This study investigated brain structural changes associated with NOTCH2NLC gene mutations in neuronal intranuclear inclusion disease (NIID) patients, focusing on the evolutionary implications of this human-specific gene in brain development. We analysed 41 NIID patients and 21 healthy controls using voxel-based morphometry and surface-based morphometry to assess differences in grey matter volume and cortical complexity. Spatial relationships between brain atrophy and white matter hyperintensity volume as well as cerebrospinal fluid fraction were examined. Additionally, we conducted exploratory Spearman correlation analyses to evaluate associations between regional grey matter volume and clinical variables, including GGC repeat length, disease duration, age at onset and cognitive scores. NIID patients exhibited extensive reductions in grey matter volume and cortical thinning in multiple brain regions, with pronounced effects in the prefrontal cortex and cerebellum. The parietal lobe, insula and posterior cingulate gyrus showed decreased gyrification index and fractal dimension, while certain regions of the temporal and frontal lobes showed increased gyrification index and fractal dimension. Furthermore, in the NIID group, white matter hyperintensity volume and cerebrospinal fluid fraction were negatively correlated with grey matter volume in the olfactory cortex, orbital gyrus, anterior cingulate gyrus, insula, amygdala and temporal pole. Exploratory analyses suggested that longer GGC repeats were associated with greater atrophy in the striatum, middle cingulate cortex, sensorimotor cortex and cerebellum; earlier age at onset with thalamic (mediodorsal/pulvinar), occipital and cerebellar atrophy; and poorer cognitive scores with atrophy in the anterior cingulate cortex, superior occipital gyrus and superior temporal pole. This study uncovers widespread and complex cerebral structural changes in NIID patients, predominantly affecting the prefrontal cortex, cerebellum, insula and limbic system structures. These findings provide new insights into the neuroanatomical basis of NIID and support the hypothesis that human-specific genetic innovations driving cortical expansion may concurrently confer selective vulnerability to neurodegeneration.

OBJECTIVE:To determine whether retinal thinning in neuronal intranuclear inclusion disease (NIID) is associated with multilevel abnormalities across the visual system and with clinical severity. METHODS:Forty patients with NIID and 40 healthy controls underwent optical coherence tomography to measure peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) thickness. Among patients with NIID, 37 underwent structural MRI for quantification of visual-region volumes and 30 underwent resting-state functional MRI for graph-theoretical assessment of visual-network topology. Cognitive function and activities of daily living were evaluated in the NIID cohort. Partial correlation and exploratory mediation analyses were used to examine associations among retinal, neuroimaging, and clinical measures. RESULTS:Patients with NIID showed diffuse thinning of the RNFL and GCC relative to controls, with mean GCC showing the best discrimination between groups. Thinner retinal measures were associated with poorer cognition, worse daily function, and lower mean cortical thickness. Structural MRI identified volume abnormalities in selected visual-system regions, particularly the lateral geniculate nucleus, early visual cortex, and dorsal/parietal regions, and retinal thickness correlated positively with the volumes of several visual regions. Poorer daily function was associated with a lower clustering coefficient of the visual network. Left V3d, the dorsal part of area V3 in the occipital visual cortex, partially mediated the association between retinal thinning and functional impairment. CONCLUSIONS:These findings support coordinated retina-brain involvement in NIID across retinal, structural, and network levels, and identify OCT-derived RNFL and GCC thickness as accessible, noninvasive candidate biomarkers of disease severity.

Objective We aimed to evaluate the detection rates of antibodies against nodal-paranodal junction proteins in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to analyze the clinical, laboratory, and neuroelectrophysiological characteristics of antibody-positive patients. Methods A total of 45 patients with CIDP were enrolled. Serum samples were collected, and cell-based assay (CBA) was used to detect IgG against human neurofascin-155 (NF155), neurofascin-186 (NF186), contactin-1 (CNTN1), contactin-2 (CNTN2) and contactin-associated protein 1 (CASPR1). Results Six patients (13.3%) had IgG against NF155, 2 (4.4%) against CASPR1, 2 (4.4%) against NF186 and 1 (2.2%) against CNTN1. Seropositive patients had elevated cerebrospinal fluid (CSF) protein, higher CSF cells than seronegative patients. Patients seropositive for NF155-IgG exhibited an earlier disease onset and demonstrated higher prevalence of limb tremors and sensory ataxia compared to their seronegative counterparts. Among 11 seropositive patients, intravenous immunoglobins (IVIG) achieved good response in 1/7 (14.3%) cases. Rituximab showed good response in 6/8 (75.0%) cases. Conclusions Auto-immune nodopathies represent a distinct clinical entity from CIDP.

OBJECTIVE:The choroid plexus (CP) is a key component of the blood-cerebrospinal fluid barrier (BCSFB), but its mechanism of action in cerebral small vessel disease (CSVD) remains unclear. This study investigated CP volume (CPV) alterations and their association with conventional imaging markers in CSVD and explored the underlying role of inflammation using ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI. METHODS:In this study, 111 CSVD patients and 69 healthy controls (HC) underwent 3.0 T conventional MRI to quantify CPV in the lateral (LV), third (3 V), and fourth (4 V) ventricles. CSVD burden was evaluated using visual assessment scales, including indicators such as white matter hyperintensities (WMH), lacunes, basal ganglia-enlarged perivascular spaces (BG-EPVS), cerebral microbleeds (CMBs), and brain atrophy (BA). A subgroup (22 CSVD, 10 HC) underwent USPIO-enhanced MRI to measure the change of signal intensity ratio (∆SIR) as a feature of inflammatory activity in the CP and deep gray matter nuclei. RESULTS:CSVD patients showed significantly larger CPV (all p < 0.001). CPV demonstrated significant positive correlations with the severity of conventional CSVD imaging markers (all p < 0.05). USPIO-enhanced MRI revealed an increased ΔSIR in the LV, 3 V, and 4 V CP (all p < 0.05). Furthermore, increased USPIO uptake was observed in deep gray matter nuclei in CSVD. Crucially, a positive correlation was found between LV CP volume and ΔSIR (r = 0.375, p = 0.034), and the LV CP inflammation was strongly correlated with the hippocampus (r = 0.582, p < 0.001). INTERPRETATION:CP enlargement is prominent in CSVD and closely linked to the CSVD imaging burden. CP inflammation is associated with increased volume. CP may be a novel biomarker to help diagnose, monitor, and treat neuroinflammation in CSVD.

Neuronal intranuclear inclusion disease is caused by abnormal GGC repeat expansion in the NOTCH2NLC gene, though its pathogenic mechanism remains incompletely understood. This study shows that the abnormally expanded polyG-uN2C protein, encoded by the repeat sequence, contains intrinsically disordered regions and forms aggregates, leading to mislocalization of nucleophosmin and downregulation of fibrillarin. PolyG aggregates interact with nucleophosmin and rRNA, disrupting ribosomal homeostasis. Furthermore, polyG facilitates the downregulation of chromatin structural proteins CTCF and RAD21, thereby impairing chromatin organization. This pathological manifestation can be mitigated by restoring CTCF/RAD21 expression. Furthermore, in brain organoids derived from neuronal intranuclear inclusion disease patients, we observe nucleolar stress accompanied by genome-wide chromatin structural alterations. These changes correlate with increased DNA damage and cellular senescence phenotypes. Notably, antisense oligonucleotides targeting GGC effectively reduce polyG aggregation and ameliorate related molecular defects, ultimately alleviating senescence-associated phenotypes. These findings establish key mechanisms underlying neuronal intranuclear inclusion disease pathogenesis and provide proof-of-concept for targeted therapy.

The I794T hotspot mutation in the colony-stimulating factor 1 receptor (CSF1R) gene is associated with primary microgliopathy manifesting as leukoencephalopathy. In this study, we identify three Chinese probands harboring the CSF1R p.I794T variant and characterize their clinical and neuroimaging profiles. To elucidate disease mechanisms and explore therapeutic avenues, we generate a Csf1rI792T/+ knockin mouse model that carries this human mutation. These Csf1rI792T/+ mice exhibit hallmark features of CSF1R-related disorder (CSF1R-RD), including cognitive deficits, ventricular enlargement, reduced microglia, axonal spheroids, and demyelination. Transcriptomic analysis reveals that Csf1rI792T/+ microglia adopt an activated and disease-associated microglia (DAM)-like phenotype. Crucially, we develop and test a microglia replacement strategy, termed “duplicate-cyclic microglial depletion for transplantation” (DCMDT), which significantly ameliorates neuropathological deficits in Csf1rI792T/+ mice. Our findings highlight the pathological significance of the CSF1R p.I794T mutation and propose DCMDT as a promising therapeutic approach for neurodegenerative disorders driven by microglial dysfunction.

ObjectiveTo summarize the clinical characteristics, antibody spectrum and neuroelectrophysiological features of autoimmune nodopathy(AN), and to explore the phenotypic differences among different antibody-positive subgroups.MethodsThe clinical and electrophysiological data of patients definitely diagnosed with AN in Beijing Tiantan Hospital, Capital Medical University, from October 2018 to January 2026 were retrospectively analyzed.ResultsA total of 33 patients with AN were included. Antibody examination results showed that, anti-neurofascin(NF)155 antibody was the most prevalent, detected in 17 patients(51.50%), followed by anti-contactin-1(CNTN1) antibody in 8 patients(24.24%). Anti-NF186 antibody(4 cases, 12.12%), anti-contactin-associated protein 1(Caspr1) antibody(2 cases, 6.06%) and dual-target antibody positivity(2 cases, 6.06%) were relatively uncommon. The main clinical manifestations of AN patients included symmetric distal paresthesia of the extremities(32 cases, 96.97%), limb weakness(31 cases, 93.93%) and sensory ataxia(25 cases, 75.76%). Different antibody-positive subgroups presented distinct phenotypic features: patients with positive anti-NF155 antibody had a relatively younger age of onset, chronic onset and a high incidence of tremor, which was dominated by immunoglobulin(Ig)G4 subclass antibodies; patients with positive anti-CNTN1 antibody had a relatively advanced age of onset, mostly presented with acute or subacute onset, and were prone to complicated nephrotic syndrome; patients with positive anti-NF186 antibody had relatively mild nerve conduction damage; patients with anti-Caspr1 antibody manifested acute or subacute onset, with relatively elevated cerebrospinal fluid protein level and 24-h intrathecal IgG synthesis rate. The prominent neuroelectrophysiological manifestations of AN included decreased motor and sensory nerve conduction velocities, prolonged distal latency, frequent non-compressive conduction block and abnormal temporal dispersion. Definite sensory nerve action potentials could not be elicited in more than half of the patients.ConclusionsPatients with AN show high heterogeneity in clinical and neuroelectrophysiological characteristics, and different antibody-positive subgroups correspond to specific clinical and neuroelectrophysiological phenotypes.

Spinocerebellar ataxia (SCA) is a group of genetic neurodegenerative disorder characterised by progressive cerebellar and associated structural dysfunction. The prevalence of SCA subtypes are considerably variation among different ethnic groups and regions. However, the relative frequencies of these SCA subtypes remain understudied in northern Chinese populations. The study aimed to characterise the geographical heterogeneity of SCA subtypes between northern and southern China. We retrospectively analysed the genotypes and the clinical features of SCA patients primarily from northern China in Beijing Tiantan Hospital over the past five years. We compared the relative frequencies of subtypes found in the northern cohort with those reported in southern China. A total of 105 unrelated Chinese families were genetically verified, comprising 80 families from northern China and 25 families from southern China. Among the 80 families from northern China, SCA3 was identified in 46 families (57.5

BACKGROUND:Neuronal intranuclear inclusion disease (NIID) pathogenesis has been strongly linked to uN2CpolyG translated from NOTCH2NLC transcript variant 1. However, emerging evidence suggests that NOTCH2NLC transcript variant 2 may also generate a disease-relevant protein, PolyGN2C-iso2, but isoform-discriminating and antibody-independent evidence remains incomplete. METHODS:We characterize the aggregation propensity of PolyGN2C-iso2 in vitro, develop isoform-discriminating monoclonal antibodies for its detection in patient tissues, and perform targeted proteomic analysis of laser-microdissected p62-positive lesion cells. An AAV-mediated mouse model expressing PolyG(108×)N2C-iso2 is generated to assess its pathogenic potential, followed by behavioral, imaging, histopathological, proteomic, and functional analyses. RESULTS:NOTCH2NLC transcript variant 2 generates a distinct protein, PolyGN2C-iso2, which forms aggregates in vitro. Using developed monoclonal antibodies together with targeted proteomics, we provide evidence that PolyGN2C-iso2 is present within the pathognomonic intranuclear inclusions in NIID patient tissues, where it co-localizes with uN2CpolyG. The PolyG(108×)N2C-iso2 mouse model recapitulates key pathological hallmarks of NIID, including white matter abnormalities and cognitive deficits not fully captured by previous models. Mechanistically, PolyGN2C-iso2 expression is found to induce profound mitochondrial dysfunction. CONCLUSIONS:Our findings support the possibility that NIID involves a dual-protein pathogenic process involving both uN2CpolyG and PolyGN2C-iso2, which may have implications for therapeutic strategies targeting NOTCH2NLC-derived pathogenic proteins.

Background:Recent evidence highlights the potential predictive value of paraspinal muscle degeneration in amyotrophic lateral sclerosis (ALS). However, the magnetic resonance imaging (MRI) characteristics of degeneration in lumbar paraspinal muscles in ALS and lumbosacral radiculopathy (LR) remain unclear. Methods:Comparison of fatty infiltration (FI) and relative cross-sectional area (rCSA) of the paraspinal muscles was conducted between 38 ALS patients and 32 LR patients. Results:The mean rCSA of the multifidus (MF), erector spinae (ES), and psoas major (PM) muscles was lower on the symptomatic onset side compared to the contralateral side at the L3-L5 segments in patients with ALS. On the symptomatic onset side, the FI of the ES (L1-L4 segments), MF (L4 segment), and PM muscles (L1, L2, and L4 segments) was significantly higher in ALS patients who had pathological spontaneous activity (PSA) than in those without PSA. At the L3-L5 segments on the symptomatic onset side, the mean rCSA of the MF, ES, and PM muscles was significantly higher in LR patients compared to ALS patients (p < 0.01). Similar differences in the rCSA of the MF, ES, and PM muscles were observed between lower limb-onset ALS patients and LR patients (p < 0.05). In addition, mild associations were observed between declines in the ALS functional rating scale (ALSFRS)-lower score and decreases in the rCSA of MF and PM muscles, as well as increased FI of the MF and ES muscles. Conclusion:The decrease in the rCSA of the paraspinal muscles on the symptomatic onset side suggests progressive involvement of muscle fibers in ALS patients. The presence of PSA in the paraspinal muscles appears to be more valuable and sensitive for evaluating fatty substitution than muscle atrophy in ALS. MRI parameters of the paraspinal muscles may be useful for monitoring disease progression in ALS and distinguishing ALS, especially lower limb-onset cases, from pauci-symptomatic LR.

BackgroundNeuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder caused by NOTCH2NLC GGC repeat expansions. Renal involvement in NIID is not well understood.MethodsWe conducted a cross-sectional study of 96 genetically confirmed NIID patients. Renal function was comprehensively assessed using the estimated glomerular filtration rate (eGFR) derived from the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI 2021; hereafter EPI-eGFR) and a panel of five urinary biomarkers (microalbumin, transferrin, immunoglobulin G, α1-microglobulin, and α2-macroglobulin). Clinical features, GGC repeat number, and skin intranuclear inclusion count were analyzed for their association with renal function. Renal biopsies from two patients with pre-neurological proteinuria were examined for intranuclear inclusions.ResultsReduced EPI-eGFR (<90 mL/min/1.73 m2) was present in 20.8% (20/96) of patients. Among 44 patients with normal eGFR who underwent urinary testing, 63.6% (28/44) had abnormal urinary biomarkers. Urinary microalbumin, transferrin, immunoglobulin G and α1-microglobulin were significantly elevated in the early renal dysfunction group when eGFR remained normal (all p < 0.001). Among individual biomarkers, urinary microalbumin showed the best discrimination for early renal involvement (AUC 0.905). Hypertension was independently associated with reduced eGFR (OR 3.96, 95% CI: 1.16–13.51, p = 0.028). GGC repeat number showed no overall correlation with eGFR, nor did skin inclusion burden (all p > 0.05). However, in patients with normal renal function, higher GGC repeat number correlated with lower eGFR (ρ = −0.528, p = 0.035). Renal biopsies from two patients with pre-neurological proteinuria revealed characteristic p62-positive intranuclear inclusions in tubular and glomerular cells.ConclusionKidney involvement is common in this hospital-based NIID cohort, with a substantial proportion showing subclinical renal impairment. Sensitive urinary biomarkers may aid early detection before eGFR declines, with microalbumin showing the highest discriminative ability. Hypertension is a potentially modifiable risk factor for reduced eGFR. Genetic burden and skin inclusion burden do not predict renal outcomes, suggesting that secondary mechanisms drive progression. For patients who present with unexplained renal impairment, pathological examination of renal biopsy specimens for intranuclear inclusions may provide critical diagnostic clues.

Neuronal Intranuclear Inclusion Disease (NIID), caused by GGC repeat expansions in the NOTCH2NLC gene, has a poorly understood molecular pathogenesis. This study aimed to systematically delineate the molecular pathology of NIID for the first time by employing an unbiased proteomic approach in sweat gland tissue. We isolated sweat gland tissue from 20 NIID patients and 6 healthy controls via Laser Capture Microdissection and performed in-depth proteomic analysis using data-independent acquisition mass spectrometry, followed by functional annotation and mechanistic prediction through bioinformatics analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis. A total of 265 differentially expressed proteins were identified. Functional enrichment analysis revealed a pathological network composed of three core dysfunctions: (1) widespread mitochondrial dysfunction, evidenced by the general downregulation of proteins associated with energy metabolism and mitochondrial structure; (2) multidimensional autophagy failure, characterized by autophagic flux blockage (macroautophagy failure) and the predicted inhibition of Chaperone-Mediated Autophagy; and (3) a paradoxical and ineffective oxidative stress response, demonstrating a functional uncoupling between the upstream NRF2 activation signal and the execution of the downstream antioxidant pathway. The cellular validation confirmed that the pathogenic uN2CpolyG protein causes the downregulation of core hub proteins, substantiating the molecular pathology observed in patient tissue. Furthermore, a signal decoupling state was identified in the pivotal PI3K-Akt survival pathway. This study provides the first systematic proteomic view of NIID pathology in sweat gland tissue, substantiating that its core pathology is a self-reinforcing vicious cycle of mitochondrial dysfunction, abnormal autophagy, and oxidative stress imbalance. These findings offer a robust molecular framework for understanding GGC repeat expansion pathogenesis and illuminate new therapeutic avenues targeting these interconnected pathways.

Late-onset cobalamin C (cblC) deficiency, an inherited metabolic disorder, is often misdiagnosed due to its heterogeneous clinical presentation. This study aims to characterize the clinical and genetic spectrum of late-onset cblC deficiency in a large northern Chinese cohort and proposes a novel clinical classification based on initial symptoms. A retrospective, multicenter study of 156 patients diagnosed between October 2012 and December 2023 was conducted. Clinical, biochemical, neuroimaging, and genetic data were analyzed. Patients were classified into six subtypes based on predominant initial symptoms, and genotype-phenotype correlations were explored. The cohort (95 males, 61 females) had a median onset age of 16 years (range: 2-65). Common symptoms included spastic paralysis (41.0%), mental and behavioral abnormalities (36.5%), and renal damage (28.8%). Genetic analysis identified 52 MMACHC variants, with c.482G>A (34.3%) and c.609G>A (17.6%) being most frequent. Elevated total homocysteine (tHcy) levels correlated with mental and behavioral abnormalities, renal damage, and anemia (p < 0.05). The proposed clinical classification identified six subtypes, with encephalopathy-dominant and encephalomyelopathy-dominant types being most prevalent. This study highlights the clinical heterogeneity of late-onset cblC deficiency and introduces a novel symptom-based classification system to aid diagnosis and management. Elevated tHcy levels and specific MMACHC variants are key biomarkers for disease severity. These findings underscore the importance of early intervention to improve outcomes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons, with a median survival of 3–5 years [1]. The key challenge in diagnosis lies in the early detection of upper motor neuron (UMN) impairment, which mainly depends on clinical examination but can be obscured by severe lower motor neuron (LMN) impairment [2]. Consequently, searching for alternative UMN impairment markers has become a critical focus of ALS research. Recent magnetic resonance imaging (MRI) studies indicated a band-shaped low signal intensity along the primary motor cortex (M1), termed the motor band sign (MBS) [3]. MBS has emerged as an imaging marker for identifying UMN impairment in ALS [2, 4, 5]. Researchers believe this hypointensity results from ferritin accumulation within activated microglia in M1 [6]. SWI has demonstrated increased sensitivity in detecting subtle, uniformly distributed iron deposits, becoming the current mainstream modality for identifying MBS. However, there is currently a lack of reports of MBS in 7T SWI.

BACKGROUND:Autoimmune nodopathy exhibits suboptimal responses to conventional immunotherapies. This study investigates the efficacy and safety of efgartigimod, a neonatal Fc receptor blocker, in this condition. METHODS:A prospective single-center study enrolled four antibody-confirmed autoimmune nodopathy patients receiving weekly efgartigimod (10 mg/kg) over 4 weeks. Disease progression was assessed using validated neurological scales (INCAT, ISS, I-RODS, and MRC) at baseline (Week 0), weekly during treatment (Weeks 1-4), and 4-week post-treatment follow-up (Week 8). RESULTS:Four patients (3 females, aged 17-72) responded to efgartigimod within 2 weeks, showing varied improvement based on antibody subtype. Patient 1 (anti-NF186 IgG3+) achieved full remission by Week 2 (INCAT 3 → 0). Patient 2 (anti-NF155 IgG4+) improved progressively (MRC 112 → 119; I-RODS 36 → 40). Patient 3 (anti-NF155 IgG1/IgG4+) quickly stabilized gait in the first week and gradually recovered (INCAT 5 → 2). Patient 4 (anti-CNTN1 IgG1/IgG2/IgG3/IgG4+) reduced tremors rapidly and improved sensorimotor function (ISS 8 → 6; I-RODS 12 → 14) despite a treatment interruption due to a fracture. Antigen-specific efficacy varied: NF186 neuropathy resolved completely, while IgG4-dominant paranodal cases (NF155/CNTN1) partially recovered, prompting sequential B-cell-targeted strategies. No severe adverse events occurred. CONCLUSIONS:Efgartigimod provided rapid functional recovery in autoimmune nodopathy. Differential responses by IgG subclass and antigenic targets highlight the necessity for biomarker-guided strategies.

Objective Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant genetic disease characterized by the misfolding and deposition of the transthyretin (TTR) protein. This study aimed to describe the clinical and genetic characteristics of ATTRv in a large multicenter Chinese cohort. Methods Patients from 14 centers were included in the study. The clinical and genetic characteristics of all patients were summarized. The peripheral blood white blood cell mitochondrial DNA (mtDNA) was detected in offspring from different genders. Results A total of 202 individuals with ATTRv from 148 families were identified. The average age of onset was 50.6 ± 12.4 years. Among these cases, 117 (57.9%) were classified as late‐onset (≥50 years) and 85 (42.1%) as early‐onset. Overall, the length dependent axonal sensorimotor peripheral neuropathy was the predominant phenotype (89.1%). A total of 42 heterozygous missense variants and 1 deletion variant were identified. The most common variants were Val30Met (19.8%) and Ala97Ser (15.8%) and patients with Val30Met and Ala97Ser were mostly late‐onset in our cohort. Thirty‐nine of these patients died with a mean age of 56.1 ± 13.5 years. Anticipation according to gender groups of offspring‐parent pairs was different, and mother‐son pairs showed the largest anticipation. The copies of mtDNA in the mother's offspring outnumbered those of the father's offspring ( p < 0.001). Interpretation This study highlights that ATTRv patients in China exhibit high heterogeneity in their initial symptoms. The most common variants observed in this cohort is Val30Met. The mtDNA copy number shows gender‐linked effects. These results can impact ATTRv diagnosis and patient care strategies. ANN NEUROL 2025

Abstract Background A correlation between various sites or types of mutations in mitochondrial DNA ND3 and the development of a specific mitochondrial disease or phenotype has yet to be fully established. Methods This study reports a rare case of adult-onset Leigh syndrome (LS) and Leber hereditary optic neuropathy and dystonia (LDYT) overlap syndrome caused by the m.10197G>A mutation in ND3. A review of the literature was conducted to investigate the clinical spectrum, treatment and outcome resulting from the m.10197G>A mutation. Phenotypes associated with the m.10197G>A mutation were classified into three categories: LS/LS+ (LS-involved overlap syndrome), Leber hereditary optic neuropathy (LHON)/LHON+ (LHON-involved overlap syndrome) and other mitochondrial encephalopathies or presentations. Results A total of 84 participants (78 patients and 6 asymptomatic carriers) with the m.10197G>A mutation retrieved from 33 articles and the patient whose case we reported were included in the review and meta-analysis. Among all the participants, 55.3% (47/85) and 28.2% (24/85) presented with LS/LS+ and LHON/LHON+, respectively. The median age at onset for LS/LS+ was significantly younger than that for LHON/LHON+ [median, (Q1–Q3), 3.0 (0.58–9.5) vs. 13.5 (5.75–41.75), P = 0.001]. A negative linear correlation was observed between mutation load and age of onset in patients who presented with LS/LS+ (R2 = 0.592, P < 0.001), with the age of onset ranging from infancy to adulthood. Patients with an older age at onset [OR (95% CI), 1.46 (1.12–1.91), P = 0.005] or higher mutation loads [OR (95% CI), 1.14 (1.03–1.26), P = 0.011] were more likely to present with LHON/LHON+ than with LS/LS+. A total of 17 patients were documented as having received a combination of mitochondrial cofactor treatments. Compared with patients with LHON/LHON+, patients with LS/LS+ exhibited an exceedingly high probability of a stable or worsen outcome (93.8% vs. 33.3%, P = 0.006). Conclusions LS/LS+ and LHON/LHON+ are the predominant presentations of the m.10197G>A mutation. An older age at onset and greater mutation load increases the probability of an LHON/LHON+ presentation. Patients presenting with LS/LS+ have an exceedingly high possibility of an unfavorable outcome. The identification of factors and outcomes associated with phenotypes in patients with the m.10197G>A mutation facilitates the provision of improved prognostic counseling for patients and their family members who are carriers of this mutation.

Neuronal intranuclear inclusion disease (NIID) is a multifaceted disorder impacting both the central and peripheral nervous systems. This study aims to investigate the clinical and electrophysiological characteristics of peripheral neuropathy in patients with NIID. In this cross-sectional study, patients diagnosed with NIID were prospectively recruited from multiple centers across China between October 2017 and May 2024. Comprehensive neurological examinations, brain magnetic resonance imaging, and NOTCH2NLC gene analysis were performed. All participants underwent electrophysiological evaluations, which encompassed nerve conduction studies, F-wave studies, and needle electromyography. This analysis included a total of 78 patients diagnosed with NIID, with a mean age of 61.0 ± 9.9 years, of whom 60.2

Background Cases of RNF216 -related disorder have been reported sporadically. However, the clinical and genetic spectrum of this disorder has not been fully studied. Methods We identified an individual with a novel causative RNF216 variant in our institution and reviewed all individuals with causative RNF216 variants in previous reports. The clinical and genetic features of all the described individuals were analysed and summarised. Results Twenty-four individuals from 17 families with causative RNF216 variants were identified. The mean age at the onset of neurological symptoms was 29.2 years (range 18–49 years). Ataxia (57%) was the most frequent initial symptoms in individuals under 30 years old, while chorea (63%) was the most frequent initial symptom in individuals over 30 years old. Over 90% of individuals presented with cognitive impairment and hypogonadotropic hypogonadism throughout the disease. White matter lesions (96%) and cerebellar atrophy (92%) were the most common imaging findings. Twenty pathogenic variants in RNF216 were detected. The variants in 12 (71%) families were inherited in a monogenic recessive pattern, whereas the variants in 5 (29%) were inherited in a digenic pattern by acting with variants in other genes. The majority of the RNF216 variants (85%) resulted in amino acid changes or the truncation of the ‘RING between RING’ (RBR) domain or C-terminal extension. Conclusion RNF216 -related disorder is an inherited neuroendocrine disease characterised by cerebellar ataxia, chorea, cognitive impairment and hypogonadotropic hypogonadism. Most causative variants in patients with RNF216 -related disorder influence the RBR domain or C-terminal extension of RNF216.