increase in speed dual-task cost in the SCA10 group. However, there were no significant differences between the SCA groups. Swing time, mean speed, and step length were correlated with disease severity, risk of falling and functionality in both clinical groups. In the SCA3 group, fear of falling was correlated with cadence. In the SCA10 group, results of the Montreal cognitive assessment test were correlated with step time, mean speed, and step length. These results show that individuals with SCA3 and SCA10 present a highly variable, short-stepped, slow gait pattern compared to healthy subjects, and their gait quality worsened with a fast pace and dual-task involvement. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant disease that arises from point mutations in the fatty acid elongase, Elongation of Very Long Chain Fatty Acids 4 (ELOVL4), which is essential for the synthesis of Very Long Chain-Saturated Fatty Acids (VLC-SFA) and Very Long Chain-Polyunsaturated Fatty Acids (VLC-PUFA) (28–34 carbons long). SCA34 is considered a neurodegenerative disease. However, a novel rat model of SCA34 (SCA34-KI rat) with knock-in of the W246G ELOVL4 mutation that causes human SCA34 shows early motor impairment and aberrant synaptic transmission and plasticity without overt neurodegeneration. ELOVL4 is expressed in neurogenic regions of the developing brain, is implicated in cell cycle regulation, and ELOVL4 mutations that cause neuroichthyosis lead to developmental brain malformation, suggesting that aberrant neuron generation due to ELOVL4 mutations might contribute to SCA34. To test whether W246G ELOVL4 altered neuronal generation or survival in the cerebellum, we compared the numbers of Purkinje cells, unipolar brush cells, molecular layer interneurons, granule and displaced granule cells in the cerebellum of wildtype, heterozygous, and homozygous SCA34-KI rats at four months of age, when motor impairment is already present. An unbiased, semi-automated method based on Cellpose 2.0 and ImageJ was used to quantify neuronal populations in cerebellar sections immunolabeled for known neuron-specific markers. Neuronal populations and cortical structure were unaffected by the W246G ELOVL4 mutation by four months of age, a time when synaptic and motor dysfunction are already present, suggesting that SCA34 pathology originates from synaptic dysfunction due to VLC-SFA deficiency, rather than aberrant neuronal production or neurodegeneration. [ABSTRACT FROM AUTHOR]

This study aimed to generate evidence to support psychometric validity of the modified functional Scale for the Assessment and Rating of Ataxia (f-SARA) among patients with spinocerebellar ataxia (SCA). Psychometric measurement properties and minimal change thresholds of the f-SARA were evaluated using data from a cohort of SCA subjects (recruited at Massachusetts General Hospital [MGH]; n = 33) and data from a phase 3 trial of troriluzole in adults with SCA (NCT03701399 [Study 206]; n = 217), including a subset of patients with the SCA3 genotype (n = 89). f-SARA item ceiling effects were absent within the MGH cohort, while floor effects were present. Excellent internal consistency reliability was demonstrated (αtotal = 0.90; αitems-removed = 0.86–0.90), and item-to-total correlations were strong (r = 0.82–0.91, per item). High test–retest reliability was demonstrated with intraclass correlation coefficients of 0.91 (total) and 0.73–0.92 (items). Convergent and divergent validity was supported, with strong correlations observed between the f-SARA and similarly constructed scales (FARS-FUNC, BARS, PROM-ADL, and FARS-ADL; all p < 0.001) and weaker correlations observed among measures of differing constructs. Mean item and total scores increased with disease severity (by FARS-FUNC quartile; p < 0.001). A 1-point threshold for meaningful changes was supported as 0.5 × SD = 0.89, SEM = 1.12, and mean changes from baseline for patients classified as "improved," "no change," or "deteriorated" were −0.68, 0.02, and 0.58, respectively. Similar trends were observed in Study 206 all-SCA and SCA3 cohorts. The measurement properties of the f-SARA provide evidence of its psychometric validity, responsiveness, and suitability as a clinical outcome measure in patients with SCA, including those with SCA3. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 34 (SCA34) is a dominantly inherited disease that causes late-onset ataxia, in association with skin lesions in the form of erythrokeratodermia variabilis. It is caused by mutations in the ELOVL4 gene, which encodes for the ELOVL4 protein and has the function of lengthening very long chain (VLC) fatty acids (FA), which are important components of central myelin. The aim of this work was to review the medical literature on the biochemical abnormalities of SCA34, and based on the obtained information, to propose supplementation of deficient FAs. A review of the ad hoc medical literature was performed. Plasma levels of the ELOVL4 products C32, C34 and C36 FA have not been reported in SCA34 yet. However, pathogenic variants of ELOVL4 revealed deficient biosynthesis of C28, C30, C32, C34 and C36 FA compared to WT in cell cultures, and the levels of ceramides and phosphatidylcholines containing ≥ 34 C FA were decreased compared to WT in HeLa cells expressing mutant SCA34 proteins. Besides, a pathological study of SCA34 revealed myelin destruction and loss of oligodendrocytes in cerebral and cerebellar white matter. Levels of VLC-FA should be determined, to identify specifically deficient FAs in SCA34. Cerebellar ataxia could possibly be improved by administration of the deficient FAs, as found in SCA38 with supplementation of docosahexaenoic acid. The authors suggest investigators with access to SCA34, to take into consideration this therapeutic hypothesis, and try to verify the potential efficacy of administration of VLCFA in this disease. [ABSTRACT FROM AUTHOR]

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCA) are rare inherited neurodegenerative disorders characterized by a progressive impairment of gait, balance, limb coordination, and speech. There is currently no composite scale that includes multiple aspects of the SCA experience to assess disease progression and treatment effects. Applying the method of partial least squares (PLS) regression, we developed the Spinocerebellar Ataxia Composite Scale (SCACOMS) from two SCA natural history datasets (NCT01060371, NCT02440763). PLS regression selected items based on their ability to detect clinical decline, with optimized weights based on the item's degree of progression. Following model validation, SCACOMS was leveraged to examine disease progression and treatment effects in a 48-week SCA clinical trial cohort (NCT03701399). Items from the Clinical Global Impression—Global Improvement Scale (CGI-I), the Friedreich Ataxia Rating Scale (FARS) – functional stage, and the Modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA) were objectively selected with weightings based on their sensitivity to clinical decline. The resulting SCACOMS exhibited improved sensitivity to disease progression and greater treatment effects (compared to the original scales from which they were derived) in a 48-week clinical trial of a novel therapeutic agent. The trial analyses also provided a SCACOMS-derived estimate of the temporal delay in SCA disease progression. SCACOMS is a useful composite measure, effectively capturing disease progression and highlighting treatment effects in patients with SCA. SCACOMS will be a powerful tool in future studies given its sensitivity to clinical decline and ability to detect a meaningful clinical impact of disease-modifying treatments. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia (SCA) results in balance and coordination impairment, and current treatments have limited efficacy. Recent evidence suggests that combining postural training with cerebellar transcranial direct current stimulation (ctDCS) can improve these symptoms. However, the combined effects of ctDCS and postural training on individuals with spinocerebellar ataxia remain underexplored. Ten volunteers with (SCA type 3) participated in a triple-blind, randomized, crossover study to receive a single session of ctDCS (2 mA for 20 min) and a sham ctDCS session separated by at least one week. The Biodex Balance System was used to assess balance at each session, measuring overall stability index, anteroposterior stability index, and medial-lateral stability index. As secondary outcomes, cerebellar ataxia symptoms were evaluated using the 8-item Scale for Assessment and Rating of Ataxia. The assessments were conducted before and after each session. The results indicated that ctDCS enhanced the overall stability index when compared to sham ctDCS (Z = -2.10, p = 0.03), although it did not significantly affect the anteroposterior or medial-lateral stability indices. Compared to the baseline, a single session of ctDCS reduced appendicular symptoms related to cerebellar ataxia, as evidenced by improvements in the nose-finger test (Z = -2.07, p = 0.04), fast alternating hand movements (Z = -2.15, p = 0.03), and heel-to-shin slide (Z = -1.91, p = 0.05). In conclusion, our study suggests that a single session of ctDCS, in combination with postural training, can enhance balance and alleviate ataxia symptoms in individuals with cerebellar ataxia. This study was approved by the local research ethics committee (No. 2.877.813) and registered on clinicaltrials.org (NCT04039048 - https://www.clinicaltrials.gov/study/NCT04039048) on 2019-07-28. [ABSTRACT FROM AUTHOR]

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuroregulatory technique used to treat neurodegenerative diseases, holds promise for spinocerebellar ataxia type 3 (SCA3) treatment, although its efficacy and mechanisms remain unclear. This study aims to observe the short-term impact of cerebellar rTMS on motor function in SCA3 patients and utilize resting-state functional magnetic resonance imaging (RS-fMRI) to assess potential therapeutic mechanisms. Twenty-two SCA3 patients were randomly assigned to receive actual rTMS (AC group, n = 11, three men and eight women; age 32–55 years) or sham rTMS (SH group, n = 11, three men and eight women; age 26–58 years). Both groups underwent cerebellar rTMS or sham rTMS daily for 15 days. The primary outcome measured was the ICARS scores and parameters for regional brain activity. Compared to baseline, ICARS scores decreased more significantly in the AC group than in the SH group after the 15-day intervention. Imaging indicators revealed increased Amplitude of Low Frequency Fluctuation (ALFF) values in the posterior cerebellar lobe and cerebellar tonsil following AC stimulation. This study suggests that rTMS enhances motor functions in SCA3 patients by modulating the excitability of specific brain regions and associated pathways, reinforcing the potential clinical utility of rTMS in SCA3 treatment. The Chinese Clinical Trial Registry identifier is ChiCTR1800020133. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the time between the first detection of postural control impairments and the evident manifestation of ataxia in preclinical SCA1 individuals. Twenty five preclinical SCA1 mutation carriers: 13 with estimated disease onset ≤ 6 years (SCA1 +) aged 27.8 ± 8.1 years; 12 with expected disease onset > 6 years (SCA1-) aged 26.6 ± 3.1 years and 26 age and sex matched healthy controls (HCs) underwent static posturography during 5 years of observation. The movements of the centre of feet pressure (COP) during quiet standing with eyes open (EO) and closed (EC) were quantified by calculating the mean radius (R), developed surface area (A) and mean COP movement velocity (V). Ataxia was evaluated by use of the Scale for Assessment and Rating of Ataxia (SARA). SCA1 + exhibited significantly worse quality of stance with EC vs. SCA1- (p < 0.05 for V) and HCs (p < 0.001) even 5 to 6 years before estimated disease onset. There were no statistically significant differences between SCA1- and HCs. A slow increase in Cohen's d effect size was observed for VEO up to the clinical manifestation of ataxia. VEO and AEC recorded in preclinical SCA1 individuals correlated slightly but statistically significantly with SARA (r = 0.47). The study confirms that static posturography detects COP sway changes in SCA1 preclinical gene carriers even 5 to 6 years before estimated disease onset. The quantitative evaluation of stance in preclinical SCA is a sensitive biomarker for the monitoring of the disease progression and may be useful in clinical trials. [ABSTRACT FROM AUTHOR]

The influence of brain atrophy on sleep microstructure in Spinocerebellar Ataxias (SCAs) has not been extensively explored limiting the use of these sleep traits as surrogate biomarkers of neurodegeneration and clinical phenotype. The objective of the study is to explore the relationship between sleep microstructure and brain atrophy in SCA2 and its role in the clinical phenotype. Fourteen SCA2 mutation carriers (7 pre-manifest and 7 manifest subjects) underwent polysomnographic, structural MRI, and clinical assessments. Particularly, markers of REM and non-REM sleep microstructure, measures of cerebellar and brainstem atrophy, and clinical scores were analyzed through correlation and mediation analyses. The sleep spindle activity exhibited a negative correlation with the number of trials required to complete the verbal memory test (VMT), and a positive correlation with the cerebellar volume, but the significance of the latter correlation did not survive multiple testing corrections. However, the causal mediation analyses unveiled that sleep spindle activity significantly mediates the association between cerebellar atrophy and VMT performance. Regarding REM sleep, both phasic EMG activity and REM sleep without atonia exhibited significant associations with pontine atrophy and disease severity measures. However, they did not demonstrate a causal mediation effect between the atrophy measures and disease severity. Our study provides evidence about the association of the pontocerebellar atrophy with sleep microstructure in SCA2 offering insights into the cerebellar involvement in cognition via the control of the sleep spindle activity. Therefore, our findings may help to understand the disease pathogenesis and to better characterize sleep microstructure parameters as disease biomarkers. Clinical trial registration number (TRN): No applicable. [ABSTRACT FROM AUTHOR]

Autosomal recessive spinocerebellar ataxia 13 (SCAR13) is a neurological disease characterized by psychomotor delay, mild to profound intellectual disability with poor or absent language, nystagmus, stance ataxia, and, if walking is acquired, gait ataxia. Epilepsy and polyneuropathy have also been documented in some patients. Cerebellar atrophy and/or ventriculomegaly may be present on brain MRI. SCAR13 is caused by pathogenic variants in the GRM1 gene encoding the metabotropic receptor of glutamate type 1 (mGlur1), which is highly expressed in Purkinje cerebellar cells, where it plays a fundamental role in cerebellar development. Here we discuss the case of an 8-year-old patient who presented with a severe neurodevelopmental disorder with balance disturbance, absence of independent walking, absence of language, diffuse hypotonia, mild nystagmus, and mild dysphagia. Whole-exome sequencing revealed a compound heterozygosity for two likely pathogenic variants in the GRM1 gene, responsible for the patient's phenotype, and made it possible to diagnose autosomal recessive spinocerebellar ataxia SCAR13. The detected (novel) variants appear to be causative of a particularly severe picture with regard to neurodevelopment, in the context of the typical neurological signs of spinocerebellar ataxia. [ABSTRACT FROM AUTHOR]

We report a case of SYNE1-associated autosomal recessive spinocerebellar ataxia (SCAR8) presenting with a complex multisystemic phenotype, including highly elevated creatine kinase levels and lower-leg muscle atrophy. In addition to identifying two novel pathogenic variants in the SYNE1 gene, whole-exome sequencing revealed three variants of uncertain significance in the DYSF gene. Electromyography and muscle magnetic resonance imaging indicated a neurogenic pattern of muscle involvement. These findings, along with the segregation analysis of the variants, allowed us to exclude DYSF-associated muscular dystrophy; however, we cannot entirely rule out the possibility that the DYSF gene variants may act as modifiers of the patient's phenotype. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 7 (SCA7) is a rare genetic disease characterized by progressive cerebellar syndrome and macular degeneration. In a previous study, we clinically and genetically characterized a group of Mexican patients, which represented one of the largest cohorts of SCA7 patients worldwide and demonstrated that all patients had a unique genetic origin. Our laboratory developed a program for the diagnosis, medical care, and long-term follow-up of these patients living in Veracruz State, and in this report, we present an update to this research, covering 2013 to 2024. So far, we identified 172 SCA7 carriers, with a few cases outside Veracruz, and our data support that the length of the CAG repeat tract mainly determines disease severity and life expectancy, and accordingly, we define three different phenotypes, early-onset (EO), classical-onset (CO), and late-onset (LO), with EO patients showing the lowest life expectancy. Furthermore, we found that parental transmission of mutant alleles leads to increased CAG repeat instability, compared to maternal ones. Interestingly, a haplotype analysis revealed that patients outside Veracruz may have different genetic origins. In conclusion, longitudinal observations of SCA7 patients provide insight into the natural history of SCA7 and help to design strategies for diagnosis, genetic counseling, physical rehabilitation, and therapeutic alternatives. [ABSTRACT FROM AUTHOR]

Polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA), including SCA1, 2, 3, 6, 7, and 17, are caused by mutant genes with expanded CAG repeats, leading to the intracellular accumulation of aggregated proteins, the production of reactive oxygen species, and cell death. Among SCA, SCA3 is caused by a mutation in the ATXN3 (ataxin-3) gene. In a circumstance of polyQ aggregation, the autophagic pathway is induced to degrade the aggregated proteins, thereby suppressing downstream deleterious effects and promoting neuronal survival. In this study, we tested the effects of synthetic indole (NC009-1, -2, -3, -6) and coumarin (LM-022, -031) derivatives as chemical chaperones to assist mutant ATXN3-Q75 folding, as well as autophagy inducers to clear aggregated protein. Among the tested compounds, NC009-1, -2, and -6 and LM-031 interfered with Escherichia coli-derived ATXN3-Q75 aggregation in thioflavin T binding and filter trap assays. In SH-SY5Y cells expressing GFP-fused ATXN3-Q75, these compounds displayed aggregation-inhibitory and neurite growth-promoting potentials compared to untreated cells. Furthermore, these compounds activated autophagy by increasing the phosphatidylethanolamine-conjugated LC3 (microtubule associated protein 1 light chain 3)-II:cytosolic LC3-I ratio in these cells. A biochemical co-immunoprecipitation assay by using a mixture of HEK 293T cell lysates containing recombinant ATXN3-Q75-Venus-C-terminus (VC) or Venus-N-terminus (VN)-LC3 protein indicated that NC009-1 and -2 and LM-031 served as an autophagosome-tethering compound (ATTEC) to interact with ATXN3-Q75 and LC3, and the interaction was further confirmed by bimolecular fluorescence complementation analysis in cells co-expressing both ATXN3-Q75-VC and VN-LC3 proteins. The study results suggest the potential of NC009-1 and -2 and LM-031 as an ATTEC in treating SCA3 and, probably, other polyQ diseases. [ABSTRACT FROM AUTHOR]

This document is a compilation of scientific articles and clinical trials related to antisense oligonucleotide (ASO) therapy for neurodegenerative diseases. ASOs have shown promise in targeting the genetic causes of diseases such as spinal muscular atrophy (SMA) and familial amyotrophic lateral sclerosis (ALS). Clinical trials have demonstrated the effectiveness of ASOs in improving motor function and survival in patients with SMA and ALS. Challenges remain in terms of target selection, biodistribution, and clinical benefit, but ASOs are a promising treatment approach that may potentially reverse or slow down disease progression. The document mentions ongoing clinical trials and potential future applications of ASOs for various neurodegenerative diseases. [Extracted from the article]

The article discusses a rare skin condition called papular epidermal naevus with 'skyline' basal cell layer (PENS). The authors describe five patients with PENS who had a specific genetic mutation called mosaic EGFR exon 20 in-frame insertion. This mutation was found in skin biopsy samples but not in blood samples, suggesting that it may be a somatic mutation. The authors also note that PENS may be associated with other neurological disorders. The findings suggest that the EGFR exon 20 in-frame insertion mutation could be a specific genetic marker for PENS. [Extracted from the article]

Background: The ethnic diversity of India provides a unique opportunity to study the history of the origin of mutations of genetic disorders. Spinocerebellar ataxia type 27B (SCA27B), a recently identified dominantly inherited cerebellar disorder is caused by GAA-repeat expansions in intron 1 of Fibroblast Growth Factor 14 (FGF14). Predominantly reported in the European population, we aimed to screen this mutation and study the founder haplotype of SCA27B in Indian ataxia patients. Methods: We have undertaken screening of GAA repeats in a large Indian cohort of ~ 1400 uncharacterised ataxia patients and kindreds and long-read sequencing-based GAA repeat length assessment. High throughput genotyping-based haplotype analysis was also performed. We utilized ~ 1000 Indian genomes to study the GAA at-risk expansion alleles. Findings: We report a high frequency of 1.83% (n = 23) of SCA27B in the uncharacterized Indian ataxia cohort. We observed several biallelic GAA expansion mutations (n = 5) with younger disease onset. We observed a risk haplotype (AATCCGTGG) flanking the FGF14-GAA locus over a 74 kb region in linkage disequilibrium. We further studied the frequency of this risk haplotype across diverse geographical population groups. The highest prevalence of the risk haplotype was observed in the European population (29.9%) followed by Indians (21.5%). The observed risk haplotype has existed through ~ 1100 generations (~ 22,000 years), assuming a correlated genealogy. Interpretation: This study provides valuable insights into SCA27B and its Upper Paleolithic origin in the Indian subcontinent. The high occurrence of biallelic expansion is probably relevant to the endogamous nature of the Indian population. [ABSTRACT FROM AUTHOR]

This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes, which has not been depicted by the known neurodegenerative disease. We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia, Parkinsonism, and cognitive function, as well as brain magnetic resonance imaging scans with seven sequences. We searched for co-segregations of abnormal repeat-expansion loci, pathogenic variants in known spinocerebellar ataxia-related genes, and novel rare mutations via whole-genome sequencing and linkage analysis. A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay. This pedigree presented novel late-onset core characteristics including cerebellar ataxia, Parkinsonism, and pyramidal signs in all nine affected members. Brain magnetic resonance imaging showed cerebellar/pons atrophy, pontine-midline linear hyperintensity, decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus, and hypo-intensities of the cerebellar dentate nuclei, basal ganglia, mesencephalic red nuclei, and substantia nigra, all of which suggested neurodegeneration. Whole-genome sequencing identified a novel pathogenic heterozygous mutation (E795V) in the CARS gene, meanwhile, exhibited none of the known repeat-expansions or point mutations in pathogenic genes. Remarkably, this CARS mutation causes a 20% decrease in aminoacylation activity to charge tRNACys with L-cysteine in protein synthesis compared with that of the wild type. All family members carrying a heterozygous mutation CARS (E795V) had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia. These findings identify novel pathogenesis of Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3'-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients' brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Depletion of PFKFB3 markedly abrogates PNKP activity without changing its protein level. Notably, the levels of both PFKFB3 and its product fructose-2,6 bisphosphate (F2,6BP), an allosteric modulator of glycolysis, are significantly lower in the nuclear extracts of postmortem brain tissues of HD and SCA3 patients. Supplementation of F2,6BP restored PNKP activity in the nuclear extracts of patients' brain. Moreover, intracellular delivery of F2,6BP restored both the activity of PNKP and the integrity of transcribed genome in neuronal cells derived from the striatum of the HD mouse. Importantly, supplementing F2,6BP rescued the HD phenotype in Drosophila, suggesting F2,6BP to serve in vivo as a cofactor for the proper functionality of PNKP and thereby, of brain health. Our results thus provide a compelling rationale for exploring the therapeutic use of F2,6BP and structurally related compounds for treating polyQ diseases. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia type 1, is a rare neurodegenerative disorder with autosomal dominant inheritance belonging to the polyglutamine diseases. The diagnosis of this disease requires genetic testing that may also include the search for CAT interruption of the CAG repeat tract. Case presentation: One 23-years-old patient suffers from a severe ataxia, with early-onset and rapid progression of the disease. His father might have been affected, but no molecular confirmation has been performed. The genetic results were negative for the Friedreich's ataxia, spinocerebellar ataxia type 2, 3, 6, 7 and 17. The numbers of CAG repeats in the ATXN1 gene was assessed by fluorescent PCR, tripled-primed PCR and enzymatic digestion for the search of sequence interruption in the CAG repeats. The patient carried one pathogenic allele of 61 CAG and one intermediate allele of 37 CAG in the ATXN1 gene. Both alleles were uninterrupted. Conclusions: We report a rare case of spinocerebellar ataxia type 1 with an intermediate allele and a large SCA1 expansion. The determination of the absence of CAT interruption brought crucial information concerning this molecular diagnosis, the prediction of the disease and had practical consequences for genetic counseling. [ABSTRACT FROM AUTHOR]

• Trehalose at concentrations of 0.1–200 mM is safe in SCA3 cell models. • Trehalose decreases the formation of aggregates of mutant ataxin-3. • Trehalose reduces full-length ataxin-3 protein levels. • Trehalose holds therapeutic potential to treat SCA3 likely by its antioxidant activity. Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by mutant ataxin-3 with an abnormally expanded polyQ tract and is the most common dominantly inherited ataxia worldwide. There are no suitable therapeutic options for this disease. Autophagy, a defense mechanism against the toxic effects of aggregation-prone misfolded proteins, has been shown to have beneficial effects on neurodegenerative diseases. Thus, trehalose, which is an autophagy inducer, may have beneficial effects on SCA3. In the present study, we examined the effects of trehalose on an SCA3 cell model. After trehalose treatment, aggregate formation, soluble ataxin-3 protein levels and cell viability were evaluated in HEK293T cells overexpressing ataxin-3-15Q or ataxin-3-77Q. We also explored the mechanism by which trehalose affects autophagy and stress pathways. A filter trap assay showed that trehalose decreased the number of aggregates formed by mutant ataxin-3 containing an expanded polyQ tract. Western blot and Cell Counting Kit-8 (CCK-8) results demonstrated that trehalose also reduced the ataxin-3 protein levels and was safe for ataxin-3-expressing cells, respectively. Western blot and total antioxidant capacity assays suggested that trehalose had great therapeutic potential for treating SCA3, likely through its antioxidant activity. Our data indicate that trehalose plays a neuroprotective role in SCA3 by inhibiting the aggregation and reducing the protein level of ataxin-3, which is also known to protect against oxidative stress. These findings provide a new insight into the possibility of treating SCA3 with trehalose and highlight the importance of inducing autophagy in SCA3. [ABSTRACT FROM AUTHOR]

The cerebellum plays a major role in balance, motor control and sensorimotor integration, but also in cognition, language, and emotional regulation. Several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism spectrum disorder (ASD), as well as neurological diseases such as spinocerebellar ataxia type 3 (SCA3) are associated with differences in cerebellar function. Morphological abnormalities in different cerebellar subregions produce distinct behavioral symptoms related to the functional disruption of specific cerebro-cerebellar circuits. The specific contribution of the cerebellum to typical development may therefore involve the optimization of the structure and function of cerebro-cerebellar circuits underlying skill acquisition in multiple domains. Here, we review cerebellar structural and functional differences between healthy and patients with ADHD, ASD, and SCA3, and explore how disruption of cerebellar networks affects the neurocognitive functions in these conditions. We discuss how cerebellar computations contribute to performance on cognitive and motor tasks and how cerebellar signals are interfaced with signals from other brain regions during normal and dysfunctional behavior. We conclude that the cerebellum plays a role in many cognitive functions. Still, more clinical studies with the support of neuroimaging are needed to clarify the cerebellum's role in normal and dysfunctional behavior and cognitive functioning. [ABSTRACT FROM AUTHOR]

Background: Biomedical data are usually collections of longitudinal data assessed at certain points in time. Clinical observations assess the presences and severity of symptoms, which are the basis for the description and modeling of disease progression. Deciphering potential underlying unknowns from the distinct observation would substantially improve the understanding of pathological cascades. Hidden Markov Models (HMMs) have been successfully applied to the processing of possibly noisy continuous signals. We apply ensembles of HMMs to categorically distributed multivariate time series data, leaving space for expert domain knowledge in the prediction process. Methods: We use an ensemble of HMMs to predict the loss of free walking ability as one major clinical deterioration in the most common autosomal dominantly inherited ataxia disorder worldwide. Results: We present a prediction pipeline that processes data paired with a configuration file, enabling us to train, validate and query an ensemble of HMMs. In particular, we provide a theoretical and practical framework for multivariate time-series inference based on HMMs that includes constructing multiple HMMs, each to predict a particular observable variable. Our analysis is conducted on pseudo-data, but also on biomedical data based on Spinocerebellar ataxia type 3 disease. Conclusions: We find that the model shows promising results for the data we tested. The strength of this approach is that HMMs are well understood, probabilistic and interpretable models, setting it apart from most Deep Learning approaches. We publish all code and evaluation pseudo-data in an open-source repository. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the genetic causes underlying the juvenile parkinsonism (JP) diagnosed in a girl with several family members diagnosed with spinocerebellar ataxia type 2 (SCA2). To achieve this, whole-exome sequencing, analysis of CAG repeats, RNA sequencing analysis on fibroblasts, and metabolite identification were performed. As a result, a homozygous missense mutation SNP T>C (rs2254562) in synaptojamin 1 (SYNJ1), which has been implicated in the regulation of membrane trafficking in the synaptic vesicles, was identified. Additionally, we observed overexpression of L1 cell adhesion molecule (L1CAM), Cdc37, GPX1, and GPX4 and lower expression of ceruloplasmin in the patient compared to the control. We also found changes in sphingolipid, inositol, and inositol phosphate metabolism. These findings help to clarify the mechanisms of JP and suggest that the etiology of JP in the patient may be multifactorial. This is the first report of the rs2254562 mutation in the SYNJ gene identified in a JP patient with seizures and cognitive impairment. [ABSTRACT FROM AUTHOR]

Background & Objectives: Ataxia is usually caused by cerebellar pathology or a decrease in vestibular or proprioceptive afferent input to the cerebellum. It is characterized by uncoordinated walking, truncal instability, body or head tremors, uncontrolled coordination of the hands, dysarthria, and aberrant eye movements. The objective of the current investigation was to identify the underlying genetic cause of the hereditary ataxia that affects the Pakistani population. Methods: We studied numerous consanguineous Pakistani families whose members had ataxia-related clinical symptoms to varying degrees. The families were chosen from the Punjab province, and the neurophysician conducted a clinical examination. Peripheral blood samples from both sick and healthy members of the family were taken after obtaining informed consent. Genomic DNA was used to find potential variations in probands using whole exome sequencing. The study was carried out at the University Hospital of Tübingen, Germany, and Government College University in Faisalabad, Pakistan, during 2018-2023. Results: The molecular analysis of these families identified different variants including SGCB: c.902C>T, c.668G>A, ATM: c.6196_6197insGAA, SPG11: c.5769del, SETX c.5525_5533del, and ATM: c.7969A>T. A noteworthy mutation in ATM and SETX was observed among them, and its symptoms were shown to cause ataxia in these families. Conclusion: The current study broadens the mutation spectrum of several hereditary ataxia types and suggests the next generation sequencing in conjunction with clinical research for a more accurate diagnosis of overlapping phenotypes of this disorder in the Pakistani population. [ABSTRACT FROM AUTHOR]

Background: Recently, an exonic GGC repeat expansion (RE) was identified by long-read genome sequencing in the ZFHX3 gen, causing spinocerebellar ataxia type 4 (SCA4), a dominant form of ataxia with sensory neuropathy. However, the analysis of larger cohorts of patients remained demanding, resulting in a challenge to diagnose patients and leaving the question of anticipation in SCA4 unanswered. Objectives: We aimed to develop a GGC repeat test for clinical SCA4 screening and to apply this test to screen two large German SCA pedigrees and samples of unrelated patients collected over the last 25 years. Methods: We modulated a commercial GGC-RE kit (Bio-Techne AmplideX® Asuragen® PCR/CE FMR1 Reagents) with ZFHX3-specific primers and adapted PCR conditions. The test was applied to patients and 50 healthy controls to determine the exact repeat number. Clinical data were revised and correlated with the expanded allele sizes and an exploratory analysis of structural MRI was performed. Results: Repeat size, determined by our protocol for (GGC)n RE analysis shows a strong inverse correlation between repeat length and age at onset and anticipation in subsequent generations. The phenotype also appears to be more strongly expressed in carriers of longer RE. Clinical red flags were slowed saccades, sensory neuropathy and autonomic dysfunction. Conclusion: Our protocol enables cost-effective and robust screening for the causative SCA4 RE within ZFHX3. Furthermore, detailed clinical data of our patients gives a more precise view on SCA4, which seems to be more common among patients with ataxia than expected. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif 'ACAAG'. [ABSTRACT FROM AUTHOR]