Genetic screening of EIF2B genes reveals mutation spectrum and predicted prevalence of vanishing white matter disease in Chinese population.

The RAR-related orphan receptor alpha (RORA) gene encodes a nuclear receptor involved in transcriptional regulation, circadian rhythm, and neurodevelopment. Dominant RORA variants are associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia, yet the phenotypic spectrum remains poorly defined. We performed comprehensive genetic and clinical analyses in four individuals with RORA variants from three unrelated families, using whole exome sequencing and chromosomal microarray analysis. Identified variants were confirmed by Sanger sequencing. Genetic analyses revealed three distinct RORA variants: a 15q21.2-q22.2 deletion encompassing RORA , a de novo nonsense variant c.499C>T (p.Gln167*), and a novel heterozygous frameshift variant c.683_686del (p.Glu228Valfs*78) segregating within a family. Clinical findings ranged from severe neurodevelopmental delay and epilepsy to mild intellectual disability and behavioral abnormalities, demonstrating marked intrafamilial variability. Notably, the same frameshift variant presented with differing phenotypes in the family, indicating variable expressivity-the first such observation reported in RORA -related disorders. Our findings broaden the genotypic and phenotypic spectrum of RORA-related neurodevelopmental disorders. The observed intrafamilial variability highlights the complexity of RORA-associated pathogenesis and underscores the importance of considering variable expressivity in future genotype-phenotype studies.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths worldwide. Although the incidence of severe acute cases has declined, the prevalence of long COVID, also known as post-acute sequelae of COVID-19 (PASC), is rising. The pathological mechanisms underlying severe COVID-19, along with the relationship to neurological disorders and potential risk for neurodegeneration, remain poorly understood. The aim of this narrative review is to summarize neuropathological features described in postmortem human COVID-19 brains (n = 352). Furthermore, analysis of biofluids and neuroimaging from PASC patients underline long-term changes in the proteome and CNS response following the infection. Postmortem brain studies from severe COVID-19 patients highlight disruption of the fluid-brain barriers and vascular dysregulation defined by endothelial inflammation and disruption, hemorrhages, and hypoxic-ischemic damage. Neuroinflammation, including astrogliosis, microglia nodules and infiltration of adaptive immune cells, has been reported in the olfactory bulb, medulla oblongata, midbrain and cerebellum. Neuronal damage was demonstrated in the hippocampus, midbrain and cerebellum in severe COVID-19 and protein aggregation was observed in the midbrain and entorhinal cortex. Neuropathological burden and elevated blood and/or cerebrospinal fluid (CSF) levels of proinflammatory cytokines (e.g. IL-6) and neuro-axonal proteins (e.g. NfL) correlated with severity of anosmia, memory deficits, and cerebellar ataxia. Elderly patients and/or patients with underlying neurological diseases were more susceptible and had worsened symptoms. Potential disease mechanisms underlying neurological symptoms observed in severe COVID-19 are vascular and fluid-brain barrier abnormalities, chronic neuroinflammation, persistent axonal damage and protein aggregation. In PASC patients, an altered biofluid proteome with increased neuronal proteins and pro-inflammatory cytokines was observed. The pathological burden in affected brain regions may contribute to manifestations such as anosmia, memory deficits, and cerebellar ataxia.

Deep Brain Stimulation for Cerebellar Ataxia: A Systematic Review on Indications, Targets and Outcomes.

Anti-Sez6L2 antibody-associated autoimmune cerebellar ataxia: a rare case with implications of rituximab therapy.

Therapeutic targeting of blood-derived protein infiltration to modulate neuroinflammation in cerebellar ataxia.

Background MSTO1 encodes a regulator of mitochondrial fusion. Mutations in MSTO1 are linked to a rare mitochondrial disorder characterized by early-onset myopathy and cerebellar ataxia, with 31 cases reported globally to date, which underscores its exceptional rarity. Methods We conducted comprehensive clinical, molecular, and biochemical investigations in a patient harboring novel MSTO1 variants. Results We identified a patient presenting with adult-onset progressive ataxia and cerebellar atrophy who carried two novel compound heterozygous variants in the MSTO1 gene (c.756A>G, p.Glu252Glu; c.1339G>A, p.Glu447Lys). Brain MRI revealed marked cerebellar abnormalities, but the patient’s clinical symptoms remained relatively mild with preserved daily function. This milder phenotype, characterized by adult onset and later disease presentation, contrasts with the more severe neurological deficits reported in a previously described case. Functional studies revealed significantly reduced MSTO1 protein expression, mtDNA depletion, and impaired mitochondrial function, as reflected by decreased mitochondrial membrane potential and respiratory capacity, suggesting a pathogenic role for these variants. Comparative analysis with fibroblasts from a previously reported case with MSTO1 mutation revealed notable differences in the severity of mitochondrial dysfunction, suggesting potential genotype–phenotype correlations. Conclusion Our findings provide evidence linking the novel MSTO1 variants c.756A>G and c.1339G>A to mitochondrial dysfunction and broaden the phenotypic spectrum of MSTO1-related mitochondrial disorders to encompass a milder, adult-onset form of cerebellar ataxia. These results emphasize the importance of integrated clinical and functional approaches in evaluating variant pathogenicity and in elucidating the clinical and molecular heterogeneity of MSTO1 -related mitochondrial disorders.

The axon initial segment (AIS) is essential for initiating action potentials and maintaining neuronal polarity, yet the developmental roles of its core molecular components—Neurofascin 186 (NF186) and Ankyrin G (AnkG)—remain incompletely defined in cerebellar Purkinje cells. Here, we generated Purkinje cell-specific NF186 and AnkG single- and double-knockout mice to investigate how these adhesion and scaffolding proteins cooperatively regulate AIS formation, ion channel localization, synaptic targeting, and neuronal survival. We found that genetic ablation of either Nfasc NF186 ( NFKO ) or Ankyrin3 ( AnkGKO ) disrupted assembly and maintenance of the AIS cytoskeleton, and that this defect was exacerbated by combined loss of both proteins during postnatal development. Other AIS-enriched proteins, including βIV Spectrin (βIVSpec), voltage-gated sodium (Na v ), and potassium (K v 1.2) channels, failed to properly localize to the AIS and progressively disintegrated between postnatal days 10 and 30. Notably, K v 1.2 clustering at the pinceau synapse was disrupted, and basket cell axons showed misaligned terminal organization, indicating defective inhibitory synapse innervation. By 2 months of age, degeneration of Purkinje cells was evident, accompanied by cerebellar dysfunction. Notably, AnkG ablation caused a progressive postnatal loss of NF186 at the AIS, whereas NF ablation resulted in much slower loss of AnkG at the AIS in Purkinje cells and closely phenocopied the severe AIS destabilization observed in NF/AnkG double-knockout mice. In addition, our RNA-seq analysis revealed that Purkinje cell-specific loss of NF186 predominantly activated immune-inflammatory pathways; AnkG loss significantly disrupted neuronal developmental and metabolic processes; and the dual loss of NF186/AnkG produced transcriptional changes that were distinct from, and in part intermediate to, those observed in NF186 and AnkG single knockout. Collectively, our results show that NF186 and AnkG have complementary, non-redundant roles in establishing and maintaining the Purkinje cell AIS, and that their loss disrupts synaptic organization at the AIS. These findings advance our understanding of AIS development in cerebellar neurons and have implications for diseases involving AIS dysfunction, including cerebellar ataxia and demyelinating neuropathies.

Typhoid fever is a common cause of febrile illness, caused by Salmonella enterica serovar Typhi (S. Typhi), which employs specialized mechanisms to invade the intestinal mucosa and subsequently disseminates to the reticuloendothelial system. Neurological complications are uncommon and typically manifest during the second week of illness. Acute cerebellar ataxia, occurring as an isolated neurological manifestation of enteric fever, is particularly rare and is usually characterised by abnormalities in gait and speech. In the reported case, the diagnosis of enteric fever was confirmed through a positive blood culture. The primary clinical features included rapid onset of gait ataxia, limb ataxia, and dysarthria. Cerebellar involvement was observed during the second week of illness, with progression over one to two days. The symptoms remained stable for approximately one week, followed by gradual recovery under appropriate antibiotic treatment. These findings indicate that timely diagnosis and administration of suitable antibiotics are associated with favourable neurological recovery in patients with cerebellar complications of enteric fever.

A case of autoimmune cerebellar ataxia associated with anti-neurochondroitin antibody.

Isolated oculomotor dysfunction with downbeat nystagmus as a rare presentation of anti-GAD autoimmunity.

Biallelic intronic AAGGG repeat expansions in RFC1 cause cerebellar ataxia with neuropathy and vestibular areflexia syndrome and may also contribute to isolated sensory neuropathy. The clinical significance of both heterozygous and homozygous (biallelic) RFC1 expansions in more diverse patient populations remains unclear-partly due to the absence of accurate, user-friendly computational pipelines specifically tailored for tandem repeat analysis. To discern the relationship between RFC1 expansions and idiopathic peripheral neuropathy (iPN), we performed whole-genome sequencing (WGS) followed by polymerase chain reaction (PCR)-based confirmation in a large, well-characterized US cohort consisting of 788 patients with iPN (369 pure small fiber neuropathy (SFN), 266 sensorimotor, 144 pure sensory, and 9 pure motor). We developed an integrative pipeline combining ExpansionHunter Denovo and Expansion Hunter coupled with unsupervised clustering to reliably detect and genotype RFC1 expansions from short-read WGS data, achieving 97.2% concordance with repeat-primed PCR-based validation. Biallelic RFC1 expansions were present in only 1 out of 778 controls but present in 18 out of 788 (2.3%) patients with iPN (Fisher's exact p = 7 × 10-5), including 6.9% (10/144) of pure sensory, 1.1% (4/369) of SFN, and 1.5% (4/266) of sensorimotor neuropathy. These data indicate that motor nerve involvement should not exclude patients from RFC1 repeat screening. Monoallelic expansions were observed at a nominally higher frequency in iPN than in controls (9.1% vs 7.2%), but this difference did not reach statistical significance (Fisher's exact p = 0.17). We also found no evidence of second mutations or expansions on the other allele among monoallelic carriers. Our approach provides a robust, cost-effective method for detecting RFC1 expansions from WGS data. Our findings indicate that homozygous (biallelic) AAGGG repeat expansions in RFC1 contribute to development of iPN. Heterozygous expansions may also confer disease risk, but future studies are needed to assess this observation and explore any phenotypic differences with biallelic cases. ANN NEUROL 2026.

Since the initial report of seizure‑related 6 homolog-like 2 (SEZ6L2) autoimmunity in a patient with cerebellar ataxia and retinopathy, subsequent reports have expanded the phenotype. Although rare, timely recognition is essential because this condition is immunotherapy-responsive.To describe a case of SEZ6L2 autoimmunity and conduct a systematic review (2014-2025) to characterize this rare disease.An 87-year-old man presented with subacute gait disturbance and cognitive decline, progressing to wheelchair dependence within 4 months. Examination showed dysarthria, appendicular and axial ataxia, dysmetria, tremor, and postural instability. Brief Ataxia Rating Scale (BARS) was 19.5. CSF studies and brain MRI were unremarkable, whereas FDG-PET demonstrated diffuse cerebellar hypometabolism. Malignancy screening was negative. After empiric intravenous immunoglobulin (IVIg) 2g/kg, SEZ6L2 antibody assays returned positive in serum and CSF. Monthly IVIg was continued with mild improvement (BARS 18 at 7 months). Systematic review identified 12 articles (18 patients). Including our case, 19 patients (median age 60 years, 63% female) were analyzed. All had subacute cerebellar ataxia. Cognitive dysfunction and Parkinsonism were seen in 78.9% and 42.1%, respectively. Other symptoms included depression, pyramidal signs, nausea, tremor, sleep disturbance, and dysautonomia. Treatment was heterogeneous, with 47.4% showing partial improvement.SEZ6L2 autoimmunity is a rare, immunotherapy-responsive cause of subacute cerebellar ataxia, often with parkinsonism and cognitive changes. Presentations may extend beyond these manifestations.

This review will discuss the latest genetic and pathophysiological spectrum of paroxysmal movement disorders and emerging therapeutic strategies. Paroxysmal movement disorders comprise a heterogenous group of rare movement disorders characterized by intermittent episodes of spontaneous or triggered attacks of hyperkinetic movement disorders. Genetic spectrum has evolved offering new insights in the pathophysiological mechanisms of known genes as PRRT2 and new ones as TMEM151A. Also, SCA27B-related adult-onset cerebellar ataxia has emerged as a new treatable cause of episodic ataxia. Exploring new pathophysiological associations can offer diagnostic precision and development of new therapeutic directions.

Case report: anti-NMDAR encephalitis with cerebellar ataxia as the initial manifestation.

Background: Parental imprinting plays a crucial role in epigenetic regulation and is increasingly recognized for its involvement in neurodevelopmental disorders. Although ATP8A2 is considered a non-imprinted gene; However, the marked phenotypic variability observed across related disorders suggests that additional regulatory layers may influence its expression. Methods: We investigated the imprinting-like status of ATP8A2 through functional analyses of a splicing variant (c.1580-3C>G) identified in a patient diagnosed with Cerebellar Ataxia, Mental Retardation, and Disequilibrium syndrome type 4 (CAMRQ4). Sanger sequencing was used to assess allelic expression and identify aberrant transcripts. Results: Our analyses revealed an allelic expression imbalance suggestive of parental imprinting of ATP8A2. Moreover, Sanger sequencing led to the identification of a novel ATP8A2-RAB3GAP2 chimeric transcript, pointing to a previously unreported transcriptional event, the functional relevance of which remains to be determined. Conclusions: These findings indicate that ATP8A2 may be subject to imprinting-like regulation and involved in atypical splicing events with unknown significance. This highlights the need for further investigation into the epigenetic and transcriptional complexity of ATP8A2-related neurodevelopmental disorders.

The epigenetic modification N6-methyladenosine (m6A) is critical for neurodevelopment. However, its interplay with histone modifications during cerebellar development remains poorly understood. Ythdf2 is a core m6A reader that promotes selective degradation of methylated transcripts to shape gene expression dynamics. However, whether Ythdf2 also coordinates epitranscriptomic regulation with chromatin remodeling during cerebellar development is unknown. Here, we generated a Ythdf2 knockout (Ythdf2KO) mouse model and examined cerebellar development at embryonic day 13.5 (E13.5) and postnatal day 3 (P3). Ythdf2KO mice developed overt cerebellar ataxia, manifested by tremors and abnormal gait. At the molecular level, loss of Ythdf2 disrupted neural progenitor maintenance and induced premature neuronal differentiation. The expression of progenitor markers, including Sox2, Nestin and Pax6 were markedly reduced, whereas markers of neuronal differentiation such as Tuj1 and Skor2 were increased. In contrast, genes associated with neuronal maturation, including Map2 and Calb1, and astrocytic marker Gfap were downregulated. m⁶A RIP seq analysis demonstrated that Ythdf2KO caused a global reduction in m⁶A levels, with the differentially expressed m⁶A modified genes enriched for histone modification and chromatin stability. Furthermore, Ythdf2 loss suppressed transcriptional activity by altering H3K4me3 deposition, thereby reducing chromatin accessibility within neuronal developmental pathways. Co-immunoprecipitation revealed a specific interaction between YTHDF2 and the H3K4 methyltransferase SETD1B, but not CXXC1 or SETD1A, and Setd1b knockdown rescued the neural self-renewal and differentiation defects caused by Ythdf2 deletion. Together, these results establish a mechanistic link in which Ythdf2 connects m6A-modified transcripts to Setd1b-mediated H3K4me3 deposition, thereby sustaining chromatin accessibility and transcriptional programs required for proper cerebellar development.

SEZ6L2 autoantibodies have been identified in patients with subacute cerebellar ataxia, but the underlying immune mechanisms and pathogenic pathways remain poorly understood. We previously established a C57BL/6 mouse model of SEZ6L2 autoimmunity that recapitulates key features of the disease. Here, we evaluated whether genetic background influences the magnitude and organization of SEZ6L2-directed immune responses. Pilot screening of autoimmune-prone strains identified SJL mice as exhibiting accelerated and enhanced antibody responses following SEZ6L2 immunization. In a large-cohort study, SEZ6L2-immunized SJL mice developed robust and sustained antibody responses, along with antigen-specific CD4⁺ and CD8⁺ T-cell activation. Expanded immune profiling revealed increased CNS infiltration of multiple lymphocyte populations, including CD4⁺ T cells, CD8⁺ T cells, B cells, and dendritic cells, as well as the presence of SEZ6L2-specific B cells within the brain. In addition, SJL mice exhibited strain-specific immunodominant T-cell epitopes distinct from those observed in C57BL/6 mice. Functionally, SEZ6L2-immunized SJL mice developed motor deficits consistent with cerebellar dysfunction. Integration of behavioral outcomes demonstrated a consistent overall impairment, and multivariate analysis revealed that coordinated humoral and cellular immune responses were associated with behavioral deficits. Together, these findings demonstrate that SEZ6L2-directed immune responses produce coordinated adaptive immune activation linked to neurological dysfunction and establish the SJL strain as an enhanced model for studying SEZ6L2 autoimmunity. This model also provides a platform for investigating disease mechanisms and therapeutic strategies.

TMEM132A autoimmunity in patients with suspected autoimmune cerebellar ataxia.

Pure cerebellar ataxia is a neurological disorder characterised by isolated cerebellar dysfunction, arising from either developmental anomalies or progressive degenerative processes. Precise genetic diagnosis remains challenging. The aim of this study was to use a whole-exome sequencing approach to study a large, highly consanguineous Italian family in order to identify a new gene correlated with pure cerebellar ataxia. Sequencing excluded the presence of mutations in known-related genes but revealed a homozygous missense variant in CLIC5; however invivo analysis of a CLIC5 KO mouse model showed vestibular dysfunction without cerebellar involvement, suggesting that CLIC5 is not directly involved in pure cerebellar ataxia onset. Further analysis identified two compound heterozygous variants in NEFM, and in silico analysis showed that they dysregulate NEFM phosphorylation. Phosphorylation of neurofilaments and subsequent formation of aggregates has already been linked to conditions such as ageffing and neurodegeneration. Moreover, invivo studies on mice transgenic for human NEFM have correlated NEFM phosphorylation and aggregation with neurodegeneration. Finally, neurofilaments have been proposed to be correlated to ataxia and autoimmune cerebellar ataxia. We therefore propose NEFM as a possible new candidate gene for hereditary cerebellar ataxia. These findings could be useful for advancing the genetic diagnosis of hereditary pure cerebellar ataxia, possibly enabling the screening of healthy carriers.