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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.

• 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]

Objectives Methods Results Interpretation Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late‐onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4‐aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post‐mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B.In our cohort of 102 patients with SCA27B, we found that SCA27B was a late‐onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post‐mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4‐aminopyridine.Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024 [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 & 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]

Polyglutamine (polyQ) disorders are monogenic neurodegenerative disorders. Currently, no therapies are available for this complex group of disorders. Here, we aim to provide an overview of recent promising preclinical studies and the ongoing clinical trials focusing on molecular therapies for polyQ disorders. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult‐onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive. Objective: To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation. Methods: Three Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing. Results: Novel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG‐PET demonstrated brain hypometabolism and [11C]Flumazenil‐PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls. Conclusions: SCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations. [ABSTRACT FROM AUTHOR]

Introduction: In this work, we describe a new case of association between SCA2 and MND. Case Report: A 58-year-old man who was diagnosed with spinocerebellar ataxia type 2 presented dysphagia and a significant decline in his ability to walk, with a reduction in autonomy and the need to use a wheelchair. We performed electromyography and electroneurography of the four limbs and of the cranial district and motor-evoked potentials to study upper and lower motor neurons. Referring to the revised El Escorial criteria of 2015, ALS diagnosis was made. Discussion: Considering different cases described in literature over the years, SCA2 could represent an important risk factor for developing ALS. In particular, the presence of alleles of ATXN2 with 27 and 28 CAG repeats seems to slightly decrease the risk of developing the disease, which would instead be progressively increased by the presence of alleles with 29, 30, 31, 32, and 33 repeats. The exact physiopathological mechanism by which the mutation increases the risk of developing the disease is currently unknown. Transcriptomic studies on mouse models have demonstrated the involvement of several pathways, including the innate immunity regulation by STING and the biosynthesis of fatty acid and cholesterol by SREBP. Conclusion: CAG repeat expansions in the ATXN2 gene have been associated with variable neurological presentations, which include SCA2, ALS, Parkinsonism, or a combination of them. Further research is needed to understand the relationship between SCA2 and ALS better and explore molecular underlying mechanisms. [ABSTRACT FROM AUTHOR]

The association of early‐onset non‐progressive ataxia and miosis is an extremely rare phenotypic entity occasionally reported in the literature. To date, only one family (two siblings and their mother) has benefited from a genetic diagnosis by the identification of a missense heterozygous variant (p.Arg36Cys) in the ITPR1 gene. This gene encodes the inositol 1,4,5‐trisphosphate receptor type 1, an intracellular channel that mediates calcium release from the endoplasmic reticulum. Deleterious variants in this gene are known to be associated with two types of spinocerebellar ataxia, SCA15 and SCA29, and with Gillespie syndrome that is associated with ataxia, partial iris hypoplasia, and intellectual disability. In this work, we describe a novel individual carrying a heterozygous missense variant (p.Arg36Pro) at the same position in the N‐terminal suppressor domain of ITPR1 as the family previously reported, with the same phenotype associating early‐onset non‐progressive ataxia and miosis. This second report confirms the implication of ITPR1 in the miosis–ataxia syndrome and therefore broadens the clinical spectrum of the gene. Moreover, the high specificity of the phenotype makes it a recognizable syndrome of genetic origin. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion The American continent populations have a wide genetic diversity, as a product of the admixture of three ethnic groups: Amerindian, European, and African Sub‐Saharan. Spinocerebellar ataxia type 10 (SCA10) and Huntington disease‐like 2 (HDL2) have very ancient ancestral origins but are restricted to two populations: Amerindian and African Sub‐Saharan, respectively. This study aimed to investigate the genetic epidemiological features of these diseases in Venezuela.In‐phase haplotypes with the expanded alleles were established in seven unrelated index cases diagnosed with SCA10 and in 11 unrelated index cases diagnosed with HDL2. The origins of remote ancestors were recorded.The geographic origin of the ancestors showed grouping in clusters. SCA10 had a minimal general prevalence of 1:256,174 families in the country, but within the identified geographic clusters, the prevalence ranged from 5 per 100,000 to 43 per 100,000 families. HDL2 had a general prevalence of 1:163,016 families, however, within the clusters, the prevalence ranged from 31 per 100,000 to 60 per 100,000 families. The locus‐specific haplotype shared by all families worldwide, including the Venezuelans, supports a single old ancestral origin in each case.Knowing the genetic ancestry and geographic origins of patients in Ibero‐American mixed populations could have significant diagnostic implications; thus, both diseases in Venezuela should always be first explored in patients with a suggestive phenotype and ancestors coming from the same known geographic clusters. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a rare genetic neurodegenerative disorder caused by an expansion of CAG repeats in the Huntingtin (HTT) gene. One hypothesis suggests that the mutant HTT gene contributes to HD neuropathology through transcriptional dysregulation involving microRNAs (miRNAs). In particular, the miR-132/212 cluster is strongly diminished in the HD brain. This study explores the effects of miR-132/212 deficiency specifically in adult HD zQ175 mice. The absence of miR-132/212 did not impact body weight, body temperature, or survival rates. Surprisingly, miR-132/212 loss seemed to alleviate, in part, the effects on endogenous Htt expression, HTT inclusions, and neuronal integrity in HD zQ175 mice. Additionally, miR-132/212 depletion led to age-dependent improvements in certain motor functions. Transcriptomic analysis revealed alterations in HD-related networks in WT- and HD zQ175-miR-132/212-deficient mice, including significant overlap in BDNF and Creb1 signaling pathways. Interestingly, however, a higher number of miR-132/212 gene targets was observed in HD zQ175 mice lacking the miR-132/212 cluster, especially in the striatum. These findings suggest a nuanced interplay between miR-132/212 expression and HD pathogenesis, providing potential insights into therapeutic interventions. Further investigation is needed to fully understand the underlying mechanisms and therapeutic potential of modulating miR-132/212 expression during HD progression. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusion Multiple system atrophy (MSA) is a progressive, adult‐onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs. Although a few genetic factors have been reported to contribute to the disease, its mutational profiles have not been systemically studied.To address the genetic profiles of clinically diagnosed MSA patients, exome sequencing and triplet repeat detection was conducted in 205 MSA patients, including one familial case. The pathogenicity of variants was determined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.In the familial patient, a novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) was identified in the MSA pedigree. In the sporadic patients, 29 pathogenic variants were revealed in 21 genes, and the PARK7 p.Ala104Thr variant was significantly associated with MSA (p = 0.0018). Moreover, burden tests demonstrated that the pathogenic variants were enriched in cerebellar ataxia‐related genes in patients. Furthermore, repeat expansion analyses revealed that two patients carried the pathogenic CAG repeat expansion in the CACNA1A gene (SCA6), one patient carried the (ACAGG)exp/(ACAGG)exp expansion in RFC1 and one carried the GAA‐pure expansion in FGF14 gene.In conclusion, a novel COQ2 pathogenic variant was identified in a familial MSA patient, and repeat expansions in CACNA1A, RFC1 and FGF14 gene were detected in four sporadic patients. Moreover, a PARK7 variant and the burden of pathogenic variants in cerebellar ataxia‐related genes were associated with MSA. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cognitive impairment in spinocerebellar ataxia patients has been reported since the early-disease stage. We aimed to assess cognitive differences in SCA1 and SCA2 patients. Methods: We performed neuropsychological (NPS) and neurophysiological (auditory event-related potentials, aERPs) assessments in 16 SCA1 and 18 SCA2 consecutive patients. Furthermore, clinical information (age at onset, disease duration, motor disability) was collected. Results: NPS tests yielded scores in the normal range in both groups but with lower scores in the Frontal Assessment Battery (p < 0.05) and Visual Analogue Test for Anosognosia for motor impairment (p < 0.05) in SCA1, and the Trail Making Test (p < 0.01), Raven's progressive matrices (p < 0.01), Stroop (p < 0.05), and emotion attribution tests (p < 0.05) in SCA2. aERPs showed lower N100 amplitude (p < 0.01) and prolonged N200 latency (p < 0.01) in SCA1 compared with SCA2. Clinically, SCA2 had more severe motor disability than SCA1 in the Assessment and Rating of Ataxia Scale. Conclusions: SCA2 showed more significant difficulties in attentional, visuospatial, and emotional function, and greater motor impairment. In contrast, SCA1 showed less cognitive flexibility/phasic ability, probably affected by a more severe degree of dysarthria. The same group revealed less neural activity during nonconscious attentional processing (N100-N200 data), suggesting greater involvement of sensory pathways in discriminating auditory stimuli. NFS did not correlate with NPS findings, implying an independent relationship. However, the specific role of the cerebellum and cerebellar symptoms in NPS test results deserves more focus. [ABSTRACT FROM AUTHOR]

Background: Chronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction with symptoms of intestinal blockage but without the actual mechanical obstruction. Currently, there are no drugs available to treat this disease. Herein, we report the characterization of the PrP-SCA7-92Q transgenic (Tg) line as a valuable CIPO mouse model and investigated the tolerability and efficacy of the 5-hydroxytryptamine type-4 receptor (5HT4R) agonist velusetrag as a promising pharmacological treatment for CIPO. Methods: To test the pharmacodynamics of velusetrag, 8-week-old SCA7 Tg mice, which express human mutated Ataxin-7 gene containing 92 CAG repeats under the mouse prion protein promoter, were treated for 5 weeks by oral route with velusetrag at 1 and 3 mg/kg doses or vehicle. Body weight was monitored throughout the treatment. After sacrifice, the small intestine and proximal colon were collected for whole-mount immunostaining. Untreated, age-matched, C57BL/6J mice were also used as controls in comparison with the other experimental groups. Results: Analysis of SCA7 Tg mice showed tissue damage and alterations, mucosal abnormalities, and ulcers in the distal small intestine and proximal colon. Morphological changes were associated with significant neuronal loss, as shown by decreased staining of pan-neuronal markers, and with accumulation of ataxin-7-positive inclusions in cholinergic neurons. Administration of velusetrag reversed intestinal abnormalities, by normalizing tissue damage and re-establishing the normal level of glia/neuron's count in both the small and large intestines. Conclusion: We demonstrated that the PrP-SCA7-92Q Tg line, a model originally developed to mimic spinocerebellar ataxia, is suitable to study CIPO pathology and can be useful in establishing new therapeutic strategies, such as in the case of velusetrag. Our results suggest that velusetrag is a promising compound to treat patients affected by CIPO or intestinal dysmotility disease. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Interpretation 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.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.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.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 [ABSTRACT FROM AUTHOR]

Purpose: To report on a patient with spinocerebellar ataxia type 14 (SCA14) and macular dystrophy with identification of a novel PRPH2 variant. Methods: Case report. Results: A 63-year-old female with molecularly confirmed SCA14 presented with symmetric pigmentary disturbances in a perifoveal distribution resembling a pattern macular dystrophy. She had no history of using medications with recognized toxic macular effects. Subsequent genetic testing confirmed a novel heterozygous missense variant of unknown significance in PRPH2 (PRPH2: c.694 G>A, p.(Ala232Thr)). Conclusions: To our knowledge, this is the first case of macular dystrophy identified in a patient with SCA14. While it is possible that the macular dystrophy observed in this patient might be an under-reported phenotype associated with SCA14, the pattern of macular changes is consistent with PRPH2-related disorders. The identified missense variant is predicted to be damaging by most in silico models, and the residue is highly conserved, adding support to a dual genetic diagnosis in this case. [ABSTRACT FROM AUTHOR]

Aim: Spinocerebellar ataxia type 2 (SCA2) is a trinucleotide repeat disorder characterized by mutations in the ataxin-2 gene. Although the primary symptoms of this disease are related to cerebellar involvement, such as ataxia and dysarthria, cognitive disorders associated with supratentorial involvement, depression, and extrapyramidal symptoms are also common. The aim of this study was to investigate volumetric changes in patients with SCA2. Materials and Methods: Nine SCA2 patients and sixteen age and gender-matched healthy controls were included in the study. Voxel-based morphometry (VBM) was used to explore changes in whole brain gray and white matter, while surface-based morphometry (SBM) was employed to investigate changes in cortical thickness (CT), local gyrification index (LGI), sulcal depth (SD), and fractal dimension (FD). Deep learning methods were utilized for the automatic segmentation of subcortical gray matter structures and extrapyramidal system structures. Comparisons between groups were made using GLM, T-Test, and Mann-Whitney U test. Results: VBM results showed widespread gray matter loss in the cerebellum and widespread white matter loss in the brain stem (Cluster size: 25918 voxels for gray matter, 24557 voxels for white matter). SBM findings indicated a decrease in cortical thickness (Cluster size:19276 vertices for left hemisphere; 17276 vertices for right hemisphere), more pronounced in the supratentorial frontoparietal region, while FD, LGI, and SD did not differ between groups. Volume loss was observed in the subthalamic nucleus, globus pallidus internus and externus, and red nucleus in SCA2 patients. Conclusion: SCA2 patients exhibit white and gray matter volume loss in the infratentorial region. Additionally, they show a decrease in frontoparietal cortical thickness, while FD, LGI, and SD do not show any changes. Moreover, atrophy is also observed in the extrapyramidal system structures. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from ataxia disorders show symptoms of incoordination often attributed to cerebellar dysfunction and eventual degeneration of Purkinje cells (PCs). In spinocerebellar ataxia 6 (SCA6), for example, reduced signalling of brain-derived neurotrophic factor (BDNF) through its receptor TrkB has been implicated in PC dysfunction and motor incoordination. Nonetheless, the TrkB receptor is also present in granule cells (GCs), which have extensive connections with PCs, suggesting that impaired BDNF–TrkB signalling in GCs would also negatively affect the function of PCs and possibly contribute to symptoms of motor incoordination in ataxia disorders. Here, we used a mouse model in which the TrkB receptor was removed from a specific subset of GCs to investigate whether this would induce motor incoordination in the mice. Analysis of these mice revealed a normal cerebellar structure and intact levels of selected synaptic markers. However, the mice exhibited motor incoordination symptoms and eventual PC dysfunction. Thus, dysfunctional BDNF–TrkB signalling in GCs alone was sufficient to induce symptoms of motor incoordination and may contribute to these symptoms in disorders such as SCA6. These findings can enhance our understanding of the causes of motor incoordination and help develop therapeutic interventions. In ataxia disorders, motor incoordination (ataxia) is primarily linked to the dysfunction and degeneration of cerebellar Purkinje cells (PCs). In spinocerebellar ataxia 6 (SCA6), for example, decreased BDNF–TrkB signalling appears to contribute to PC dysfunction and ataxia. However, abnormal BDNF–TrkB signalling in granule cells (GCs) may contribute to PC dysfunction and incoordination in ataxia disorders, as TrkB receptors are also present in GCs that provide extensive input to PCs. This study investigated whether dysfunctional BDNF–TrkB signalling restricted to a specific subset of cerebellar GCs can generate ataxia in mice. To address this question, our research focused on TrkbPenk-KO mice, in which the TrkB receptor was removed from enkephalinergic precursor-derived cerebellar GCs. We found that deleting Ntrk2, encoding the TrkB receptor, eventually interfered with PC function, leading to ataxia symptoms in the TrkbPenk-KO mice without affecting their cerebellar morphology or levels of selected synaptic markers. These findings suggest that dysfunctional BDNF–TrkB signalling in a subset of cerebellar GCs alone is sufficient to trigger ataxia symptoms and may contribute to motor incoordination in disorders like SCA6. [ABSTRACT FROM AUTHOR]

The circadian rhythm is a nearly 24‐h oscillation found in various physiological processes in the human brain and body that is regulated by environmental and genetic factors. It is responsible for maintaining body homeostasis and it is critical for essential functions, such as metabolic regulation and memory consolidation. Dysregulation in the circadian rhythm can negatively impact human health, resulting in cardiovascular and metabolic diseases, psychiatric disorders, and premature death. Emerging evidence points to a relationship between the dysregulation circadian rhythm and neurodegenerative diseases, suggesting that the alterations in circadian function might play crucial roles in the pathogenesis and progression of neurodegenerative diseases. Better understanding this association is of paramount importance to expand the knowledge on the pathophysiology of neurodegenerative diseases, as well as, to provide potential targets for the development of new interventions based on the dysregulation of circadian rhythm. Here we review the latest findings on dysregulation of circadian rhythm alterations in Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and multiple‐system atrophy, focusing on research published in the last 3 years. [ABSTRACT FROM AUTHOR]

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C. [ABSTRACT FROM AUTHOR]

Experimental and clinical studies have indicated a potential role of the protein S100β in the pathogenesis and phenotype of neurodegenerative diseases. However, its impact on spinocerebellar ataxia type 2 (SCA2) remains to be elucidated. The objective of the study is to determine the serum levels of S100β in SCA2 and its relationship with molecular, clinical, cognitive, and peripheral inflammatory markers of the disease. Serum concentrations of S100β were measured by enzyme-linked immunosorbent assay in 39 SCA2 subjects and 36 age- and gender-matched controls. Clinical scores of ataxia, non-ataxia symptoms, cognitive dysfunction, and some blood cell count–derived inflammatory indices were assessed. The SCA2 individuals manifested S100β levels similar to the control group, at low nanomolar concentrations. However, the S100β levels were directly associated with a better performance of cognitive evaluation within the SCA2 cohort. Moreover, the S100β levels were inversely correlated with most peripheral inflammatory indices. Indeed, the neutrophil-to-lymphocyte ratio significantly mediated the effect of serum S100β on cognitive performance, even after controlling for the ataxia severity in the causal mediation analysis. Our findings suggested that, within physiologic concentrations, the protein S100β exerts a neuroprotective role against cognitive dysfunction in SCA2, likely via the suppression of pro-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCAs) are inherited neurodegenerative diseases characterized by loss of balance, coordination, and slurred speech. Recently, a digenic mode of inheritance of TBP/STUB1 contributing to SCA was demonstrated. The clinical manifestations of SCATBP/STUB1 include not only ataxia but also obvious cognitive and behavioral impairment. Here, we describe a Chinese family with SCATBP/STUB1 and performed a literature search for similar cases. We identified a Chinese family with SCATBP/STUB1 and compare our clinical findings with other cases described in the literature so far. Four individuals in this family have been found to carry SCATBP/STUB1, of which three have clinical manifestations. A heterozygous deletion mutation in the STIP1-homologous and U-box containing protein 1 (STUB1) gene, NM_005861.4:c433_435del(p.K145del), was identified. The proband is a 34-year-old female with progressive dementia and dysarthria. The mother and uncle of the proband first presented with motor abnormalities and gradually developed cognitive impairment. The proband and her uncle showed cerebellar atrophy on MRI. The proband's brother carried digenic variants but was asymptomatic. SCATBP/STUB1 is a novel SCA subtype. The main clinical manifestations are motor, cognitive, and behavioral abnormalities. Brain MRI shows significant cerebellar atrophy and cortical thinning. The independent segregation of TBP and STUB1 alleles should be considered when evaluating patients with cognitive impairment and ataxia. [ABSTRACT FROM AUTHOR]

Background: Little is known about the progression of health-related quality of life (HRQoL) and predicting factors in spinocerebellar ataxia (SCA). Such knowledge is crucial to identify modifiable factors promoting everyday life with SCA and attenuating HRQoL decline. Objectives: This study is to assess HRQoL progression and identify factors affecting SCA patients' HRQoL. Methods: Longitudinal data (three-year follow-up) of 310 SCA patients of the European SCA3/Machado-Joseph-Disease Initiative (ESMI) (2016-2022) and 525 SCA patients (SCA1, SCA2, SCA3 or SCA6) of the EUROSCA natural history study cohort (2006–2015) were assessed. Both large cohort studies share standardized assessments of clinical measures, SARA, INAS, PHQ-9, and HRQoL (EQ-5D-3L). The association between HRQoL and clinical measures was assessed by Spearman Correlation (rs). Multivariable panel regression models were performed to evaluate the impact of patients' socio-demographics, age of onset, SCA type and body mass index (BMI), and clinical measures on HRQoL progression. Results: HRQoL significantly decreased over one (− 0.014, p = 0.095), two (− 0.028, p = 0.003), and three years (− 0.032, p = 0.002). Ataxia severity and mental health strongly correlated with HRQoL (rsSARA = − 0.589; rsPHQ-9 = − 0.507). HRQoL more intensively declined in male (ß = − 0.024, p = 0.038) patients with an earlier age of onset (ß = 0.002, p = 0.058). Higher progression of ataxia severity (ß = − 0.010, p ≤ 0.001), mental health problems (ß = − 0.012, p < 0.001), and higher BMI (ß = − 0.003, p = 0.029) caused more severe decline of patients' HRQoL over time. Discussion: In absence of curative treatments, stronger focus on mental health and weight influence could help clinical evaluation and accompany treatment improving SCA patients' HRQoL, especially in male patients with early disease onset. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia 19 (SCA19) represents a rare autosomal dominant genetic disorder resulting in progressive ataxia and cerebellar atrophy. SCA19 is caused by variants in the KCND3 gene, which encodes a voltage-gated potassium channel subunit essential for cerebellar Purkinje cell function. We describe six cases from Chile and Mexico, representing the largest report on SCA19 in Latin America. These cases encompass a range of clinical presentations, highlighting the phenotypic variability within SCA19 from an early-onset, severe disease to a late-onset, slowly progressive condition with normal lifespan. While some patients present with pure ataxia, others also show cognitive impairment, dystonia, and other neurological symptoms. The correlations between specific KCND3 variants and phenotypic outcomes are complex and warrant further investigation. As the genomic landscape of spinocerebellar ataxias evolves, comprehensive genetic testing is becoming pivotal in improving diagnostic accuracy. This study contributes to a better understanding of the clinical spectrum of SCA19, laying the groundwork for further genotype-phenotype correlations and functional studies to elucidate the underlying pathophysiology. [ABSTRACT FROM AUTHOR]

A clinical scale fully dedicated to evaluating ocular motor abnormalities is required for now. We investigated the utility of a recently developed Scale for Ocular motor Disorders in Ataxia (SODA) in patients with multiple system atrophy (MSA). We prospectively assessed SODA in consecutive patients with MSA between August 2021 and August 2023 at the Korea University Medical Center. The results of the clinical exam-based SODA were compared with those measured using video-oculography (VOG-guided SODA). We also compared the findings with other established clinical scales targeting patients with MSA, including the Unified Multiple System Atrophy Rating Scale (UMSARS) I-II, Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (UPDRS-III), Scale for Assessment of Rating of Ataxia (SARA), Composite Autonomic Symptom Score-31 (COMPASS-31), and Composite Autonomic Severity Score (CASS). Twenty patients were enrolled in our study (17 with cerebellar-type MSA and three with Parkinson-type MSA). Scores ranged from 1 to 14 (median [interquartile range (IQR)] = 8 [5−10]). Among the subscales, saccades had a median score of 2.5 (IQR = 1–3), followed by ocular pursuit (1 [0–1]), nystagmus (1 [0–2]), saccadic intrusions (1 [0–1]), vestibulo-ocular reflex (VOR) (0.5 [0–1]), ocular alignment (0 [0–1]), and VOR cancellation (1 [0–1]). The clinical-exam-based SODA (p = 0.020) and VOG-guided SODA (p = 0.034) positively correlated with disease duration. No correlation was found between clinical exam-based SODA and other scales. Skew deviation, gaze-evoked nystagmus, VOR cancellation, and smooth pursuit had the highest precision among the items. Ocular misalignment and spontaneous and positional nystagmus were frequently false positive and were poorly detected with clinical exam-based SODA. Six patients with repeated evaluation exhibited higher scores, along with deterioration documented on other clinical scales. The SODA can reliably predict neurodegeneration as an additional clinical surrogate in MSA. [ABSTRACT FROM AUTHOR]

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes. [ABSTRACT FROM AUTHOR]

Spectral domain optical coherence tomography (SD-OCT) allows noninvasive measurements of retinal neuron layers. Here, we evaluate the relationship between clinical features and anatomical SD-OCT measurements in patients with spinocerebellar ataxia type 3 (SCA3) and how they change with time. A retrospective review was conducted on SCA3 patients. Clinical variables such as disease duration, number of CAG repeats, and the Scale for the Assessment and Rating of Ataxia (SARA) score were correlated with SD-OCT measurements, including retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, macular volume (MV), and central macular thickness (CMT). Seventeen SCA3 patients with an average follow-up of 44.9 months were recruited. Clinical features with significant baseline correlations with SD-OCT measurements included disease duration (CMT r = − 0.590; GCC r = − 0.585), SARA score (CMT r = − 0.560; RNFL r = − 0.390), and number of CAG repeats (MV r = − 0.552; RNFL r = − 0.503; GCC r = − 0.493). The annual rate of change of the SARA score during follow-up was associated with that of both the MV (r = − 0.494; p = 0.005) and GCC thickness (r = − 0.454; p = 0.012). High disability (stages 2 and 3) was independently inversely associated with the annual change in MV (ß coefficient − 17.09; p = 0.025). This study provides evidence of an association between clinical features and objective anatomical measurements obtained by SD-OCT in SCA3 patients. MV and GCC thickness could serve as potential biomarkers of disease severity, as their rates of decrease seem to be related to a worsening in the SARA score. These findings highlight the potential of SD-OCT as a noninvasive tool for assessing disease severity and progression in SCA3 patients. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated the potential of non-invasive brain stimulation (NIBS) techniques as a viable treatment option for cerebellar ataxia. However, there is a notable dearth of research investigating the efficacy of NIBS specifically for hereditary ataxia (HA), a distinct subgroup within the broader category of cerebellar ataxia. This study aims to conduct a comprehensive systematic review and meta-analysis in order to assess the efficacy of various NIBS methods for the treatment of HA. A thorough review of the literature was conducted, encompassing both English and Chinese articles, across eight electrical databases. The focus was on original articles investigating the therapeutic effectiveness of non-invasive brain stimulation for hereditary ataxia, with a publication date prior to March 2023. Subsequently, a meta-analysis was performed specifically on randomized controlled trials (RCTs) that fulfilled the eligibility criteria, taking into account the various modalities of non-invasive brain stimulation. A meta-analysis was conducted, comprising five RCTs, which utilized the Scale for the Assessment and Rating of Ataxia (SARA) as the outcome measure to evaluate the effects of transcranial magnetic stimulation (TMS). The findings revealed a statistically significant mean decrease of 1.77 in the total SARA score following repetitive TMS (rTMS) (p=0.006). Subgroup analysis based on frequency demonstrated a mean decrease of 1.61 in the total SARA score after high-frequency rTMS (p=0.05), while no improvement effects were observed after low-frequency rTMS (p=0.48). Another meta-analysis was performed on three studies, utilizing ICARS scores, to assess the impact of rTMS. The results indicated that there were no statistically significant differences in pooled ICARS scores between the rTMS group and the sham group (MD=0.51, 95%CI: -5.38 to 6.39; p=0.87). These findings align with the pooled results of two studies that evaluated alterations in post-intervention BBS scores (MD=0.74, 95%CI: -5.48 to 6.95; p=0.82). Despite the limited number of studies available, this systematic review and meta-analysis have revealed promising potential benefits of rTMS for hereditary ataxia. However, it is strongly recommended that further high-quality investigations be conducted in this area. Furthermore, the significance of standardized protocols for NIBS in future studies was also emphasized. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS), comprising targeted panels (TP), exome sequencing (ES), and genome sequencing (GS) became robust clinical tools for diagnosing hereditary ataxia (HA). Determining their diagnostic yield (DY) is crucial for optimal clinical decision-making. We conducted a comprehensive systematic literature review on the DY of NGS tests for HA. We searched PubMed and Embase databases for relevant studies between 2016 and 2022 and manually examined reference lists of relevant reviews. Eligible studies described the DY of NGS tests in patients with ataxia as a significant feature. Data from 33 eligible studies showed a median DY of 43% (IQR = 9.5–100%). The median DY for TP and ES was 46% and 41.9%, respectively. Higher DY was associated with specific phenotype selection, such as episodic ataxia at 68.35% and early and late onset of ataxia at 46.4% and 54.4%. Parental consanguinity had a DY of 52.4% (p = 0.009), and the presumed autosomal recessive (AR) inheritance pattern showed 62.5%. There was a difference between the median DY of studies that performed targeted sequencing (tandem repeat expansion, TRE) screening and those that did not (p = 0.047). A weak inverse correlation was found between DY and the extent of previous genetic investigation (rho = − 0.323; p = 0.065). The most common genes were CACNA1A and SACS. DY was higher for presumed AR inheritance pattern, positive family history, and parental consanguinity. ES appears more advantageous due to the inclusion of rare genes that might be excluded in TP. [ABSTRACT FROM AUTHOR]

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials. This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes. [ABSTRACT FROM AUTHOR]

Machado Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disease. Mentalizing is the ability to think and understand the mental state of the other and of the self in terms of thoughts, feelings, and intentions. The aim of this study is to fill the gap in our understanding of mentalizing in MJD since there is currently very little and inconsistent research on MJD and mentalizing. A total of 18 Jews of Yemenite origin with clinically and genetically confirmed MJD, 5 pre-symptomatic MJD with a positive genetic test, and 17 Jews of Yemenite origin healthy controls, underwent a battery of tests consisting of reading the mind in the eyes (RME), Toronto Alexithymia Scale (TAS-20), and false belief test (FBt). The MJD group scored lower on the RME and FBt, and higher on TAS-20 test compared to control. A significant negative correlation was found between disease duration and RME score. All the pre-symptomatic participants scored within the normal clinical range in all tests. MJD patients demonstrated a widespread deficiency in the ability to mentalizing on a clinical level with autistic characteristics. These impairments may impact the patient's interpsychic experience and daily life interactions and have important clinical implication. Pre-symptomatic participants demonstrated normal mentalizing in all tests, suggesting that the mentalizing impairments do not precede the symptoms of ataxia and are part of the clinical picture of MJD. [ABSTRACT FROM AUTHOR]

This article describes a case of co-existing Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease (MOGAD) and Spinocerebellar Ataxia type 1 (SCA1). MOGAD is an autoimmune demyelinating disorder of the central nervous system, while SCA1 is a genetic disorder that affects the cerebellum. The patient in this case inherited an expansion in the ataxin-1 (ATX-1) gene from her father, who had SCA1. This is the first reported case of a patient with both MOGAD and ATX-1 gene expansion. The article suggests that ATX-1 may have an immunomodulatory role and could potentially influence the pathogenesis and severity of demyelinating diseases. Further research is needed to understand the impact of ATX-1 expansion or variants in the development and clinical course of MOGAD. [Extracted from the article]

Since 1991, several genetic disorders caused by unstable trinucleotide repeats (TNRs) have been identified, collectively referred to as triplet repeat diseases (TREDs). They share a common mutation mechanism: the expansion of repeats (dynamic mutations) due to the propensity of repeated sequences to form unusual DNA structures during replication. TREDs are characterized as neurodegenerative diseases or complex syndromes with significant neurological components. Spinocerebellar ataxia type 17 (SCA17) falls into the former category and is caused by the expansion of mixed CAA/CAG repeats in the TBP gene. To date, a five-unit organization of this region [(CAG)3 (CAA)3] [(CAG)n] [CAA CAG CAA] [(CAG)n] [CAA CAG], with expansion in the second [(CAG)n] unit being the most common, has been proposed. In this study, we propose an alternative organization scheme for the repeats. A search of the PubMed database was conducted to identify articles reporting both the number and composition of GAC/CAA repeats in TBP alleles. Nineteen reports were selected. The sequences of all identified CAG/CAA repeats in the TBP locus, including 67 cases (probands and b relatives), were analyzed in terms of their repetition structure and stability in inheritance, if possible. Based on the analysis of three units [(CAG)3 (CAA)2] [CAA (CAG)n CAA CAG] [CAA (CAG)n CAA CAG], the organization of repeats is proposed. Detailed analysis of the CAG/CAA repeat structure, not just the number of repeats, in TBP-expanded alleles should be performed, as it may have a prognostic value in the prediction of stability/instability during transmission and the possible anticipation of the disease. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a neurodegenerative disorder caused by the ATXN3 CAG repeat expansion. Preimplantation genetic testing for monogenic disorders (PGT-M) of SCA3/MJD should include reliable repeat expansion detection coupled with high-risk allele determination using informative linked markers. One couple underwent SCA3/MJD PGT-M combining ATXN3 (CAG)n triplet-primed PCR (TP-PCR) with customized linkage-based risk allele genotyping on whole-genome-amplified trophectoderm cells. Microsatellites closely linked to ATXN3 were identified and 16 markers were genotyped on 187 anonymous DNAs to verify their polymorphic information content. In the SCA3/MJD PGT-M case, the ATXN3 (CAG)n TP-PCR and linked marker analysis results concurred completely. Among the three unaffected embryos, a single embryo was transferred and successfully resulted in an unaffected live birth. A total of 139 microsatellites within 1 Mb upstream and downstream of the ATXN3 CAG repeat were identified and 8 polymorphic markers from each side were successfully co-amplified in a single-tube reaction. A PGT-M assay involving ATXN3 (CAG)n TP-PCR and linkage-based risk allele identification has been developed for SCA3/MJD. A hexadecaplex panel of highly polymorphic microsatellites tightly linked to ATXN3 has been developed for the rapid identification of informative markers in at-risk couples for use in the PGT-M of SCA3/MJD. [ABSTRACT FROM AUTHOR]

Background: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. Objective: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. Methods: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. Results: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. Conclusion: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Clinical trials for upcoming disease‐modifying therapies of spinocerebellar ataxias (SCA), a group of rare movement disorders, lack endpoints sensitive to early disease progression, when therapeutics will be most effective. In addition, regulatory agencies emphasize the importance of biological outcomes.READISCA, a transatlantic clinical trial readiness consortium, investigated whether advanced multimodal magnetic resonance imaging (MRI) detects pathology progression over 6 months in preataxic and early ataxic carriers of SCA mutations.A total of 44 participants (10 SCA1, 25 SCA3, and 9 controls) prospectively underwent 3‐T MR scanning at baseline and a median [interquartile range] follow‐up of 6.2 [5.9–6.7] months; 44% of SCA participants were preataxic. Blinded analyses of annual changes in structural, diffusion MRI, MR spectroscopy, and the Scale for Assessment and Rating of Ataxia (SARA) were compared between groups using nonparametric testing. Sample sizes were estimated for 6‐month interventional trials with 50% to 100% treatment effect size, leveraging existing large cohort data (186 SCA1, 272 SCA3) for the SARA estimate.Rate of change in microstructural integrity (decrease in fractional anisotropy, increase in diffusivities) in the middle cerebellar peduncle, corona radiata, and superior longitudinal fasciculus significantly differed in SCAs from controls (P < 0.005), with high effect sizes (Cohen's d = 1–2) and moderate‐to‐high responsiveness (|standardized response mean| = 0.6–0.9) in SCAs. SARA scores did not change, and their rate of change did not differ between groups.Diffusion MRI is sensitive to disease progression at very early‐stage SCA1 and SCA3 and may provide a >5‐fold reduction in sample sizes relative to SARA as endpoint for 6‐month‐long trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Introduction/Aims Methods Results Discussion Oculopharyngodistal myopathy type 4 (OPDM4) arises from a CGG repeat expansion in the 5′ UTR of the RILPL1 gene. Reported cases of OPDM4 have been limited. The aim of this study was to investigate the clinical and myopathological characteristics of OPDM4 patients with advanced disease.We assessed a total of 8 affected and 12 unaffected individuals in an OPDM4 family with autosomal dominant inheritance. Muscle biopsy tissue from the proband underwent histological, enzyme histochemical, and immunohistochemical stains, and electron microscopy analysis. Whole exome sequencing and repeat primer PCR (RP‐PCR) were conducted to investigate underlying variants.OPDM4 patients displayed a progressive disease course. Most experienced lower limb weakness and diminished walking ability in their 20s and 30s, followed by ptosis, ophthalmoplegia, swallowing difficulties, and dysarthria in their 30s to 50s, By their 50s to 70s, they became non‐ambulatory. Muscle magnetic resonance imaging (MRI) of the proband in advanced disease revealed severe fatty infiltration of pelvic girdle and lower limb muscles. Biopsied muscle tissue exhibited advanced changes typified by adipose connective tissue replacement and the presence of multiple eosinophilic and p62‐positive intranuclear inclusions. Immunopositivity for the intranuclear inclusions was observed with anti‐glycine antibody and laboratory‐made polyA‐R1 antibody. RP‐PCR unveiled an abnormal CGG repeat expansion in the 5′ UTR of the RILPL1 gene.The clinical and radiological features in this family broaden the phenotypic spectrum of OPDM4. The presence of intranuclear inclusions in the proliferative adipose connective tissues of muscle biopsy specimens holds diagnostic significance for OPDM4 in advanced disease. [ABSTRACT FROM AUTHOR]

Ataxin-2 (ATXN2) was originally discovered in the context of spinocerebellar ataxia type 2 (SCA2), but it has become a key player in various neurodegenerative diseases. This review delves into the multifaceted roles of ATXN2 in human diseases, revealing its diverse molecular and cellular pathways. The impact of ATXN2 on diseases extends beyond functional outcomes; it mainly interacts with various RNA-binding proteins (RBPs) to regulate different stages of post-transcriptional gene expression in diseases. With the progress of research, ATXN2 has also been found to play an important role in the development of various cancers, including breast cancer, gastric cancer, pancreatic cancer, colon cancer, and esophageal cancer. This comprehensive exploration underscores the crucial role of ATXN2 in the pathogenesis of diseases and warrants further investigation by the scientific community. By reviewing the latest discoveries on the regulatory functions of ATXN2 in diseases, this article helps us understand the complex molecular mechanisms of a series of human diseases related to this intriguing protein. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited expansion disorder with highly variable penetrance. ATXN8OS/ATXN8 expanded alleles have been identified in association with other types of hereditary ataxias, pointing to a possible genetic synergism.We aimed to further investigate the molecular background of patients with SCA8 diagnosis.Patients were selected from our cohort of 346 families. A total of 14 probands with SCA8 underwent additional investigation through exome sequencing.Pathogenic heterozygous STUB1 variants were found in 21.4% of SCA8 patients (3 of 14) compared to only 0.5% in the non‐SCA8 group (1 of 222), indicating a statistically significant association (P < 0.05).The findings reported in this study might suggest a genetic synergism between STUB1 and ATXN8OS/ATXN8 expanded alleles. Further studies are needed to validate this observation and better define the clinical impact of this genetic interaction. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Nucleotide repeat expansions in the human genome are a well-known cause of neurological disease. In the past decade, advances in DNA sequencing technologies have led to a better understanding of the role of non-coding DNA, that is, the DNA that is not transcribed into proteins. These techniques have also enabled the identification of pathogenic non-coding repeat expansions that cause neurological disorders. Mounting evidence shows that adult patients with familial or sporadic presentations of epilepsy, cognitive dysfunction, myopathy, neuropathy, ataxia, or movement disorders can be carriers of non-coding repeat expansions. The description of the clinical, epidemiological, and molecular features of these recently identified non-coding repeat expansion disorders should guide clinicians in the diagnosis and management of these patients, and help in the genetic counselling for patients and their families. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. Methods: Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). Results: Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. Conclusions: Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD. [ABSTRACT FROM AUTHOR]

We aimed to produce a mouse model of spinocerebellar ataxia type 3 (SCA3) using the mouse blood–brain barrier (BBB)-penetrating adeno-associated virus (AAV)-PHP.B. Four-to-five-week-old C57BL/6 mice received injections of high-dose (2.0 × 1011 vg/mouse) or low-dose (5.0 × 1010 vg/mouse) AAV-PHP.B encoding a SCA3 causative gene containing abnormally long 89 CAG repeats [ATXN3(Q89)] under the control of the ubiquitous chicken β-actin hybrid (CBh) promoter. Control mice received high doses of AAV-PHP.B encoding ATXN3 with non-pathogenic 15 CAG repeats [ATXN3(Q15)] or phosphate-buffered saline (PBS) alone. More than half of the mice injected with high doses of AAV-PHP.B encoding ATXN3(Q89) died within 4 weeks after the injection. No mice in other groups died during the 12-week observation period. Mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89) exhibited progressive motor uncoordination starting 4 weeks and a shorter stride in footprint analysis performed at 12 weeks post-AAV injection. Immunohistochemistry showed thinning of the molecular layer and the formation of nuclear inclusions in Purkinje cells from mice injected with low doses of AAV-PHP.B encoding ATXN3(Q89). Moreover, ATXN3(Q89) expression significantly reduced the number of large projection neurons in the cerebellar nuclei to one third of that observed in mice expressing ATXN3(Q15). This AAV-based approach is superior to conventional methods in that the required number of model mice can be created simply by injecting AAV, and the expression levels of the responsible gene can be adjusted by changing the amount of AAV injected. Moreover, this method may be applied to produce SCA3 models in non-human primates. [ABSTRACT FROM AUTHOR]

Background: The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale to assess cerebellar ataxia but faces some criticisms about the relevancy of all its items. Objectives: To prepare for future clinical trials, we analyzed the progression of SARA and its items in several polyQ spinocerebellar ataxias (SCA) from various cohorts. Methods: We included data from patients with SCA1, SCA2, SCA3, and SCA6 from four cohorts (EUROSCA, RISCA, CRC-SCA, and SPATAX) for a total of 850 carriers and 3431 observations. Longitudinal progression of the SARA and its items was measured. Cohort, stage and genetic effects were tested. We looked at the respective contribution of each item to the total scale. Sensitivity to change of the scale and the impact of item removal was evaluated by calculating sample sizes needed in various scenarios. Results: Longitudinal progression was significantly different between cohorts in SCA1, SCA2 and SCA3, the EUROSCA cohort having the fastest progression. Advanced-stage patients were progressing slower in SCA2 and SCA6. Items were not contributing equally to the full scale through ataxia severity: gait, stance, hand movement, and heel-shin contributed the most in the early stage, and finger-chase, nose-finger, and sitting in later stages. Few items drove the sensitivity to the change of SARA, but changes in the scale structure could not improve its sensitivity in all populations. Conclusion: SARA and its item's progression pace showed high heterogeneity across cohorts and SCAs. However, no combinations of items improved the responsiveness in all SCAs or populations taken separately. [ABSTRACT FROM AUTHOR]

This document is a letter to the editors of the Journal of Neurology discussing a case of RFC1-related disorder presenting recurrent syncope. RFC1-related disorder is a neurodegenerative disorder characterized by cerebellar ataxia, sensory neuropathy, and bilateral vestibular dysfunction. The patient in this case was an 81-year-old man who experienced repeated episodes of syncope. The letter provides a detailed description of the patient's symptoms and medical history, as well as the diagnostic tests conducted. The authors conclude that RFC1-related disorder should be considered in cases of autonomic dysfunction and syncope. [Extracted from the article]

Objective: Biallelic mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32. In this study, which aims to contribute to the growing body of knowledge on this rare disease, we identified two unrelated patients with mutations in PRDX3. We explored the impact of PRDX3 mutation in patient skin fibroblasts and the role of the gene in neurodevelopment. Methods: We performed trio exome sequencing that identified mutations in PRDX3 in two unrelated patients. We also performed functional studies in patient skin fibroblasts and generated a "crispant" zebrafish (Danio rerio) model to investigate the role of the gene during nervous system development. Results: Our study reports two additional patients. Patient 1 is a 19‐year‐old male who showed a novel homozygous c.525_535delGTTAGAAGGTT (p. Leu176TrpfsTer11) mutation as the genetic cause of cerebellar ataxia. Patient 2 is a 20‐year‐old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one. While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function, our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species‐triggered apoptosis, and an impaired oxygen consumption rate. Conclusions: We identified a new variant, thereby expanding the genetic spectrum of PRDX3‐related disease. We developed a novel zebrafish model to investigate the consequences of prdx3 depletion on neurodevelopment and thus offered a potential new tool for identifying new treatment opportunities. [ABSTRACT FROM AUTHOR]