To define the clinical spectrum and treatment responses of anti-Kelch-like protein 11 (KLHL11) IgG-associated neurological syndromes by screening a large, expanded cohort of patients with suspected autoimmune cerebellar ataxia (ACA), autoimmune encephalitis (AE), and related neurological disorders. In this retrospective, observational study, serum samples from 930 patients collected from over 100 medical institutions across Japan between 2002 and 2025 were screened. The study population was categorized into five cohorts: cerebellar ataxia (CA) of unknown etiology (n = 778), AE (n = 49), brainstem encephalitis (n = 2), myelitis (n = 12), and multiple system atrophy (MSA) (n = 89). Anti-KLHL11 antibodies were detected using a fixed cell-based assay with HEK293T cells. Cerebrospinal fluid was analyzed in all serum-positive cases. Anti-KLHL11 antibodies were identified in four cases, three males and one female with a mean onset age > 60 years, all showing dual positivity in serum and cerebrospinal fluid. The clinical phenotypes consisted of predominantly CA (n = 2), combined limbic encephalitis (LE) and CA (n = 1), and isolated LE associated with small-cell lung cancer (n = 1). Notably, none of the cases were associated with testicular tumor. While typical paraneoplastic presentations were observed, one patient had no detectable malignancy and improved with immunotherapy alone, and another showed neurological recovery following treatment of a non-testicular tumor. Anti-KLHL11 antibodies were absent in all disease controls with MSA. Expanding our initial findings, this nationwide study indicates that anti-KLHL11 antibody-associated ACA and AE are rare but increasingly recognized in Japan and may be under-recognized globally. The clinical spectrum of anti-KLHL11 antibody-associated neurological diseases is broad, including females and individuals without a detectable testicular tumor. Importantly, patients presenting with AE may show more favorable responses to immunotherapy or tumor-directed treatment than those with isolated CA, highlighting the importance of early recognition and phenotype-specific management.

Autoimmune cerebellar ataxia (ACA) is a potentially treatable cause of cerebellar dysfunction, but remains underrecognized because of diagnostic challenges, including limited access to autoantibody testing and heterogeneous clinical presentations. We aimed to describe the clinical and laboratory characteristics of patients with clinically diagnosed ACA (cdACA) in Japan, based on expert diagnoses, and evaluate associations between clinical factors and response to immunotherapy. This study was a retrospective, multi-center, descriptive study based on a two-step nationwide survey. We inquired at facilities accredited by the Japanese Society of Neurology about the number of patients with cdACA. Furthermore, we asked the facilities with cdACA experience for clinical information. Of 92 cdACA patients, 96.7

Objectively quantifying cerebellar motor dysfunction remains a challenge in clinical trials. The Adaptability Index, derived from the Prism Adaptation Test, evaluates motor learning but lacks multicenter validation. We aimed to validate the Adaptability Index as a robust biomarker across multiple hospitals and investigate its relationship with the Scale for the Assessment and Rating of Ataxia. We enrolled 74 patients with cerebellar degeneration across seven hospitals using a standardized touchscreen system. We analyzed the correlation between Adaptability Index and the Scale for the Assessment and Rating of Ataxia and evaluated inter-hospital robustness using Linear Mixed-effects Modeling. Consistency of Adaptability Index variance between distinct genotypes (Spinocerebellar Ataxia type 6 and type 31) was assessed using Levene’s test and normalized standard deviations. The Adaptability Index correlated negatively with the Scale for the Assessment and Rating of Ataxia (r = − 0.364, p < 0.01). Notably, Linear Mixed-effects Modeling revealed negligible inter-hospital variance, confirming robustness against site-specific biases. Levene’s test indicated consistent Adaptability Index variance across these genotypes (p = 0.41). However, the Adaptability Index exhibited higher resolution than the Scale for the Assessment and Rating of Ataxia in detecting phenotypic variability (larger normalized standard deviations), particularly in the Spinocerebellar Ataxia type 31 cohort, likely reflecting cerebellar motor learning capacity distinct from motor execution deficits. The Adaptability Index is a valid, genotype-stable, and site-independent biomarker of cerebellar motor learning. Its high resolution and robustness make it a promising objective endpoint for multicenter interventional trials targeting cerebellar dysfunction.

Prion disease is a general term for a disease that causes cognitive disorders due to the accumulation of abnormal prion protein in the brain. Creutzfeldt-Jakob disease (CJD) is the most common case of prion disease, and sporadic Creutzfeldt-Jakob disease (sCJD) accounts for more than 70% of CJD cases. Early and accurate diagnosis of sCJD remains challenging. The aim of this study is to classify 6 sCJD patients from 10 healthy older adults and 23 Alzheimer's disease (AD) patients using resting-state scalp-recorded electroencephalogram (EEG)-derived indices. Power spectrum, SL values by Synchronization Likelihood (SL), and graph metrics by SL values were calculated for 5 frequency bands as EEG-derived indices. In addition, power spectrum and SL values were standardized and exponentially transformed for each subject and each frequency band. Graph metrics were calculated by these SL values. These indices were used as features for classification. Classifiers were constructed by features selected by Recursive Feature Elimination (RFE). The highest classification accuracy was 97.44% using a 12-dimensional feature. This accuracy was confirmed by indices after standardization and exponential transformation. Additional validation analyses were performed to assess the reliability of the selected classifier. Accuracy of nested LOOCV was 84.62%, supporting meaningful classification ability under a leakage-controlled validation framework. An analysis of robustness removing a group of subjects with high similarity with many others showed that the selected classifier maintained a micro-F1 score of 90.32%. Permutation test indicated that the observed performance was significantly higher than chance level, and repeated stratified 10-fold cross-validation showed relatively stable performance across different data partitions. These findings suggest that resting-state EEG-derived indices may provide useful candidate features for classification of sCJD, AD, and healthy older adults. However, further validation using larger independent cohorts is required to establish the generalizability and clinical reliability of the proposed classifier.

One of the challenges in clinical genetics for rare diseases and personalized medicine is evaluating isoform alterations arising from heterozygous putative splicing variants at the allele level. Our aim was to analyze these variants by dividing cDNA or direct RNA nanopore long reads into two alleles, referencing whole-genome sequencing data containing allele-informative single nucleotide variants and then comparing the allele-separated reads using Full-Length Alternative Isoform analysis of RNA (FLAIR), a previously published bioinformatics tool for isoform analysis. In this study, we developed an allele-separative bioinformatics pipeline and described its performance. We applied our pipeline to previously published nanopore direct RNA sequencing data, as well as 5’ cap-trapping full-length cDNA nanopore sequencing (CTR-seq) data from blood samples of three individuals. We successfully identified heterozygous splicing variants associated with significant isoform differences between alleles. Furthermore, we uncovered the effects of a novel pathogenic splicing variant in PYGM on isoforms in a compound-heterozygous case of McArdle disease using nanopore cDNA amplicon and targeted genomic sequencing. This study demonstrates the utility of nanopore long-read sequencing for isoform analysis at the allele level, providing a valuable approach to evaluating the direct consequences of heterozygous splicing variants in individuals.

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.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia caused by abnormal CAG expansions (≥ 34 repeats) in the ATXN2 gene (ATXN2), whereas intermediate CAG expansions (27–33 repeats) have been linked to amyotrophic lateral sclerosis (ALS). A 53-year-old woman with longstanding cerebellar ataxia developed progressive upper limb weakness and muscle atrophy at the age of 51 years. On neurological examination, she was found to have ataxic dysarthria, slow saccadic eye movements, tongue atrophy with fasciculations, muscle atrophy and weakness in both upper limbs, hyperreflexia with Babinski’s sign, and limb and gait ataxia. Brain magnetic resonance imaging (MRI) showed brainstem and cerebellar atrophy. Genetic analysis identified an expanded CAG-repeat of 39/22 in ATXN2, and screening for other known ALS-related gene mutations was negative, leading to a diagnosis of both SCA2 and ALS associated with ATXN2. SCA2 is typically associated with uninterrupted CAG-repeat expansions, whereas ALS-related ATXN2 expansions usually contain at least one CAA triplet. However, despite carrying an uninterrupted CAG-repeat expansion, this patient developed ALS. This case shows that ALS can emerge several decades after SCA2 onset, even in patients with pure CAG-repeats, underscoring the need for long-term monitoring in SCA2 patients. Further research is needed to clarify the roles of repeat length, CAA interruptions, and other factors in ATXN2-related ALS.

Invasive tests like cerebrospinal fluid (CSF) examination are highly effective for diagnosing human prion disease (HPD). Real-time quaking-induced conversion (RT-QuIC) CSF assay demonstrates 80–90% sensitivity for HPD diagnosis. To establish a minimally invasive diagnostic approach, we evaluated RT-QuIC testing on hair root and scalp samples. We collected scalp samples from 22 HPD and 5 non-HPD patients during pathological examinations and analyzed them using RT-QuIC assay and neuropathological methods. In our prospective study, hair root and CSF samples from 300 patients were tested using RT-QuIC assay along with other biomarkers, including 14-3-3 protein, total tau protein, RT-QuIC CSF assay, and MRI findings. All 22 HPD patients demonstrated positive prion seeding activity in scalp and hair root RT-QuIC assays. Neuropathological examination in one HPD patient revealed abnormal prion protein in scalp tissue. Among 177 HPD patients diagnosed by Japan Prion Surveillance Committee and 123 non-HPD patients, RT-QuIC assay of hair roots demonstrated sensitivity and specificity of 45.8% and 100%, respectively. Sensitivities of 14-3-3 protein, total tau protein, RT-QuIC CSF assay, and MRI findings were 83.1%, 86.4%, 74.6%, and 100%, respectively, with specificities of 65.0%, 65.0%, 100%, and 56.1%, respectively. RT-QuIC assays could be developed into novel diagnostic methods for neurodegenerative diseases.

Background and ObjectivesSpinocerebellar ataxia type 6 (SCA6) is caused by expansion of CAG repeat units (RUs) in CACNA1A. While the pathologic threshold has been considered to be 20 or 21 RUs, the lower limit remains controversial. This study aimed to clarify the pathologic significance of RUs in SCA6, including the role of opposite alleles (OAs).MethodsThis was an observational study of patients with suspected spinocerebellar ataxia who underwent SCA6 genetic testing. We analyzed the relationship between CACNA1A RUs and age at onset (AAO). Family history positivity rates were examined for different RUs of the expanded allele (EA). Regression analyses were performed for AAO estimation based on the EA RUs. The influence of OAs on AAO was investigated, particularly in cases with 21-22 EA RUs.ResultsIn total, 2,768 participants were enrolled. Family history positivity rates increased progressively above 19 RUs and plateaued at >= 23 RUs. Regression analysis of cases with >= 23 RUs showed that 96.20% of cases with >= 23 RUs, 90.67% of cases with 22 RUs, 91.15% of cases with 21 RUs, 61.54% of cases with 20 RUs, and 33.33% of cases with 19 RUs fell within the 95% prediction interval for AAO. However, no patients with <= 18 RUs were included. In the 21-22 RU group, OAs significantly influenced AAO, and >= 17 RUs had a significant effect. For >= 23 RUs, no significant OA effect was observed. Cases with 19-20 RUs showed a higher prevalence of OA with >= 19 RUs compared with cases with >= 23 RUs.DiscussionOur findings suggest that clinical manifestation within a typical lifespan likely requires at least 19 RUs. The 19-20 RU range represents an intermediate zone where OA may influence disease likelihood. For 21-22 RUs, OA significantly affects AAO, indicating a complex interplay between EA and OA. >= 23 RUs seem sufficient to cause disease onset within a typical lifespan, regardless of OA. These results provide a new paradigm for SCA6 diagnosis and genetic counseling, emphasizing the need for cautious interpretation of the intermediate RU range and consideration of OA.

Recently, gain- or loss-of-function variants in the calcium voltage-gated channel subunit alpha1I gene (CACNA1I) have been shown to cause neurodevelopmental disorders. As only 10 cases have been reported to date, clinical information remains limited. This article describes a patient carrying a previously identified CACNA1I variant (NM_021096.4: c.2579T>A, p.Ile860Asn). Notably, our patient exhibited previously unreported clinical findings resembling those observed in disorders associated with other CACNA1 family members, suggesting that these features may be characteristic of this disorder. Brain MRI revealed previously unreported excess iron accumulation in the globus pallidus and substantia nigra. These findings indicate that this disorder may be part of the spectrum of neurodegeneration with brain iron accumulation.

Background and Purpose: Clinical manifestations of Lyme borreliosis (LB), caused by Borrelia burgdorferi sensu lato (Bbsl), include erythema migrans, Lyme neuroborreliosis (LNB), carditis, and arthritis. LB is a notifiable disease in Japan with <30 surveillance-reported LB cases annually, predominately from Hokkaido Prefecture. However, LB, including LNB, may be under-diagnosed in Japan since diagnostic tests are not readily available. We sought to determine if LNB could be a cause of previously undiagnosed encephalitis or meningitis in Japan. Methods: Investigators at 15 hospitals in 10 prefectures throughout Japan retrieved serum and/or cerebrospinal fluid (CSF) samples collected in 2010-2021 from 517 patients hospitalized with encephalitis or meningitis which had an etiology that had not been determined. Samples were tested for Bbsl-specific antibodies using ELISA and Western blot tests. In alignment with the European Union LNB case definition, a confirmed LNB case had CSF pleocytosis and intrathecal production of Bbsl-specific antibodies and a probable LNB case had a CSF sample with pleocytosis and Bbsl-specific antibodies. Results: LNB was identified in three hospitalized patients with meningitis of previously undetermined etiology: a male resident of Aomori Prefecture was a confirmed LNB case, and two female residents of Oita Prefecture were probable LNB cases. None of the patients with confirmed or probable LNB had traveled in the month prior to symptom onset and none had samples previously tested for LB. Conclusion: The identification of previously undiagnosed LNB cases indicates a need for enhanced disease awareness in Japan, particularly beyond Hokkaido Island, and more readily available LB diagnostic testing.

Introduction: SATB1 encodes a protein of the same name, and its genetic alteration causes SATB1 (special AT-rich sequence-binding protein 1) dysfunction, which clinically presents as developmental delay, intellectual disability, facial features, and epilepsy. However, detailed clinical information, especially regarding respiratory disorders, has not yet been fully described.Case Presentation: We report the case of a 3-year-old Japanese girl with a de novo variant of SATB1, c.1588G > A:p.(Glu530Lys), who presented with a frequent breath-holding and hyperventilation while awake, in addition to typical phenotype. The long-term EEG showed no corresponding epileptiform changes, and breath-holding was considered non-epileptic rather than epilepsy, such as ictal central apneas. Valproic acid and acetazolamide alleviated breath-holding; however, it was intractable.Conclusion: Respiratory disorders were thought to be non-epileptic, not reported in SATB1 disorders, and were resistant to treatment. The case was considered critical and may provide new research clues to this severe and not yet fully understood phenomenon.

Prion diseases are caused by prions, which are proteinaceous infectious particles that have been identified as causative factors of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). Prion diseases are devastating neurodegenerative disorders in humans and many animals, including sheep, cows, deer, cats, and camels. Prion diseases are classified into sporadic and genetic forms. Additionally, a third, environmentally acquired category exists. This type includes kuru, iatrogenic CJD caused by human dura mater grafts or human pituitary-derived hormones, and variant CJD transmitted through food contaminated with bovine spongiform encephalopathy prions. Bovine spongiform encephalopathy and variant CJD have nearly been controlled, but chronic wasting disease, a prion disease affecting deer, is spreading widely in North America and South Korea and recently in Northern Europe. Recently, amyloid-beta, alpha-synuclein, and other proteins related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases were reported to have prion features such as transmission to animals. Amyloid-beta transmission to humans has been suggested in iatrogenic CJD cases and in cerebral amyloid angiopathy cases with cerebral bleeding occurring long after childhood neurosurgery with or without cadaveric dura mater transplantation. These findings indicate that diseases caused by various prions, namely various transmissible proteins, appear to be a threat, particularly in the current longevity society. Prion disease represented by CJD has obvious transmissibility and is considered to be an “archetype of various neurodegenerative diseases”. Overcoming prion diseases is a top priority currently in our society, and this strategy will certainly contribute to elucidating pathomechanism of other neurodegenerative diseases and developing new therapies for them.

Background: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and various motor symptoms. While MSA-C (cerebellar type) predominates in East Asia, MSA-P (parkinsonian type) predominates in Europe and North America. This nationwide patient registry aimed to (1) conduct a prospective natural history study of MSA in Japan, (2) facilitate patient recruitment for clinical trials, and (3) deposit bioresources and clinical information in a biobank. Methods: Thirteen institutions participated in this study. Clinical information was obtained by neurologists from the patients visiting the hospital every 12 months to assess the UMSARS Part 2 scores and by telephone interviews by nurses every 6 months to assess UMSARS Part 1 scores and to determine whether clinical events had occurred. Results: Demographic data from 329 MSA patients (216 MSA-C and 113 MSA-P) were analyzed. The mean age at symptom onset was 58.2 years (standard deviation, 8.9); the mean duration of symptoms at enrollment was 3.5 years (standard deviation, 2.2). The mean 12-month changes in the UMSARS Part 1 and Part 2 scores were 7.9 (standard deviation, 5.6) and 6.4 (standard deviation, 5.9), respectively. The patient registry proved useful in recruiting participants for clinical trials, including those with gene variants. Clinical information and biospecimens were deposited in a biobank. Discussion: The study highlighted the importance of telephone interviews in minimizing drop-out rates in natural history studies and demonstrated similar MSA progression rates across populations. The deposited bioresources are available to researchers upon request, aiming to contribute to future MSA researches.

Spinocerebellar ataxia type 6 (SCA6) is a polyglutamine (polyQ) disease, which is caused by the elongation of CAG repeats encoding polyQ in the CACNA1A gene. The CACNA1A gene encodes two proteins, namely, α1A (a subunit of the plasma membrane calcium channel), which is translated in its entire length, and α1ACT, which is translated from the second cistron, and both proteins have a polyQ tract. The α1A-polyQ and α1ACT-polyQ proteins with an elongated polyQ stretch have been reported to form aggregates in cells and induce neuronal cell death, but the subcellular localization of these proteins and their cytotoxic properties remain unclear. In this study, we first analyzed SCA6 model mice and found that α1A-polyQlong localized mainly to the Golgi apparatus, whereas a portion of α1ACT-polyQlong localized to the nucleus. Analysis using Neuro2a cells also showed similar subcellular localizations of these proteins, and a proportion of both proteins localized to the endoplasmic reticulum (ER). Cytotoxic studies demonstrated that both proteins induce both the ER stress response and apoptosis, indicating that they are able to induce ER stress-induced apoptosis.

Background/Objectives: Sporadic Creutzfeldt–Jakob disease (sCJD) is a fatal neurodegenerative disorder traditionally diagnosed based on the World Health Organization (WHO) criteria in 1998. Recently, Hermann et al. proposed updated diagnostic criteria incorporating advanced biomarkers to enhance early detection of sCJD. This study aimed to evaluate the sensitivity and specificity of Hermann’s criteria compared with those of the WHO criteria in a large cohort of patients suspected of prion disease in Japan. Methods: In this retrospective cohort study, we examined the new criteria using data of 2004 patients with suspected prion disease registered with the Japanese Prion Disease Surveillance (JPDS) between January 2009 and May 2023. Patients with genetic or acquired prion diseases or incomplete data necessary for the diagnostic criteria were excluded, resulting in 786 eligible cases. The sensitivity and specificity of the WHO and Hermann’s criteria were calculated by comparing diagnoses with those made by the JPDS Committee. Results: Of the 786 included cases, Hermann’s criteria helped identify 572 probable cases compared with 448 by the WHO criteria. The sensitivity and specificity of the WHO criteria were 96.4% and 96.6%, respectively. Hermann’s criteria demonstrated a sensitivity of 99.3% and a specificity of 95.2%, indicating higher sensitivity but slightly lower specificity. Fifty-five cases were classified as “definite” by both criteria. Conclusions: The findings suggest that Hermann’s criteria could offer improved sensitivity for detecting sCJD, potentially reducing diagnostic oversight. However, caution is advised in clinical practice to avoid misdiagnosis, particularly in treatable neurological diseases, by ensuring thorough exclusion of other potential conditions.