UNASSIGNED: For various genetic disorders characterized by expanded cytosine-adenine-guanine (CAG) repeats, such as spinocerebellar ataxia (SCA) subtypes and Huntington\'s disease (HD), genetic interventions are currently being tested in different clinical trial phases. The patient\'s perspective on such interventions should be included in the further development and implementation of these new treatments.
UNASSIGNED: To obtain insight into the thoughts and perspectives of individuals with SCA and HD on genetic interventions.
UNASSIGNED: In this qualitative study, participants were interviewed using semi-structured interview techniques. Topics discussed were possible risks and benefits, and logistic factors such as timing, location and expertise. Data were analyzed using a generic thematic analysis. Responses were coded into superordinate themes.
UNASSIGNED: Ten participants (five with SCA and five with HD) were interviewed. In general, participants seemed to be willing to undergo genetic interventions. Important motives were the lack of alternative disease-modifying treatment options, the hope for slowing down disease progression, and preservation of current quality of life. Before undergoing genetic interventions, participants wished to be further informed. Logistic factors such as mode and frequency of administration, expertise of the healthcare provider, and timing of treatment are of influence in the decision-making process.
UNASSIGNED: This study identified assumptions, motives, and topics that require further attention before these new therapies, if proven effective, can be implemented in clinical practice. The results may help in the design of care pathways for genetic interventions for these and other rare genetic movement disorders.

BACKGROUND: 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)].
CONCLUSIONS: 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.
UNASSIGNED: NCT03701399.

OBJECTIVE: This study aimed to correlate the symptoms and signs with the findings of laboratory vestibular function tests in patients with spinocerebellar ataxia (SCA).
METHODS: We retrospectively recruited 26 patients with SCA (9 men, median age: 52, age range: 21-67). Assessments included Dizziness Handicap Inventory, EuroQoL Five-Dimension, symptom questionnaires manifesting during walking in daily life, the Scale for the Assessment and Rating of Ataxia (SARA), and vestibular function tests including 3D video-oculography, video head impulse test, subjective visual vertical, and cervical and ocular vestibular evoked myogenic potentials (VEMP).
RESULTS: Cross-analyses revealed that the patients with VEMP abnormalities showed higher SARA (p = 0.014) and prevalence of unpredictable falls (p = 0.046). The patients with SCA1 more frequently had unpredictable falls (75%, p = 0.038) and VEMP abnormalities (88%, p = 0.001) compared to SCA2 (29% falls, 17% VEMP abnormalities) and SCA6 (no falls or VEMP abnormalities).
CONCLUSIONS: Abnormal VEMPs are strongly associated with unpredicted falls in patients with SCA, particularly in those with SCA1. Impaired processing of otolithic information may contribute to falls in SCAs, and VEMP may help identifying the patients with a risk for unpredicted falls and preventing fall-related injuries in SCA. Limited number of patients with lower SARA scores warrant further confirmatory studies.

Although health-related quality of life (HRQoL) has developed into a crucial outcome parameter in clinical research, evidence of the EQ-5D-3L validation performance is lacking in patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The objective of this study is to assess the acceptability, validity, reliability, and responsiveness of the EQ-5D-3L. For n = 842 predominantly European SCA patients of two longitudinal cohort studies, the EQ-5D-3L, PHQ-9 (Patient Health Questionnaire), and ataxia-specific clinical assessments (SARA: Scale for Assessment and Rating of Ataxia; ADL: activities of daily living as part of Friedreich\'s Ataxia Rating Scale; INAS: Inventory of Non-Ataxia Signs) were assessed at baseline and multiple annual follow-ups. The EQ-5D-3L was evaluated regarding acceptability, distribution properties, convergent and known-groups validity, test-retest reliability, and effect size measures to analyze health changes. The non-item response was low (EQ-5D-3L index: 0.8%; EQ-VAS: 3.4%). Ceiling effects occurred in 9.9% (EQ-5D-3L) and 3.0% (EQ-VAS) with a mean EQ-5D-3L index of 0.65 ± 0.21. In total, convergent validity showed moderate to strong Spearman\'s rho (rs > 0.3) coefficients comparing EQ-5D-3L and EQ-VAS with PHQ-9, SARA, ADL, and INAS. EQ-5D-3L could discriminate between groups of age, SARA, ADL, and INAS. Intra-class correlation coefficients (EQ-5D-3LICC: 0.95/EQ-VASICC: 0.88) and Kappa statistics (range 0.44 to 0.93 for EQ-5D-3L items) indicated tolerable reliability. EQ-5D-3L shows small (effect size < 0.3) to moderate (effect size 0.3-0.59) health changes regarding ataxia severity. The analysis confirms an acceptable, reliable, valid, and responsive recommended EQ-5D-3L in SCA patients, measuring the HRQoL adequately, besides well-established clinical instruments.

Spinocerebellar ataxias (SCAs) are familial neurodegenerative diseases involving the cerebellum and spinocerebellar tracts. While there is variable involvement of corticospinal tracts (CST), dorsal root ganglia, and motor neurons in SCA3, SCA6 is characterized by a pure, late-onset ataxia. Abnormal intermuscular coherence in the beta-gamma frequency range (IMCβγ) implies a lack of integrity of CST or the afferent input from the acting muscles. We test the hypothesis that IMCβγ has the potential to be a biomarker of disease activity in SCA3 but not SCA6. Intermuscular coherence between biceps brachii and brachioradialis muscles was measured from surface EMG waveforms in SCA3 (N = 16) and SCA6 (N = 20) patients and in neurotypical subjects (N = 23). IMC peak frequencies were present in the β range in SCA patients and in the γ range in neurotypical subjects. The difference between IMC amplitudes in the γ and β ranges was significant when comparing neurotypical control subjects to SCA3 (p < 0.01) and SCA6 (p = 0.01) patients. IMCβγ amplitude was smaller in SCA3 patients compared to neurotypical subjects (p < 0.05), but not different between SCA3 and SCA6 patients or between SCA6 and neurotypical subjects. IMC metrics can differentiate SCA patients from normal controls.

UNASSIGNED: Cerebellar ataxia (CA) is a movement disorder that can affect balance and gait, limb movement, oculomotor control, and cognition. Multiple system atrophy-cerebellar type (MSA-C) and spinocerebellar ataxia type 3 (SCA3) are the most common forms of CA, for which no effective treatment is currently available. Transcranial alternating current stimulation (tACS) is a non-invasive method of brain stimulation supposed to alter cortical excitability and brain electrical activity, modulating functional connectivity within the brain. The cerebellar tACS can modulate the cerebellar outflow and cerebellum-linked behavior and it is a proven safe technique for humans. Therefore, the aim of this study is to 1) examine whether cerebellar tACS improves ataxia severity and various non-motor symptoms in a homogeneous cohort of CA patients consisting of MSA-C and SCA3, 2) explore the time course of these effects, and 3) assess the safety and tolerance of cerebellar tACS in all participants.
UNASSIGNED: This is a 2-week, triple-blind, randomised, sham-controlled study. 164 patients (MSA-C: 84, SCA3: 80) will be recruited and randomly assigned to either active cerebellar tACS or sham cerebellar tACS, in a 1:1 ratio. Patients, investigators, and outcome assessors are unaware of treatment allocation. Cerebellar tACS (40 min, 2 mA, ramp-up and down periods of 10s each) will be delivered over 10 sessions, distributed in two groups of five consecutive days with a two-day break in between. Outcomes are assessed after the tenth stimulation (T1), and after 1 month (T2) and 3 months (T3). The primary outcome measure is the difference between the active and sham groups in the proportion of patients with an improvement of 1.5 points in the Scale for the Assessment and Rating of Ataxia (SARA) score after 2 weeks of treatment. In addition, effects on a variety of non-motor symptoms, quality of life, and autonomic nerve dysfunctions are assessed via relative scales. Gait imbalance, dysarthria, and finger dexterity are objectively valued via relative tools. Finally, functional magnetic resonance imaging is performed to explore the possible mechanism of treatment effects.
UNASSIGNED: The results of this study will inform whether repeated sessions of active cerebellar tACS benefit CA patients and whether this form of non-invasive stimulation might be a novel therapeutic approach to consider in a neuro-rehabilitation setting.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05557786; https://www.clinicaltrials.gov/ct2/show/NCT05557786.

In an open pilot trial, six patients with various hereditary forms of spinocerebellar ataxia (SCA) were assigned to topiramate (50 mg/day) for 24 weeks. Four patients completed the protocol without adverse events. Of these four patients, topiramate was effective for three patients. Some patients with SCA could respond to treatment with topiramate.

BACKGROUND: The genetics of hereditary ataxia (HA) are complex and multigenic. The diversity of genes that cause ataxia varies considerably between populations. We aimed to investigate the clinical, neuroimaging, and genetic findings of HA in children from a tertiary center in Turkey.
METHODS: The clinical and neuroimaging evaluations of patients, laboratory investigations, and molecular genetic evaluations of those with ataxia were performed at the pediatrics, pediatric neurology, and genetics outpatient clinics between October 2020 and October 2021. With repeated expansions in the ATXN 1, 2, 3, 7, and 8 genes for spinocerebellar ataxia (SCA) and FXN genes for Friedreich\'s ataxia (FA), whole-exome sequencing (WES) was used to analyze every patient.
RESULTS: 25 patients from 24 families had ataxia and an unsteady gait as their main symptoms. The patients had a mean age of 8.5 ± 3.78 years, and the symptoms had begun at a mean age of 2 ± 0.62 years; five of these were males and three were females. A genetic cause of ataxia was found in 8/25 patients (32%). Seven of the eight gene mutations detected in the patients were novel mutations. Spinocerebellar ataxia was found in 16% of cases (n = 4), L-2-Hydroxyglutaric aciduria was found in 12% of cases (n = 3), and ataxia-telangiectasia was found in 4% of cases (n = 1).
CONCLUSIONS: Our research adds to the body of knowledge by describing the clinical and genetic traits of HA patients in our area and by finding unusual gene changes linked to ataxia.

Coding and noncoding repeat expansions are an important cause of neurodegenerative diseases.
This study determined the clinical and genetic features of a large German family that has been followed for almost 2 decades with an autosomal dominantly inherited spinocerebellar ataxia (SCA) and independent co-occurrence of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
We carried out clinical examinations and telephone interviews, reviewed medical records, and performed magnetic resonance imaging and positron emission tomography scans of all available family members. Comprehensive genetic investigations included linkage analysis, short-read genome sequencing, long-read sequencing, repeat-primed polymerase chain reaction, and Southern blotting.
The family comprises 118 members across seven generations, 30 of whom were definitely and five possibly affected. In this family, two different pathogenic mutations were found, a heterozygous repeat expansion in C9ORF72 in four patients with ALS/FTD and a heterozygous repeat expansion in DAB1 in at least nine patients with SCA, leading to a diagnosis of DAB1-related ataxia (ATX-DAB1; SCA37). One patient was affected by ALS and SCA and carried both repeat expansions. The repeat in DAB1 had the same configuration but was larger than those previously described ([ATTTT]≈75 [ATTTC]≈40-100 [ATTTT]≈415 ). Clinical features in patients with SCA included spinocerebellar symptoms, sometimes accompanied by additional ophthalmoplegia, vertical nystagmus, tremor, sensory deficits, and dystonia. After several decades, some of these patients suffered from cognitive decline and one from additional nonprogressive lower motor neuron affection.
We demonstrate genetic and clinical findings during an 18-year period in a unique family carrying two different pathogenic repeat expansions, providing novel insights into their genotypic and phenotypic spectrums. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology-ranging from clinical activity to the genealogical reconstruction of families/populations across the centuries, the creation of databases, and molecular/genetic research-was modelled on the characteristics of the Calabrian population for more than three decades. This methodology allowed the identification of several novel genetic mutations or variants associated with neurodegenerative diseases. In addition, a higher prevalence of several hereditary neurodegenerative diseases has been reported in this population, such as Alzheimer\'s disease, frontotemporal dementia, Parkinson\'s disease, Niemann-Pick type C disease, spinocerebellar ataxia, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker disease. Here, we summarize and discuss the results of research data supporting the view that Calabria could be considered as a genetic isolate and could represent a model, a sort of outdoor laboratory-similar to very few places in the world-useful for the advancement of knowledge on neurodegenerative diseases.