Cerebellum最新文献

GRM1 encodes type 1 metabotropic glutamate receptor (mGluR1). Its pathogenic variants are associated with the rare autosomal recessive cerebellar ataxia 13 (SCAR13) due to loss of mGluR1 function, and the even rarer spinocerebellar ataxia 44 (SCA44) due to a gain-of-function molecular basis. We report a new case of SCA44 caused by a novel and de novo GRM1 variant c.2303 C > T (p.Thr768Ile), which was considered "likely pathogenic" by the American College of Medical Genetic criteria (PS2, PM2, PP3). This variant was predicted to lead to a stability effect on mGluR1 in the evaluation with DynaMut2, like the other known SCA44 GRM1 variants and in contrast to lower stability or destabilizing effects for SCAR13 missense variants. The affected residue Thr768 was located close to the binding pockets of allosteric modulators and within the highly conserved cholesterol recognition association/interaction consensus motif. Collectively, this novel GRM1 variant caused SCA44 by increasing the constitutive activity of mGluR1. Our findings underscore the distinct molecular mechanisms of mGluR1 aberration for the two GRM1-associated hereditary ataxias, and provide a mechanism-relevant prospect in the pharmacological therapies for restoring mGluR1 function.

Hereditary or genetic ataxias are hundreds of disorders characterized by large phenotypic, genetic, and epidemiological heterogeneity. In Argentina, 35 genetic ataxias have been identified, with SCA1 (ATX-ATXN1), SCA2 (ATX-ATXN2), SCA3 (ATX-ATXN3), and Friedreich ataxia (ATX-FXN) as the most prevalent causes, reflecting the epidemiology of most Western European countries, the main origin of immigration to the country. Genetic diagnostic studies of ataxia cohorts in Argentina have found high rates of undiagnosed patients, ranging from 65 to 82%. Deep phenotyping, comprehensive genetic testing, and knowledge of the prevalence of different genetic ataxias are essential for an accurate diagnostic and treatment approach in clinical practice. This narrative review proposes a targeted, tiered genetic diagnostic approach for undiagnosed patients based on the Argentinian epidemiological and healthcare system data. Future national efforts should support comprehensive screening studies on ataxia cohorts, including testing for repeat expansions in RFC1 and FGF14 genes. In addition, establishing a trial-ready patient registry for genetic ataxias, enhancing networking with international clinical and research initiatives, and developing specialized centers for interdisciplinary care of genetic ataxia patients are recommended.

Pathogenic variants in KIF1A are associated with a spectrum of neurological disorders collectively known as KIF1A-associated neurological disorders (KAND). We present the case of a 57-year-old female with lifelong dysarthria, gait instability, and progressive ataxia, diagnosed with cerebellar ataxia in her late 40s. Brain MRI revealed diffuse cerebellar atrophy. Genetic testing identified a novel heterozygous KIF1A (NM_004321.6) variant, c.1788_1790delinsACG (p.His596_Pro597delinsGlnArg), which is absent from population databases and predicted to be deleterious by multiple in silico tools. Unlike most pathogenic KIF1A variants that cluster within the motor domain, this variant lies outside this region. In silico structural modeling suggests this substitution likely affects local protein architecture through two concurrent changes: the substitution of histidine 596 with glutamine represents a modest change to the local biochemical environment, while the replacement of the conformationally restrictive proline 597 with arginine removes the characteristic cyclic structure that constrains the peptide backbone. Family history was notable for cerebellar atrophy in the mother and similar neurological symptoms in the maternal brother, suggesting possible autosomal dominant inheritance. The identification of this novel KIF1A variant outside the motor domain expands our understanding of KAND's genetic basis and suggests that non-motor domain variants may be associated with slowly progressive neurological symptoms.

Spinocerebellar ataxia type 6 (SCA6) homozygotes are known to have an earlier onset and faster disease progression than heterozygotes. Although several studies have reported more severe clinical manifestations in SCA6 homozygotes, longitudinal, quantitative assessments remain lacking. A 55-year-old female presented with intermittent positional dizziness/vertigo and gradually progressive gait disturbance. She denied a family history of similar symptoms. Neuro-ophthalmologic evaluations revealed spontaneous downbeat nystagmus, horizontal gaze-holding deficits and hypermetric saccades with preserved saccadic velocity. Bedside horizontal head impulses showed a perverted response. Video head impulse test (HIT) showed normal VOR gain in all six semicircular canals and bithermal caloric test was also normal. Brain magnetic resonance imaging (MRI) showed diffuse and prominent, pure cerebellar atrophy. Genetic testing for SCA using Sanger sequencing confirmed the expanded repeats for SCA6 with homozygous abnormal allele 20 repeats. During the 8-year follow-up, bedside HIT turned positive on both sides and accordingly decreased VOR gains with abnormal catch-up saccades in both horizontal canals (HCs) were detected during video HITs, while bithermal caloric test revealed canal paresis only on the right side. Follow-up brain MRI demonstrated more prominent diffuse cerebellar atrophy and indicated mild brainstem atrophy as well. Vestibular performance in SCA6 is characterized by frequent high-frequency angular VOR impairments, predominantly affecting the horizontal and posterior canals, while low-frequency responses remain variable. Neuro-otologic deterioration during follow-up in our patient may be partly attributed to involvement of the brainstem VOR pathway including the medial vestibular nuclei, in contrast to SCA6 heterozygotes who typically exhibit pure cerebellar involvement.

Background: Subacute progressive cerebellar ataxia poses a diagnostic challenge due to its wide-ranging etiologies and symptom overlap with acute and chronic cerebellar disorders. Prompt identification and treatment are essential to improve clinical outcomes.

Case presentation: A 62-year-old woman presented with worsening vertigo, gait instability, and evolving neurological signs over five months, consistent with a syndrome of subacute progressive cerebellar ataxia. Despite normal findings on serial MRI and PET imaging, as well as negative serological and genetic testing, her recent history of influenza vaccination and clinical progression suggested immune-mediated cerebellitis. High-dose corticosteroid therapy resulted in marked improvement, allowing her to achieve near-complete recovery, with a final diagnosis of autoimmune cerebellar ataxia reached by exclusion.

Discussion: Even when imaging findings are unremarkable, it is crucial to recognize immune-mediated cerebellar ataxia in patients with progressive symptoms, particularly following potential triggers such as vaccination. Empirical corticosteroid therapy demonstrated both diagnostic and therapeutic value, facilitating recovery.

Conclusion: Subacute cerebellar ataxia with normal imaging requires careful consideration of immune-mediated etiologies. This case demonstrates the potential benefits of corticosteroid therapy in achieving favorable outcomes, even in diagnostically challenging scenarios.

Gluten ataxia (GA) is the primary neurological manifestation of gluten sensitivity, characterised by loss of Purkinje cells throughout the cerebellar cortex and rooted in autoimmunity to transglutaminase 6 (TG6). Previous studies have shown the contribution of serum anti-TG6 antibodies to disease progression; however, it remains unclear where these antibodies are produced and how they gain access into the brain parenchyma. This study aims to provide an immunological assessment of the CSF in patients with GA to better define the humoral response contributing to disease pathophysiology. In this observational study we assessed the presence of plasma cells in the CSF of 20 patients with GA and 6 controls. CSF from 16 of the GA patients and from all 6 controls was investigated for the presence of anti-TG6 IgA antibodies. Immunohistochemistry for CD138 was performed to assess the presence of plasma cells in the cerebellum and spinal cord of 4 cases with GA, 4 ataxia controls and 4 neurologically healthy controls. A significant increase in anti-TG6 IgA antibodies was detected in the CSF of patients with GA compared to controls, with no correlation between CSF and serum levels of anti-TG6 IgA antibodies for either experimental group. CD138⁺ cells were present in the CSF of 2 patients with GA and in the cerebellum and spinal cord of 3 post-mortem cases of GA. In a subpopulation of patients with GA intrathecal presence of plasma cells and TG6 antibodies is a feature of the disease, likely associated with prolonged disease duration and continuous exposure to gluten.

Background: Patients with spinocerebellar degeneration (SCD) and multiple system atrophy (MSA) encounter various challenges in daily life due to ataxia and other symptoms. A comprehensive understanding of their diverse needs can improve the effectiveness of rehabilitation interventions.

Objective: This study aims to identify the daily challenges faced by patients with SCD and MSA in Japan, focusing on differences between ambulatory and non-ambulatory patients.

Methods: A postal survey was conducted from March to May 2023, targeting members of the Japanese Society of Ataxia Patients diagnosed with SCD and MSA. The questionnaire assessed respondent demographics and symptoms impacting daily life.

Results: From the 283 responses received, 152 were deemed valid for analysis. Non-ambulatory patients reported significantly more difficulties across multiple items in the activities domain. Furthermore, subjective unsteadiness, difficulty speaking, and increased fall risk were identified as having the most significant impact on daily life, regardless of walking ability.

Conclusion: These findings highlight the need to adapt rehabilitation approaches for patients with SCD and MSA as their disease progresses, emphasizing comprehensive assessment methods and multidisciplinary care to enhance their quality of life.

In multiple system atrophy with parkinsonian type (MSA-P), the dual-task cost and the underlying neurological mechanisms remain under-researched. We included 20 early-stage MSA-P patients and 10 matched healthy controls (HC). Using a video-based gait analysis machine, we explored gait characteristics under three conditions: single-task gait (STG), dual-task gait with backward counting (DTG-BC), and dual-task gait with spontaneous animal naming (DTG-SAN). Neuroimaging scans were collected to analyze the gray matter and white matter structures related to the dual-task cost in MSA-P. Our neuroimaging analysis focused on the infratentorial structures, as previous studies have indicated that these regions are closely related to dual-task cost. There were no differences in gait metrics between MSA-P and HC in STG. In the DTG-BC, patients with MSA-P exhibited a higher dual-task cost burden, as indicated by longer turning durations and shorter swing cycles compared to HC. MSA-P patients had decreased gray matter volume in the right culmen and increased radial diffusivity in the left declive compared to HC. Diffusion tensor imaging analysis showed that the higher dual-task cost of the right swing cycle in DTG-BC was related to the higher mean diffusivity of the left mesencephalic locomotor region (MLR). Additionally, a higher dual-task cost of turning duration in DTG-BC was related to increased axial diffusivity and radial diffusivity in the white matter of the bilateral culmen. Patients with MSA-P exhibited a higher dual-task burden compared to HC, and WM deficit in MLR and culmen were related to the disease's specific dual-task cost in MSA-P.

RGS8-associated paraneoplastic neurologic syndrome (PNS) is a recently-described disorder associated with lymphomas and typically presenting with severe, rapidly-progressing cerebellar dysfunction. We describe a patient who presented with mild signs of cerebellar dysfunction, including ocular motor abnormalities and impaired tandem gait. CSF showed elevated protein and a neural-restricted antibody pattern. Mesenteric lymphadenopathy on abdominal CT was biopsied and diagnosed as follicular B-cell lymphoma. After four years, the previously-detected antibody pattern was identified as RGS8 antibodies. This case describes the first RGS8-PNS patient presenting with a subtle and ocular motor predominant cerebellar syndrome with low-grade lymphoma.

Post-stroke dysphagia (PSD) is common and associated with poor outcomes. We aimed to explore the feasibility, safety, and proof of concept of cerebellar rTMS in patients with sub-acute PSD. We intended to recruit 48 participants with PSD. Randomised to: (i) sham treatment twice-daily for five days, (ii) cerebellar rTMS daily for three days, and (iii) cerebellar rTMS twice-daily for five days (1:1:1). Participants were blinded to treatment group. Primary outcomes were feasibility, safety, and functional outcome intake scale (FOIS), dysphagia severity rating scale (DSRS), and feeding status scale (FSS) at two weeks. However, due to lower-than-expected enrolment, the active rTMS groups were combined. We recruited 14 participants in total, (mean 68 years, 57% female). Due to the time-limited funding period, recruitment was adversely affected by the COVID-19 pandemic. DSRS and FSS trended lower in the combined active rTMS groups at two weeks, i.e. less swallowing impairment. However, at death/discharge FOIS was higher/better (mean, (standard deviation)), 4.0 (2.1) vs. 1.8 (1.0) (p = 0.032) with active TMS, with trends to lower/better DSRS and FSS. There was no difference in the acceptability of treatment between groups. High-intensity (n = 5) vs. low-intensity (n = 5) cerebellar rTMS was associated with lower DSRS 3.0 (1.4) vs. 9.4 (2.7) and FSS 0.6 (0.5) vs. 1.6 (0.5) at 2 weeks, and DSRS 3.0 (1.4) vs. 9.0 (3.7) at hospital discharge or death. Cerebellar rTMS is a feasible ward-based treatment for reducing swallowing impairment. Although enrolment was lower than desired, there was evidence for proof of concept, particularly for high-intensity cerebellar rTMS. Larger studies are warranted.