Spinocerebellar ataxia type 41 (SCA41) is a rare autosomal dominant cerebellar ataxia caused by mutations in the transient receptor potential canonical 3 (TRPC3) gene. We report a case of a patient with SCA41 whose clinical manifestations were initially suspected to be multiple system atrophy cerebellar-type (MSA-C). Whole-exome sequencing (WES) revealed a c.1955A>G (p.K652R) mutation in the TRPC3 gene of this patient. After treatment with transcranial magnetic stimulation and rehabilitation training, the patient reported a slight improvement in unsteady gait compared with before. This is the first report of SCA41 caused by the c.1955A>G variant in the TRPC3 gene, which expands the mutation spectrum of the TRPC3 gene. Clinicians should have sufficient awareness of SCA41, as SCA and MSA-C share overlapping clinical phenotypes and imaging features, which may easily lead to misdiagnosis, and genetic testing plays a crucial role in differentiating between the two disorders.

Post-mortem evidence suggests neurodegeneration in the visual pathway in multiple system atrophy-cerebellar type (MSA-C), yet robust in vivo evidence remains scarce. This study aimed to characterize these visual pathway changes in MSA-C patients by integrating optical coherence tomography (OCT), visual evoked potential (VEP), and magnetic resonance imaging (MRI). This cross-sectional study prospectively recruited 156 participants, including 53 healthy controls and 103 early-stage MSA-C patients (mean disease duration: approx. 2 years). All participants underwent retinal layer evaluation using OCT. A randomly selected subset of 34 MSA-C patients and 19 controls also received VEP and MRI to assess visual pathway structure and function comprehensively. OCT analysis revealed significant parafoveal thinning within the 3-mm inner ring in MSA-C patients, predominantly affecting the ganglion cell layer (GCL) (P < 0.001) and inner plexiform layer (IPL) (P < 0.001). VEP recordings demonstrated significantly prolonged P100 latency (P < 0.001). MRI confirmed reduced cerebellar volume (P < 0.001). DTI detected microstructural degeneration in the cerebellum and visual pathways, with increased mean and axial diffusivity in optic tracts and radiation. Notably, retinal thinning correlated significantly with longer P100 latency (GCL: r = 0.49, P = 0.003; IPL: r = 0.41, P = 0.015) and cerebellar atrophy (GCL: r = 0.53, P = 0.001; IPL: r = 0.49, P = 0.003), indicating integrated visual pathway degeneration. This large-scale multimodal study provides robust in vivo evidence that MSA-C involves early retinal neurodegeneration, functional conduction delay, and central white matter degeneration. The convergence of OCT, VEP, and DTI parameters suggests bidirectional retinocortical degeneration. Our findings support the potential of these parameters for early detection and highlight the visual pathway as a promising potential biomarker in synucleinopathies.

Multiple system atrophy (MSA) is a progressive and fatal α-synucleinopathy characterized by α-synuclein-positive (α-syn+) glial cytoplasmic inclusions in oligodendrocytes. The cerebellar variant (MSA-C) primarily affects olivopontocerebellar fibers, resulting in extensive demyelination and glial activation. To model this pathology, we developed a Tet-Off-based MSA-C mouse model with oligodendrocyte-specific overexpression of human A53T α-syn. Upon doxycycline withdrawal at 8 weeks of age, mice developed progressive cerebellar ataxia by 26 weeks and succumbed by 30 weeks. These mice exhibited severe demyelination and marked activation of microglia and astroglia in the brainstem and cerebellum, along with widespread propagation of α-syn oligomers and phosphorylated α-syn (p-α-syn) aggregates in oligodendrocytes, astrocytes, and neurons. Single-cell RNA sequencing of CD11b+ cells from the brain and spinal cord identified a distinct microglial cluster expressing Toll-like receptor 2 (Tlr2), transglutaminase 2 (Tgm2), arginase-1, macrophage scavenger receptor-1 (Msr1), inflammatory genes (such as Nfkbia, Nfkbiz, and Il1b), and chemokines (including Ccl3, Ccl4, and Ccl12). These microglia were located adjacent to p-α-syn aggregates and were distinct from previously described protective disease-associated microglia and border-associated macrophages. TLR2- and TGM2+Iba1+ microglia were particularly enriched in demyelinating lesions. Prophylactic administration of the CSF1R inhibitor BLZ945 exacerbated motor deficits and demyelination, significantly increasing this microglial population. Similarly, MSR1+ and CD68+ microglia/macrophages were observed in early pontocerebellar lesions of six human MSA-C autopsy cases. These findings suggest that this pro-inflammatory microglia subset plays a central role in disease progression and may represent a promising therapeutic target for modifying the course of MSA-C and related synucleinopathies.

Patients initially diagnosed with idiopathic late-onset cerebellar ataxia (ILOCA) may develop multiple system atrophy cerebellar type (MSA-C). However, data on conversion time, associated clinical factors, and the role of the neurofilament light chain (NFL) in this process remain limited. This study aims to investigate the conversion from ILOCA to MSA-C and examine the associated factors and the predictive value of NFL. This retrospective study included patients with ILOCA at the initial visit, recording the conversion to MSA-C and its duration. The median time to conversion was estimated using the Kaplan-Meier analysis. The roles of baseline orthostatic dizziness, rapid eye movement sleep behavior disorder (RBD), hot cross-bun sign, and urinary symptoms in conversion were analyzed. In a subset of patients, NFL levels in plasma collected before conversion were measured to examine their ability to predict conversion. Seventy-two patients with ILOCA at the initial visit were included, of whom 32 experienced conversion to MSA-C. The median time-to-conversion was 5.0 years. RBD or orthostatic dizziness at baseline was associated with conversion, whereas hot cross-bun sign and urinary symptoms demonstrated no significant effect. Receiver operating characteristic analysis revealed moderate discriminative ability (area under the curve: 0.69) when NFL, orthostatic dizziness, and age at blood collection were included. This study identified that orthostatic dizziness and RBD, assessable in outpatient settings, correlated with ILOCA-to-MSA-C progression. Additionally, the NFL may play an auxiliary role in estimating the conversion time. Therefore, further studies incorporating diverse clinical and serological markers are required.

Multiple system atrophy-cerebellar type (MSA-C) is a rapidly progressive neurodegenerative disorder, yet objective digital biomarkers for disease severity remain scarce. This cross-sectional study aimed to identify disease-relevant gait patterns using a 2D video-based gait analysis algorithm and examine their clinical and neuroimaging correlates. Gait features were extracted from videos of patients with MSA-C using Gaitome, and an MSA-C gait pattern score was derived. This score significantly distinguished MSA-C from healthy controls (area under the curve = 0.98) and showed significant correlations with UMSAR part I (r = 0.49, p = 0.0014), part II (r = 0.51, p = 0.0014), MMSE (r = - 0.43, p = 0.012), and MoCA (r = - 0.34, p = 0.049). Tractography revealed significant associations between the gait score and structural connectivity in the middle cerebellar peduncle, cerebellum, and cingulate. Voxel-based morphometry showed that the gait score correlated with gray matter volume in the middle temporal and cerebellar regions, whereas UMSAR part II did not show significant structural associations. These findings suggest that gait patterns extracted from a single video camera can reflect both motor and cognitive severity in MSA-C, and may serve as a practical, non-invasive digital biomarker for disease monitoring.