Deleterious variants in the CACNA1A gene, encoding the CaV2.1 P/Q-type voltage-gated calcium channel, cause a broad spectrum of neurological disorders, including familial hemiplegic migraine, episodic ataxia, and developmental and epileptic encephalopathy (DEE). Information on genotype-phenotype correlations and on the factors influencing clinical variability is still limited, hindering potential applications in precision medicine. We present three adults (aged 26, 27, and 40 years) from two families with heterozygous CACNA1A deleterious variants and DEE, highlighting striking interindividual and intrafamilial variability in adult-onset presentations. Genetic testing revealed two distinct pathogenic variants [p.(Val1392Met) and p.(Glu1263Lys)], including one instance of germinal/gonosomic mosaicism in unaffected parents. The electroclinical details demonstrated profound differences, notably: a pair of siblings with the same variant showing discordant clinical severity, and an unrelated patient whose complex phenotype, dominated by cerebellar ataxia, required prolonged video-EEG to accurately diagnose a high burden of subtle absence seizures. These cases significantly expand the phenotypic spectrum and highlight the critical role of comprehensive electroclinical characterization in adults with CACNA1A-related DEE for personalized management.

SCN2A loss-of-function (LoF) variants are associated with epilepsy (onset age ≥ 3 months), intellectual disability (ID), and autism spectrum disorder (ASD). Despite numerous identified variants and the description of phenotypic subgroups, relationships between Nav1.2 channel dysfunction and clinical phenotypes remain unclear. This study examined how distinct LoF mechanisms relate to phenotypic outcomes. Whole-cell patch-clamp electrophysiology was used to characterize 15 presumed LoF SCN2A variants. Mechanism-phenotype correlations were assessed in 33 patients with these variants (six recurrent) and 41 patients with 15 previously characterized LoF variants (four recurrent). Phenotypic subgroups were categorized as later onset epilepsy-midinfancy (onset between 3 and 18 months), later onset epilepsy-childhood (onset after 18 months), ID/ASD without epilepsy, and "other" for unclassified cases. Of the 15 electrophysiologically characterized SCN2A variants, 11 caused total Nav1.2 LoF, three caused partial LoF, and one showed mixed LoF and gain-of-function (GoF) effects. Among previously published variants, seven showed total LoF, five partial LoF, and two mixed LoF/GoF, and one was undetermined. Across both cohorts, seven of 10 recurrent variants (70%) were associated with multiple phenotypic subgroups. Partial or total Nav1.2 LoF variants were identified in all subgroups. Notably, a midinfancy epilepsy phenotype was observed in 22 of 24 individuals (92%) carrying a mixed LoF variant, with phenotype data unavailable for seven additional individuals. A novel LoF-associated phenotype-episodic ataxia with or without developmental delay or ID-was identified in five of six individuals with the L1650P variant. Although episodic ataxia has been previously associated with GoF variants in SCN2A, this is the first reported instance in individuals with a confirmed LoF variant. Distinct SCN2A LoF phenotypes cannot be reliably linked to specific biophysical mechanisms, as both total and partial Nav1.2 LoF occurs across diverse phenotypes. For efficient personalized treatment, it is crucial not to rely solely on clinical phenotype to predict the underlying LoF mechanism.

Diagnostic value of genetic testing, with focus on CACNA1A, in children with episodic neurologic disorders: a single-centre retrospective study.

Background and ObjectivesAntibody-associated neurologic diseases often present with movement disorders (MDs). The frequency and clinical course of specific MDs in most antibody-associated disease subtypes remain largely unknown.MethodsWe performed a retrospective nationwide observational study on a large cohort of Dutch patients with antibody-associated neurologic diseases between January 2000 and April 2024 to describe associated MDs.ResultsWe identified 1,140 patients (56% female; 58/1,140 [5%] aged < 18 years; mean age 56 years [range 1–87]). The most common antibody targets were HuD (n = 212, 19%), NMDA receptor (NMDAR; n = 189, 17%), leucine-rich glioma inactivated 1 (LGI1; n = 187, 16%), and high-concentration glutamic acid decarboxylase 65-kilodalton isoform (GAD65; n = 135, 12%). MDs were present in 459 patients (42%) and represented the predominant and/or first symptom in 56% and 50% of cases, respectively. Cerebellar ataxia was by far the most common MD symptom (n = 235, mainly represented by Yo and GAD65), followed by dyskinesia (n = 61, mainly NMDAR), myoclonus (n = 51, mainly NMDAR), and stiff-person syndrome (n = 51, mainly GAD65). Syndromes associated with Yo- and delta/notch-like epidermal growth factor–related receptor (DNER/Tr) antibodies presented (almost) exclusively with MD (cerebellar ataxia) while the lowest MD frequency was observed in anti–gamma-aminobutyric acid B receptor (GABABR; 6/56, 11%) and anti-LGI1 encephalitis (19/181, 10%; excluding faciobrachial dystonic seizures). Furthermore, we identified MD associations that have not been previously reported, including chorea/dystonia (n = 1) and catatonia (n = 1) in anti-kelch like protein 11–associated brainstem encephalitis, chorea (n = 2) in anti-glycine receptor encephalitis, and episodic ataxia in anti-LGI1 and anti-GAD65–associated neurologic syndrome (both n = 1).DiscussionMDs are common in antibody-associated neurologic diseases, occurring in 42% of patients, with varying frequencies depending on the specific subtype and antibody. MDs can be the first, predominant, and even only manifestation of these diseases. In addition, we also describe some novel antibody-MD associations. Antibody-associated neurologic diseases should be in the differential diagnosis of new-onset MDs, and we provide recommendations for rational antibody testing in different phenotypes.

Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs in cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE), differentially expressed and required for initiation of dystonia, while α2-ARs are not. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous totteringtg/tg mice but had no impact on ataxia amelioration. In vivo recordings and live calcium (Ca2+) imaging of PCs demonstrated that α1D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of Ca2+ from intracellular stores, thus preventing stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1D-ARs in the formation of stress-induced dystonia in totteringtg/tg mice.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05843-1.

Mutation T226R in the Kv1.1 α-subunit of voltage-gated potassium Kv1 channels is associated with episodic ataxia type 1, severe neuromyotonia, and epilepsy. In vitro, this mutation was reported to considerably distort the functioning of homotetrameric channels Kv1.1; however, in the brain, Kv1.1 α-subunits form heterochannels predominantly associating with Kv1.2 α-subunits. Using the patch-clamp technique, fluorescent and Förster resonance energy transfer confocal microscopy, we revealed that heterochannels Kv(1.1(T226R)-1.2)2 formed by concatemers Kv1.1(T226R)-Kv1.2 in Neuro-2a cells have significantly slower activation and deactivation rates, and their activation occurs at a much less negative membrane potential compared to channels Kv(1.1-1.2)2 formed by concatemers Kv1.1-Kv1.2. This mutation does not noticeably affect the formation of complexes between α-subunits Kv1.1 and Kv1.2, but it does induce a delayed and possibly decreased presentation of heterochannels Kv(1.1(T226R)-1.2)2 on the plasma membrane. At the same time, the T226R mutation has a much stronger negative effect on the membrane presentation of homotetrameric Kv1.1 channels. Since heterochannels Kv1.1-Kv1.2 but not homotetrameric channels Kv1.1 are present in the brain, the heterochannels bearing mutation T226R are most likely underlying the pathogenesis of the disease by decreasing the responsiveness of cells to mild membrane depolarization and, thus, increasing the excitability of neurons.

P/Q-type (CaV2.1) Ca2+ channels regulate the release of neurotransmitter at central synapses. Missense and nonsense mutations in CACNA1A, the gene that encodes the principal α1A subunit of the CaV2.1 channel complex, are well-known to cause Episodic Ataxia type 2 (EA2) and Familial Hemiplegic Migraine type 1 (FHM1). These CaV2.1 channelopathies are typically caused by either channel loss/reduction-of-function (LOF) or gain-of-function (GOF), respectively. However, recent genome-wide sequencing has revealed that point mutations in CaV2.1, in fact, underlie a spectrum of neurological disorders that feature epilepsy, tremor, nystagmus, hypotonia, cerebellar atrophy, cognitive deficits, and global developmental delay. Given the multiple manifestations of the mutations and the broad range of severity among these disorders, the assessment of the impact of an individual pathological mutation on channel function is essential for understanding the etiology of a given case. To this end, we expressed the rat orthologues of one newly identified and one previously reported, but yet to be characterized, human CaV2.1 variants (V176M and R1673C, respectively) in HEK 293 cells and investigated their biophysical properties using patch-clamp electrophysiology. The corresponding rat variants (V178M and R1624C, respectively) had multiple effects on channel function, though each mutation affected channel gating differently. V178M displayed a ~10 mV hyperpolarizing shift in activation and slowed deactivation, while R1624C slowed channel activation kinetics, delayed closure, and accelerated recovery from inactivation. Molecular modeling revealed structural alterations that may account for the observed changes in channel gating. Taken together, our results indicate that V176M and R1673C likely cause human CaV2.1 channelopathies through multiple, distinct mechanisms.

The clinical hallmark of episodic ataxia type 2 (EA2) consists of episodes of recurrent severe vestibulo-cerebellar dysfunction, characterized by marked postural unsteadiness and oscillopsia. Triggering factors of EA2 attacks, such as physical exertion and sensory stimulation, the high comorbidity with migraine, and the increased risk of epilepsy in EA2 suggest abnormal brain excitability. To investigate this, we assessed brain excitability in response to visual (checkerboard) and visual motion (optic flow) stimuli using interictal functional magnetic resonance imaging. Visual stimulation elicited strong bilateral neural activity in the primary visual cortex (V1–V3) and in motion-sensitive visual areas (V5) in 21 EA2 patients and 21 age-matched healthy participants (HP). Compared to HP, EA2 patients revealed decreased activity in the primary visual cortex (V1), cerebellar Crus I and II and caudal vermis but increased activation of multisensory vestibular processing areas (posterior insula, superior temporal and supramarginal gyrus, inferior parietal lobe). Interestingly, the abnormal excitability in the vestibular processing cortex areas was primarily found in patients without medication (4-aminopyridine, acetazolamide) but hardly seen in patients on medication. Our findings in treatment-naïve patients reflect disease-inherent changes in visual cortical excitability in EA2, which may be reversible through anti-episodic medication. As excitability by visual motion stimuli in multi-sensory vestibular processing cortical areas was largely found in patients on medication it may also indicate an inhibitory effect on the physiological reciprocal inhibitory visual–vestibular interaction as a multisensory mechanism for self-motion perception: the annoying oscillopsia of EA2 patients is counterbalanced by decreased visual cortex activity and hence smaller inhibition of the vestibular cortex.

Misleading EEG in CACNA1A mutation: A case of late-onset episodic ataxia type 2.

The CACNA1A gene encodes the pore-forming subunit of the Cav2.1 (P/Q type) neuronal calcium channel and pathogenic variants cause a variety of neurological disorders including episodic and congenital ataxia, familial hemiplegic migraine, developmental delay and epilepsy. Multiple types of seizures have been described in affected patients, including status epilepticus as the first manifestation. In mice harboring the homozygous gain-of-function variant p.Ser218Leu, seizures leading to SUDEP triggered by brainstem spreading depolarization with subsequent apnea and cardiac arrest have been reported. Clinical, genetic and functional data are presented. The 9-year-old boy with global developmental delay and congenital ataxia developed recurrent seizures and status epilepticus with prolonged, life-threatening apnea implying a high risk for SUDEP. Genetic testing showed a novel de novo missense variant in CACNA1A (c.5398T>A, p.Phe1800Ile). Functional analysis revealed a gain of channel function as the molecular pathomechanism. Therefore, an increased risk of SUDEP in patients with CACNA1-associated epilepsy seems reasonable and preventive strategies should be discussed with caregivers.

Developmental and epileptic encephalopathy type 32 (DEE32) is a severe neurological disorder caused by pathogenic variants in the KCNA2 gene, encoding the Kv1.2 voltage-gated potassium channel. DEE32 typically presents with early-onset seizures, ataxia, and intellectual impairment, though severity varies widely. We describe a family with a rare KCNA2 loss-of-function variant in two siblings, evaluating their clinical phenotype, neuroimaging, electroencephalography (EEG), developmental assessments, and treatment response. Cognitive function in patients 1 and 2 was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI), while cognitive function in patient 3 was inferred from his ability to maintain employment and function independently. The family included a father and two children, all with early-onset seizures in infancy and normal development. Patient 1, a male, exhibited delayed myelination at 15months, with seizures initially controlled but later recurring after medication weaning. His WPPSI assessment indicated normal cognition with a standard score of 113, and his mild speech delay resolved. Patient 2, a female, had a normal brain MRI and normal WPPSI evaluation (standard score of 111), with well-controlled seizures on zonisamide. The father had childhood-onset epilepsy persisting into adulthood, ultimately leading to Sudden Unexpected Death in Epilepsy (SUDEP) at age 30. Genetic testing confirmed that both children carried the c.765_773del (p.Met255_Ile257del) KCNA2 variant, linking their seizures to the father's epilepsy. Patients 1 and 2 responded well to zonisamide, while patient 3's response remains unknown due to a lack of medical records. This study highlights the variability of KCNA2-related epilepsy, ranging from early-onset seizures to long-term epilepsy with developmental delays and episodic ataxia. Despite carrying a loss-of-function variant, both children demonstrated a favorable response to zonisamide without additional neurological manifestations. Our findings underscore the need for further research into genetic modifiers of KCNA2 phenotypes. The interpretation of any association between SUDEP and KCNA2-related epilepsy and the determination of cause of death is hampered by limited data, as it is based on a single case with normal cardiac evaluation.

Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an exceptionally rare autosomal recessive neurodegenerative disorder. It is caused by biallelic inactivating variants in the ADP-ribosyl-serine hydrolase (ADPRS) gene that encodes for the enzyme ADP-ribosyl hydrolase3 (ARH3) involved in DNA repair. A distinctive feature of this condition is the exacerbation of clinical symptoms triggered by physical or emotional stress, as well as febrile illnesses. In this report, we describe three unrelated patients diagnosed with CONDSIAS, each having variable clinical phenotypes and responses to treatment. Patient 1 is a 26-year-old female with language delay, intellectual disability, and infrequent seizures in childhood. She later developed parkinsonism, truncal dystonia, ataxia, peripheral neuropathy, and neuropsychiatric symptoms in her second decade. Patient 2, an 8-year-old boy born to consanguineous parents, presented with infection-triggered episodic ataxia and ichthyosis. His elder sibling had suffered from progressive ataxia and succumbed to sudden death at the age of 8. Patient 3 is a 6-year-old girl who presented with progressive ataxia, myoclonus, oculomotor apraxia, and upward gaze palsy. Both patients 2 and 3 responded favourably to treatment with high-dose vitamin supplementation, while patient 1 showed stable disease progression without specific therapeutic intervention, suggesting spontaneous stabilization of her condition. Extra-neurological manifestations included ichthyosis in patients 1 and 2 and cataracts in patient 1. These three cases illustrate the heterogeneity in clinical presentation and prognosis of CONDSIAS, highlighting the occurrence of predominant extrapyramidal features and systemic involvement, thereby expanding the phenotypic spectrum beyond the typical manifestations of ataxia and seizures.

The NALCN channelosome regulates the resting membrane potential through sodium leak currents, influencing cellular excitability. Genetic variants in NALCN and UNC80, a subunit of the NALCN channelosome, cause ultra-rare and severe neurodevelopmental disorders. Autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome is associated with gain-of-function (GOF) variants in NALCN. Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) 1 syndrome is associated with biallelic variants in NALCN and IHPRF 2 syndrome with biallelic variants in UNC80, both resulting in a loss-of-function (LOF). This study aims to expand the phenotypes associated with these syndromes, exploring potential genotype-phenotype associations. This is a cross-sectional study including patients with pathogenic or likely pathogenic variants in NALCN and UNC80. Phenotypes were evaluated through a structured interview, questionnaires, and review of medical records. Associations between variants, clinical features, and syndromes were analyzed. Fifty-one patients were included (34 with CLIFAHDD, 9 with IHPRF 1, 8 with IHPRF 2; 3 months-27 years; 37.3% female). All exhibited neurodevelopmental delay, more severe in patients with LOF variants (p = 0.019). Neurodevelopmental regression was observed in 29.4% of patients with CLIFAHDD syndrome, associated with the onset of ataxia (70%). Patients with CLIFAHDD had more severe respiratory symptoms at birth (11.7% orotracheal intubation). Distal arthrogryposis (76.5%), episodic ataxia (41.2% of ambulatory patients), and paroxysmal dystonia (11.7%) were exclusively diagnosed in patients with CLIFAHDD. Patients with LOF variants presented more frequently with failure to thrive (88.2%, p = 0.001), central sleep apnea (CSA, 64.7%, p < 0.001), and epilepsy (70.6%, p < 0.001). Epilepsy was associated with more severe cognitive delays (p = 0.016) and was refractory in 58.8% of patients. Earlier seizure onset was associated with refractory epilepsy (p = 0.014). Patients with CLIFAHDD and premature death, epilepsy, or paroxysmal dystonia carried variants within NALCN pore domains. This study provides an in-depth clinical characterization of NALCN-related and UNC80-related disorders. Distal arthrogryposis, episodic ataxia, and paroxysmal dystonia were diagnosed in patients with CLIFAHDD while failure to thrive, CSA, and epilepsy were associated with LOF variants. We suggest potential genotype-phenotype associations, formulating hypotheses for validation in future studies with larger cohorts.

Pediatric paroxysmal movement disorders - A clinical epidemiological study in an Irish cohort.

To describe the epidemiology, clinical features, degree of disability and genetic characteristics of a cohort of patients with a vestibulo-cerebellar ataxia of very late onset (LOVCA). We analysed the clinical, radiological, and genetic characteristics of a cohort of 50 patients with LOVCA. Where possible, patients were followed over the full course of the disease, including clinical, and molecular genetic analysis of genes known to cause episodic ataxia. Ten patients are familial and 40 sporadic. Forty-three patients had an episodic onset, with episodes of gait ataxia characterized especially by sudden instability with downbeat nystagmus, visual symptoms, dizziness, and falls. Progression began on average 1.5years after the onset of episodes. Of the patients followed over the full course of the disease, 87% became disabled. Women seem more prone to disability than men. An FGF14 intronic GAA repeat expansion was found in 61% of patients with available DNA. The prevalence of LOVCA is 5.03/105 inhabitants. Treatment with 4-aminopyridine reduced the number and severity of episodes. LOVCA appears after the age of 50 and commonly leads to an inability to stand up and walk. The disease caused mild atrophy only in half of the patients and few changes were observed by MRI. The most common genetic cause was a heterozygous GAA expansion in FGF14 (SCA27B). One third of our patients have no aetiological diagnosis. Disability seems to be a result of the complete loss of the vestibulocerebellar function, which is presumably a result of degeneration of this system.

Efficacy and safety of 4-aminopyridine in episodic ataxia type 2: a case series.

This case highlights a 27-year-old male with Dravet syndrome caused by an SCN2A mutation, ADHD, autism, insomnia, migraine headaches, and episodic ataxia, demonstrating an unusual tolerance to bupropion therapy. He was prescribed bupropion XL at 150 mg daily, which was later reduced to 75 mg daily due to insomnia, and he experienced no seizures while on this medication. This case suggests that, with close monitoring, bupropion may be a treatment option for certain epilepsy patients who also need management for coexisting conditions like ADHD. Further studies are required to understand whether genetic mutations, such as SCN2A, influence how patients metabolize and respond to bupropion, potentially expanding options for managing complex cases of Dravet syndrome.

Episodic ataxias (EAs) are a rare group of paroxysmal movement disorders (PMD) described in human medicine with only one suspected case described in veterinary literature. This study aimed to provide clinical description of a suspected primary EA in working Cocker Spaniel (WCS) dogs. Seven WCS dogs with suspected primary EA. Descriptive, retrospecitve, multicenter study. Clinical signs, video footage, investigations, treatment, and outcome were reviewed. Owners of affected dogs were invited to complete a questionnaire. The mean age at clinical onset was 4 months. Signs were acute and included episodic body swaying, titubation, cerebellar ataxia, wide-base stance, and hypermetria, all while mentation remained unaltered. Neither autonomic nor vestibular signs nor hyperkinetic movements were observed. Duration of episodes ranged from 30 minutes up to 24 hours, and their frequency varied from weekly to once every 5 months. When investigations were performed, results revealed no abnormalities except for 1 dog that had increased gluten antibody titers. None of the dogs deteriorated, and in dogs with available follow-up (5/7) the frequency of episodes decreased or completely resolved, from which the majority (4/5) received gluten-free diet. A novel PMD was identified in young WCS, manifesting as EA. The condition is suspected to have a primary (genetic) etiology, although the cause of this manifestation has not yet been identified. Episodic ataxia in our WCS had a good prognosis. Veterinarians must be aware of this presentation, and further investigations are needed to determine the origin of the clinical signs.

Abstract Paroxysmal movement disorders (PxMDs) are a clinically, genetically, and pathophysiologically a diverse group of disorders, characterized by their sudden, short-lasting, episodic nature, onset in early childhood, reduced severity during adulthood, and often a normal neurological examination between episodes. PxMDs include paroxysmal dyskinesias (PxD), which present with sudden episodes of dystonia and chorea, and episodic ataxias (EA), which present with episodes of cerebellar dysfunction. PxDs can also be precipitated by secondary causes, including metabolic or immunological factors, and structural lesions. Newer genetic advances, such as next-generation sequencing, have revolutionized how we classify and investigate PxMDs. However, a significant proportion of patients still remain undiagnosed despite current advances in genetic testing. In this review, we revisit the updated genetic underpinnings of paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dyskinesia, and the EAs, review the recently described individual genes causing PxD, discuss the causes of secondary PxMD, describe a pragmatic, clinically based approach to ordering genetic tests in PxMD, and conclude with a brief overview of all cases of PxMD reported from India to date.

Oculomotor deficits are common in hereditary cerebellar ataxias (HCAs) and their quantitative assessment offers a sensitive and reliable manner to capture disease-severity and progression. As a group of experts of the Ataxia Global Initiative to support trial readiness, we previously established harmonized methodology for quantitative oculomotor assessments in HCAs. Here, we aimed to identify to most promising oculomotor/vestibular outcomes as endpoints for future trials. Through a systematic MEDLINE search we identified 130 articles reporting oculomotor/vestibular recordings in patients with HCAs. A total of 2,018 subjects were included: 1,776 with genetically-confirmed and 242 with clinically-defined HCAs. Studied diseases included spinocerebellar ataxias (SCA) 1/2/3/6/7/27B, episodic ataxia type 2, Friedreich ataxia, RFC1-related ataxia, fragile X-associated tremor/ataxia syndrome, cerebrotendinous xanthomatosis, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1&2, and Niemann-Pick disease type C. We identified up to four oculomotor/vestibular outcomes per diagnostic entity, based on their ability to robustly discriminate patients from controls, correlate with disease-severity, detect longitudinal change, and represent different disease stages. For each parameter we provide recommendations for recordings. While the implementation of quantitative assessments into clinical trials offers a unique opportunity to track dysfunction of oculomotor/vestibular networks and to assess the impact of interventions, in some HCAs, endpoint qualification of available outcomes requires further validation to characterize their reliability, sensitivity to change, and minimally important change to patients. For all HCAs for which quantitative data are scarce or lacking, there is an urgent need for prospective studies covering a broader range of oculomotor/vestibular domains as approaching new treatments require harmonized and reliable endpoints.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12311-025-01894-z.