Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are lethal neurodegenerative diseases affecting motor function. Though their etiology and pathology are distinct, recent evidence suggests commonalities between TAR DNA-binding protein (TDP-43), which is associated with 97% of ALS cases, and huntingtin (HTT), the causative protein of HD. ALS is a heterogeneous, lethal neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons, as well as brainstem and spinal cord degeneration. The causes of ALS are complex, variable, and, in some cases, unknown, but most cases involve mislocalization of the protein TDP-43. In contrast, HD is a monogenic, autosomal dominant, lethal neurodegenerative disease caused by polyglutamine expansion in HTT protein and characterized by the progressive loss of neurons in the brain, particularly in the striatum, which results in motor, cognitive, and behavioral changes. Although HD is not typically associated with motor neuron loss, recent evidence suggests a link between HTT and TDP-43 within the context of both ALS and HD, as well as links to related neurodegenerative diseases, such as frontotemporal dementia (FTD) and spinocerebellar ataxia type 2 (SCA2). Herein, we discuss confirmed cases of concurrent ALS and HD and the overlap of underlying disease mechanisms that potentially contribute to the onset and progression of these two devastating neurodegenerative diseases, with a focus on commonalities between TDP-43 and HTT. We propose that elucidating these commonalities will aid in the identification of broad-spectrum disease risk factors and potential overlapping treatment targets.

Autosomal dominant mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that regulate high-frequency repetitive firing of cerebellar Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the in vivo mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus (Fgf14F145S ). Current-clamp recordings from Purkinje neurons in acute cerebellar slices from adult male and female Fgf14F145S/+ mice revealed that high-frequency repetitive firing, which is characteristic of wild-type Purkinje neurons, was replaced by prolonged bursts of action potentials. A shift from tonic to burst firing was mimicked in wild-type Purkinje neurons by bath application of the Nav channel toxin, tetrodotoxin. Burst firing was also measured in heterozygous Fgf14 knock-out (Fgf14+/- ) Purkinje neurons, suggesting that the impaired firing of Fgf14F145S/+ Purkinje neurons reflects reduced Nav channel availability, owing to the loss of the iFGF14 protein. Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from Fgf14F145S/+ (and Fgf14+/- ) animals and voltage-clamp experiments revealed a hyperpolarizing shift in the voltage dependence of closed-state Nav channel inactivation in Fgf14F145S/+ (and Fgf14+/- ) Purkinje neurons. Together, these results indicate that Fgf14 haploinsufficiency and reduced Nav channel availability underlie impaired firing in Fgf14F145S/+ Purkinje neurons.

Background: Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder characterized not only by motor impairment but also by significant cognitive decline. While cognitive training programs have shown promising results in other neurological conditions, evidence regarding their efficacy in SCA2 remains scarce. Objective: To assess cognitive performance in patients with SCA2 and to evaluate the impact of a digital cognitive training program on cognitive functions. Methods: Twelve SCA2 patients (50% male; 46 ± 11.51 years old; 8 ± 3.69 years of education) underwent a comprehensive neuropsychological assessment before and after a six-month cognitive training program delivered through the NeuroNation® digital platform. The evaluated cognitive functions included memory, executive function, language, complex attention, and perceptual–motor abilities. A control group of 12 healthy individuals from the community was selected and matched for sex, age, and education (50% male; 47 ± 11.68 years old; 8 ± 3.85 years of education). Results: SCA2 patients exhibited significantly lower performance across multiple cognitive functions compared to controls, with marked impairments in verbal and visual memory, verbal fluency, attention, and executive function. Following the intervention, significant improvements were observed in several memory subcomponents, including incidental, immediate, delayed, and recognition memory. However, changes in executive functions were limited or absent. No strong correlations were found between game difficulty level and neuropsychological test outcomes. Conclusion: SCA2 patients demonstrated significant cognitive impairments, particularly in memory-related functions, and responded to digital cognitive training. These findings suggest the potential role of targeted interventions in supporting cognitive function in SCA2. The online version contains supplementary material available at 10.1007/s12311-025-01956-2.

A 61-year-old woman presented with episodic dizziness that met diagnostic criteria for vestibular migraine. Vestibular and ocular motor examination was normal, aside from a 1°/second downbeat nystagmus (DBN) that was only seen with removal of fixation (in the dark) using video oculography. Two years later, lithium was initiated for treatment of depression and visual bouncing and jumping developed even when her head was still. On repeat examination, she had clear spontaneous (20°/second) DBN even with fixation in room light. Lithium therapy was discontinued, and for days and weeks, there was subjective improvement in oscillopsia and objective lessening of her DBN. However, DBN remained significant and symptomatic after several months. A broad search for reversible nutritional, metabolic, and immune-mediated causes of DBN and cerebellar dysfunction was completed and was unremarkable. Therapy with 4-aminopyridine was initiated and she had a robust improvement in oscillopsia and DBN. During the following years, she developed mild gait ataxia, and genetic testing revealed GAA repeat expansions in 1 copy of the fibroblast growth factor 14 (FGF14) gene, consistent with a diagnosis of spinocerebellar ataxia type 27B (SCA27B).

Spinocerebellar Ataxia Type 3 (SCA3), the most common hereditary ataxia in China, is characterized by progressive gait dysfunction. While quantitative gait analysis provides critical insights into movement disorder management, conventional motion capture systems are often cost-prohibitive and impractical for clinical use. We propose using the markerless Azure Kinect, a cost-effective and portable tool for gait analysis, to detect SCA3-specific gait patterns and identify gait parameters associated with disease severity and duration. We enrolled 38 patients with SCA3 patients and 42 healthy controls (HCs). Gait was recorded using an Azure Kinect. Multiple gait parameters were computed and compared with t-tests/Mann-Whitney U tests. The receiver operating characteristic (ROC) analysis identified discriminatory biomarkers, while Pearson's test assessed gait-clinical characteristic associations. Patients with SCA3 exhibited increased mediolateral margins of stability (MOS, p < 0.01), wider step width (p < 0.001), shorter stride length (p = 0.003), slower gait speed (p = 0.007), and reduced hip/knee/ankle joint angles (p < 0.05) compared to HCs. Step width demonstrated the highest diagnostic accuracy (AUC = 0.878, cutoff = 0.197). Increased medial-lateral MOS was negatively correlated with step length (r = -0.52∼-0.45, P < 0.005). Minimal hip frontal angles negatively correlated with SARA scores (r = -0.46, p = 0.004) and disease duration (r = -0.35, p = 0.028), reflecting a progressive cerebellar degeneration. In SCA3, gait abnormalities such as increased step width and shortened stride length indicate compensatory adaptations exist to enhance dynamic stability. Step width is identified as a sensitive biomarker for SCA3 screening.