Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disorder with prominent upper limb tremors. No trials have evaluated tremor-targeted therapies in this population. We evaluated long-acting propranolol for efficacy and safety in reducing tremors and improving ataxia and quality of life in SCA12. In this single-center, randomized, double-blind, placebo-controlled trial, 60 genetically confirmed SCA12 patients (aged 18-65 years; TETRAS PS [The Essential Tremor Rating Assessment Scale Performance Subscale] upper limb component ≥2) were randomized 1:1 to receive extended-release propranolol or placebo. Propranolol was escalated by 40 mg/week (placebo by one tablet/week) up to 240 mg/day, limiting side effects or ≥30% reduction in TETRAS PS/ADL (Activities-of-Daily-Living Subscale) + PS. The stable dose was continued for 8 weeks (maintenance phase). Primary outcomes were changes from baseline in TETRAS PS and ADL + PS at maintenance weeks 4 and 8. Secondary outcomes included changes in the Scale for the Assessment and Rating of Ataxia (SARA), RAND 36-Item Short-Form Health Survey (SF-36) domains, and accelerometric tremor parameters. Propranolol significantly reduced TETRAS PS (LSM ± SE: -4.4 ± 0.3 at week 4; -4.42 ± 0.4 at week 8) and ADL + PS (-5.5 ± 0.63 at week 4; -5.56 ± 0.62 at week 8; P < 0.001 vs. placebo). Significant improvements were also noted in SARA and five of nine SF-36 domains at both time points. Accelerometry confirmed reductions in tremor peak frequency and power in all positions except rest. Fatigue and headache were the commonest adverse effects, with no discontinuations due to adverse events. Propranolol effectively reduced tremors and improved quality of life in SCA12, with good tolerability. © 2025 International Parkinson and Movement Disorder Society.

Spinocerebellar ataxia type 3 (SCA3) is characterized by strong phenotypic heterogeneity, underscoring the need to explore subtypes using objective structural neuroimaging approaches. Identifying neuroimaging heterogeneity in SCA3 could help inform the prognosis and guide the development of personalized interventions. Here, we calculated gray matter volumes using voxel-based morphometry from 3D T1-weighted magnetic resonance images across two independent cohorts (discovery cohort: n = 222; replication cohort: n = 90). Non-negative matrix factorization was used to identify atrophy subtypes in SCA3. An independent cohort of 29 patients with SCA3, who underwent repetitive transcranial magnetic stimulation (rTMS), was used to explore the treatment effects across subtypes. Two atrophy subtypes were identified: subtype1 (ST1) was characterized by predominant involvement of the basal ganglia, with mild cerebellar and cortical deficits, and subtype2 (ST2) was characterized by severe cerebellar atrophy with neostriatal atrophy and thalamic subregion hypertrophy. These results were replicated in the subtype validation cohort. The ST1 atrophy pattern correlated with the International Cooperative Ataxia Rating Scale (ICARS) kinetic function subscale scores, whereas the ST2 atrophy pattern correlated with the ICARS posture and gait scores. Exploratory analysis of longitudinal data from the rTMS cohort revealed significant overall clinical improvement, but no statistically significant interaction between subtype and treatment response was detected, despite the observation of promising subtype-specific patterns of improvement. These findings suggest that patients with SCA3 have robust structural atrophy subtypes, which may provide a new framework for stratifying patients in future clinical and therapeutic research.

The READISCA study aims to prepare for clinical trials in SCA1 and SCA3. Hence, we searched for predictive variables of ataxia onset (phenoconversion) and progression. Individuals with SCA1 or SCA3 and controls were enrolled from 2018-2021 in US and Europe. Clinical scores, MRI measures and NfL levels were assessed annually for 5 years. In the pre-ataxic group at baseline, we compared phenoconverters with non-converters. A Bayesian mixed model was used to model the longitudinal progression of clinical scores and NfL levels. The impact of data-driven selected baseline variables (demographic, clinical, MRI) on the expected SARA progression was tested. Forty-three controls, 55 SCA1 and 124 SCA3 carriers were included; a subset of the cohort (n=109) had MRI data. Converters from pre-ataxic to ataxic stages represented 5/22 (22%) and 12/38 (32%) for SCA1 and SCA3. Converters were more depressed (PHQ9: 3.9±2.9 vs 2.3±2.6 p = 0.04), had higher plasma NfL levels (17.6±5.7 pg.mL-1 vs 11.1±5.9, p<0.0001), more cerebellar white matter atrophy (1.44±0.12 % of total intracranial volume vs 1.54±0.16, p=0.032) and more INAS signs (1.8±1.3 vs 0.7±0.8, p = 0.002). All clinical scores except CCAS significantly worsened during the study. NfL levels significantly increased in non-converters and ataxic SCA3 (1.06±0.33 pg.mL-1/year, p=0.002 and 0.57±0.21, p=0.01) but not in controls and ataxic SCA1 (0.31±0.26, p=0.24 and 0.26±0.42, p=0.55). In the best predictive model of SARA progression after 1 year (R2=0.54), factors linked with faster progression were higher functional stage (p<0.001), higher CCFS score (p=0.002), and higher total creatine in cerebellar white matter (p=0.026). Factors significantly linked to conversion, namely NfL levels, depression, and lower motor neuron involvement, differ from those driving disease progression. NfL levels and lower motoneuron signs could be used as predictors of phenoconversion and MRI variables as ataxia progression predictors. Psychological care should be provided in the pre-ataxic phase of the disease.

Hereditary spinocerebellar ataxia (SCA) is a group of genetic neurodegenerative disorders caused by a variety of gene variants. At least 44 types of SCAs have been identified to date, and more than 35 genes and hundreds of variants have been reported that are associated with SCAs. We have investigated a Pakistani consanguineous six-generation family with SCA by using whole-exome sequencing analysis. We identified a reported SCA-associated variant, c.C2687G (p.P896R) in CACNA1A, in only a subgroup of the family, while a c.C262T (p.P88S) variant in ARFIP1 serves as a candidate pathogenic variant in the other subgroup as a possible novel cause of SCA. Our study showed that intra-familial heterogeneity may exist in SCA families and presented a candidate new causative gene for SCA.

This study aimed to investigate nerve fiber bundle damage associated with spinocerebellar degeneration, a dominant inherited neurological disorder, using magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). Four cases of spinocerebellar degeneration and ten matched healthy subjects were retrospectively enrolled. DTI software was used for processing and analysis. All patients had an abnormal spinocerebellar ataxia (SCA) type 3 gene mutation, with cerebellar and brainstem atrophy, a decreased signal in the pons and projection fibers. Significant interruption and destruction were revealed in the midline of the cerebellar peduncle, cerebellar arcuate fibers, and the spinothalamic and spinocerebellar tracts. Significant (p <0.05) decreases were detected in FA values in the cerebellar peduncle (0.51±0.04 vs. 0.68±0.02), cerebellar arcuate fibers (0.37±0.08 vs. 0.51±0.05), spinothalamic tract (0.42±0.03 vs. 0.49±0.05), and spinocerebellar tract (0.44±0.06 vs. 0.52±0.06) compared with healthy controls. Compared with healthy controls, significant (p <0.05) increases were detected in ADC values in the cerebellar peduncle (0.84±0.11 vs. 0.67±0.03), cerebellar arcuate fibers (0.87±0.12 vs. 0.66±0.05), spinothalamic tract (0.89±0.13 vs. 0.70±0.03) within the brainstem, and spinocerebellar tract (0.79±0.07 vs. 0.69±0.06). The MRI DTI technique provides sufficient information for studying spinocerebellar degeneration and for conducting further research on its etiology and diagnosis. Some limitations were present, including the retrospective and single-center study design, a limited patient sample, and enrollment of only Chinese patients. The MRI DTI technique can clearly demonstrate the degree of damage to nerve fiber bundles in the cerebellum and the adjacent relationship between the fiber bundles entering and exiting the cerebellum in patients with spinocerebellar degeneration.