Puneet Opal

Objective: Inherited ataxias are clinically diverse neurodegenerative diseases, complicating the choice of outcome measures for trials. In spinocerebellar ataxia (SCA), regulatory concerns about the Scale for the Assessment and Rating of Ataxia (SARA) caused a shift toward functional SARA (f‐SARA), contributing to pivotal trial failure. We investigated whether the Upright Stability Score (USS), validated in Friedreich ataxia (FRDA), retains its psychometric properties in SCA, and how it compares with SARA, f‐SARA, and the Friedreich Ataxia Activities of Daily Living scale (FA‐ADL). Methods: Cross‐sectional data from ambulatory participants in two large international natural‐history studies (CRC‐SCA and UNIFAI) were analyzed with correlation‐based psychometric methods, comparing score distributions across scales and genotypes. Results: Data from 406/343 participants in CRC‐SCA/UNIFAI were analyzed. In SCA, the USS captured a wider spectrum of balance performance, while in FRDA, early proprioceptive deficits—particularly impaired stance with eyes closed—constrained score variability. USS correlated strongly with SARA, f‐SARA, and FA‐ADL in both cohorts. SARA showed moderate skew, and f‐SARA showed pronounced floor effects in mildly affected SCA, whereas USS and FA‐ADL preserved discrimination at the low end. FA‐ADL distributions were broadly comparable across genotypes. Interpretation: USS showed cross‐sectional convergent validity with established measures across ambulatory FRDA and SCA, reflecting perceived disease burden (FA‐ADL) at least as well as SARA. f‐SARA is poorly discriminating in ambulatory SCA and is unlikely to work as an outcome measure, in particular in early cohorts. USS showed the potential to serve as a primary outcome assessment in pivotal SCA trials, but longitudinal evidence is required. Limitations include cross‐sectional design and a substantial age difference between cohorts.

Background: A comprehensive synthesis of nonpharmacological interventions (NPI) in degenerative cerebellar ataxia will clarify their efficacy and inform clinical practice and trial design in a field with limited therapeutic options. Methods: A Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA)‐compliant systematic review was conducted (PROSPERO CRD42025649802). PubMed/MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane CENTRAL were searched from inception to April 16, 2025. Randomized and nonrandomized interventional studies evaluating rehabilitation, speech therapy, noninvasive neuromodulation (repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation [tDCS]), virtual reality, vibration therapy, biofeedback‐based, assistive devices, and complementary approaches were included. Methodological quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklists. Given substantial clinical and methodological heterogeneity, findings were consolidated narratively. Results: A total of 100 studies met inclusion criteria. Structured physical therapy, rTMS, and tDCS demonstrated statistically significant short‐term reductions in ataxia severity (measured using Scale for the Assessment and Rating of Ataxia [SARA] or International Cooperative Ataxia Rating Scale [ICARS]). Improvements were most consistent in axial domains, including gait and postural control. Limited mechanistic studies reported restoration of cerebellar inhibitory modulation, increased cerebellar–frontal connectivity, and enhanced regional perfusion following tDCS. Evidence for speech therapy, virtual reality–based rehabilitation, vibration therapy and complementary approaches was limited. Across all modalities, durability beyond the short‐term remained unclear. Conclusions: NPI may confer short‐term symptomatic and functional benefits in degenerative cerebellar ataxia, particularly in axial motor domains, supported by the largest evidence for structured rehabilitation followed by neuromodulation, although heterogeneous. Future multicenter, biomarker‐informed trials are required to define optimal dosing, durability and stage‐specific therapeutic strategies.

Spinocerebellar ataxia type 27B (SCA27B) is a recently identified autosomal dominant form of late-onset cerebellar ataxia (LOCA) caused by a guanine-adenine-adenine (GAA) > 250 intronic repeat expansion in the fibroblast growth factor 14 (FGF14) gene. Recent studies suggest that SCA27B may account for 10%-60% of undiagnosed patients with LOCA. Age at onset ranges from 40s to 70s, and clinical features include slowly progressive pancerebellar syndrome with prominent gait ataxia and cerebellar oculomotor abnormalities. Positive family history may be absent, particularly given the characteristically late onset of this condition. It is important to note that up to half of the patients with SCA27B report episodic symptoms, including imbalance, vertigo, visual disturbances, or dysarthria, which might initially manifest without clear interictal clinical or radiologic features of cerebellar ataxia. These features can result in the misdiagnosis of SCA27B. We present 2 patients with LOCA. Both patients initially received alternative working diagnoses, which were re-examined several years later only after symptoms and imaging findings progressed. First-line genetic testing for both patients was unrevealing because of the deep intronic location of the causative variant. Ultimately, whole-genome-based testing in one case and targeted FGF14 trinucleotide repeat analysis in the other revealed the diagnosis of SCA27B. These cases highlight SCA27B as a cause of episodic neurologic symptoms in an older adult population. Furthermore, these cases demonstrate the potential pitfalls of panel and exome-based genetic testing, given the important role of pathogenic intronic variants in the spectrum of neurogenetic disorders.

A 63-year-old female patient presents with orthostatic hypotension and slowly progressive cerebellar ataxia. Neurologic examination revealed ataxia, pyramidal signs, and vibration/proprioception deficits. Neuroimaging showed diffuse white matter abnormalities, cord atrophy, and corticospinal tract involvement. This case highlights how a careful history, with special attention to tempo of symptoms and family history, combined with examination findings and neuroimaging can be used to reach a rare diagnosis.

Neurofilament accumulation is associated with many neurodegenerative diseases, but it is the primary pathology in giant axonal neuropathy (GAN). This childhood-onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that enables neurofilament degradation. Using a combination of genetic and RNA interference approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through 2 mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations attract the chaperone 14-3-3, which is responsible for the proper localization of the key autophagy regulator transcription factor EB (TFEB). We propose that this dual disruption of autophagy contributes to the pathogenesis of other neurodegenerative diseases involving neurofilament accumulations.

N -methyl-d-aspartate (NMDA) receptor–mediated autoimmune encephalitis (NMDAR-AE) is the most common cause of autoimmune encephalitis, especially in children and young adults. The disorder is caused by antibodies directed against the GluN1 protein, an obligatory constituent of NMDA receptors, which are key signaling molecules in brain development, learning and memory, and executive function. The manuscript by Zhou et al. offers key insights into aberrant development of cortical pathways that may underly persistent sensorimotor deficits associated with this encephalitis in a newly generated mouse model. This study convincingly links transient exposure to a patient-derived anti-GluN1 mAb during a critical developmental period to lasting disruptions in interhemispheric connectivity through callosal projections. These findings provide insight into the impact of a prevalent autoimmune disorder on fundamental aspects of brain development and establish a model system that could be further employed to probe other aspects of NMDAR-AE pathogenesis.

Neurofilament accumulation is a marker of several neurodegenerative diseases, but it is the primary pathology in Giant Axonal Neuropathy (GAN). This childhood onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that is essential for neurofilament degradation. Using a combination of genetic and RNA interference (RNAi) approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through two mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations sequester the chaperone 14-3-3, a protein responsible for the localization of the transcription factor EB (TFEB), a key regulator of autophagy. This dual disruption of autophagy likely contributes to the pathogenesis of other neurodegenerative diseases with neurofilament accumulations.

Purpose of Review Spinocerebellar ataxias (SCAs) are autosomal dominant degenerative syndromes that present with ataxia and brain stem abnormalities. This review describes the cognitive and behavioral symptoms of SCAs in the context of recent knowledge of the role of the cerebellum in higher intellectual function. Recent Findings Recent studies suggest that patients with spinocerebellar ataxia can display cognitive deficits even early in the disease. These have been given the term cerebellar cognitive affective syndrome (CCAS). CCAS can be tracked using newly developed rating scales. In addition, patients with spinocerebellar ataxia also display impulsive and compulsive behavior, depression, anxiety, fatigue, and sleep disturbances. Summary This review stresses the importance of recognizing non-motor symptoms in SCAs. There is a pressing need for novel therapeutic interventions to address these symptoms given their deleterious impact on patients’ quality of life.

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.