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.

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: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.

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.

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.

Cerebral small vessel disease (CSVD) is a common condition among the elderly population. In patients with CSVD, imaging markers, motor function, and cognition are closely interrelated. This study aimed to analyze the effect of cognition on the association between CSVD burden and motor function. This cross-sectional study included 134 patients with CSVD, recruited from the China Imaging-based Biobank of Cerebral Small Vessel Diseases (CIBB-CSVD) at Beijing Tiantan Hospital between January 2020 and May 2023. We obtained demographic and medical profiles, as well as the Montreal Cognitive Assessment (MoCA) score, Short Physical Performance Battery (SPPB) score, a four-point CSVD burden score determined through magnetic resonance imaging (MRI), and gait parameters evaluated using the Codamotion analysis system from all participants. The mean age of all CSVD patients was 60 ± 12 years. The median scores for the CSVD burden, MoCA, SPPB and modified Rankin Scale (mRS) were 3 (2, 4), 20 (16, 24), 11 (9, 12) and 0 (0, 1), respectively. Significant correlations were observed between age and the CSVD burden score, MoCA score, SPPB score, speed, and stride length (P < 0.05). Patients with higher CSVD burden scores exhibited significantly lower SPPB scores, reduced speed, shorter stride length, and decreased hip and knee range of motion (ROM), as revealed by both univariable linear regression and multivariable regression analyses adjusted for age (P < 0.05). However, after further adjustment for MoCA score, only the association between CSVD burden score and SPPB score remained statistically significant (P < 0.05). Mediation analysis indicated that the MoCA score significantly mediated the associations between CSVD burden score and both SPPB score and knee ROM. The proportion of the effect mediated by the MoCA score was 33.835

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.

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

To investigate the clinical characteristics of Guillain–Barré syndrome (GBS) in patients with primary Sjögren’s syndrome (SS). Records of patients with positive anti-SSA antibodies hospitalized in the Beijing Tiantan Hospital between December 2011 and May 2020 were retrieved. Patients who fulfilled the criteria for diagnosis of GBS and primary SS were included, and their clinical data were analyzed. Among the 785 patients with positive anti-SSA, 52 patients were identified in this study. They were 27 males and 25 females with median age of 59 years old. Besides anti-SSA antibodies, multiple autoantibodies were detected in these patients including antinuclear antibody, anti-Ro52, anti-mitochondrial M2, anti-thyroid peroxidase and anti-thyroglobulin autoantibodies. Preceding infection was reported in 42 patients. Hyporeflexia/areflexia and limbs weakness were the most common manifestation and 35 patients presented cranial nerve injuries. GBS disability score of 3, 4 and 5 was scaled in 28 (53.8%), 15 (28.8%) and 3 (5.8%) patients respectively. Forty-six patients received intravenous immunoglobulin (IVIG) monotherapy, 5 patients were treated by IVIG plus glucocorticoids, and 51 patients improved during hospitalization. The frequency of male gender among the patients with both GBS and primary SS suggests an independent onset of GBS and the co-existence of these autoimmune diseases in patients with multiple autoantibodies. Majority of patients with GBS and primary SS experience benign disease course.

PNPLA8 is a gene that causes an autosomal recessive mitochondrial disease characterised by microcephaly and intractable epilepsy in infants and cerebellar ataxia and limb weakness in adults. Herein, we report the clinical, muscle pathology, and brain imaging features of an adult patient with new variants of PNPLA8. A 27-year-old Chinese woman presented with abnormal gait at age 11, remained amenorrhoeic with an infantile uterus at age 17, and presented with head and limb tremors at age 21. The results of brain magnetic resonance imaging suggested mild cerebellar atrophy. Whole-exome sequencing was performed, and mitochondrial and spinal cerebellar ataxia genes were screened. In addition, a biceps muscle biopsy was performed. Furthermore, a comprehensive literature search was conducted, and all patients with detailed clinical and genetic data up to October 2024 were included in the analysis. The patient's genetic screening revealed compound heterozygous variants c.1777T > G (p.Tyr593Asp) and c.1515-1516delTT (p.Tyr506Serfs*27) of PNPLA8 inherited from her parents. Her muscle biopsy showed mild myopathic changes on light microscopy and mitochondrial inclusions on electron microscopy. A total of 25 patients from 21 families were reviewed. Age of onset is a very important factor in terms of patient clinical phenotype and prognosis of PNPLA8-related disorders. It has been observed that adult females with PNPLA8 variants may present with primary ovarian dysfunction. The presence of mitochondrial inclusion bodies may serve as a pathological hallmark, extending the existing spectrum of the clinical phenotypes and pathogenic variants of PNPLA8.

Objective: The aim of our study was to compare the clinical value of pathological spontaneous activity (PSA) in different thoracic paraspinal muscles (TPMs) in amyotrophic lateral sclerosis (ALS). Methods: A total of 116 ALS patients were retrospectively analyzed over 31 +/- 8 months concerning the occurrence of PSA in T9-T11 TPM. The occurrence of PSA was correlated with pulmonary function and clinical disability. Results: The positive sharp wave (PSW) potentials were more frequently observed than fibrillation (fib) in T9-T11 segments. The PSA positive frequency of bulbar-onset ALS (B-ALS) is less than upper limb-onset ALS (U-ALS) and lower limb-onset ALS (L-ALS) at the levels of T10 and T11 TPM (p = 0.050, p = 0.001). The fibs/PSWs in TPM indicated high sensitivity and negative predictive value for forced vital capacity (FVC) < 80%. Linear correlation analysis indicated that PSA of TPM was associated with pulmonary ventilation function (PVF). Associations also exist between clinical parameters and PVF as well as the disease severity. Conclusions: The occurrence of T9-TPM fibs/PSWs was correlated with clinical disability and is extremely helpful in implying an involvement of PVF. The T9-TPM typically provided a good practical indicator for comprehensive disease evaluation, which was irrelevant to the site of onset.

Functional tremor is the most common subtype of functional movement disorder (FMD). At present, there is no "gold standard" for diagnosis. Most clinical manifestations coincide with organic tremor, which can easily lead to misdiagnosis and mistreatment. Characteristic electrophysiological manifestations can provide objective and repeatable diagnostic information, effectively supplement the history and physical examination, and can also be used in the differential diagnosis from organic tremor. This article reviews the electrophysiological characteristics of functional tremor and its application in diagnosis and differential diagnosis, in order to improve the clinical understanding of this disease.

AbstractBackgroundWe aimed to identify different Guillain–Barré syndrome (GBS) subtypes, demyelination, axonal degeneration, and reversible conduction failure (RCF) as early as possible by analyzing the initial clinical and electrophysiological examinations.MethodsThis study retrospectively collected GBS patients between October 2018 and December 2022 at Beijing Tiantan Hospital. The diagnostic criteria for the initial electrophysiological study were based on Rajabally's criteria, and the criteria for the serial electrophysiological study were based on Uncini's criteria. All subjects underwent clinical and electrophysiological evaluations at least twice within 8 weeks.ResultsA total of 47 eligible patients with GBS were included, comprising 19 acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 18 axonal degenerations, and 10 RCFs. In the RCF group, 40%, 30%, and 30% patients were diagnosed as AIDP, axonal, and equivocal at the initial study, respectively. The AIDP group had significantly higher cerebrospinal fluid (CSF) protein than the RCF (123.8 [106.4, 215.1] mg/dL vs. 67.1 [36.8, 85.6] mg/dL, p = 0.002) and axonal degeneration (123.8 [106.4, 215.1] mg/dL vs. 60.8 [34.8, 113.0] mg/dL, p < 0.001) groups. The RCF group had significantly lower Hughes functional grades at admission (3 [2, 4] vs. 4 [4, 4], p = 0.012) and discharge (1.0 [1.0, 2.0] vs. 3.0 [2.0, 3.0], p < 0.001) than the axonal degeneration group and showed significantly shorter distal motor latency (DML), Fmin, Fmean, Fmax, and lower F% than the AIDP group (p < 0.05).DiscussionThe early identification of RCF from AIDP had relatively obvious features, including slightly elevated CSF protein levels and normal or slightly prolonged DML and F‐wave latencies, contrasting with the apparent elevation and prolongation seen in AIDP. Differentiating RCF from axonal degeneration remains challenging. One potential distinguishing factor is that the motor function in RCF tends to be better than in the latter.

OBJECTIVE:To delineate the characteristics of stroke-like episodes (SLEs) in patients with adult-onset neuronal intranuclear inclusion disease (NIID) and to compare these characteristics with those of patients with MELAS. METHODS:Twenty-three adult-onset NIID patients who presented with acute or subacute brain disorders and 13 late-onset MELAS patients were enrolled in the study. Patients with NIID were categorized into the SLEs group and the encephalopathy-like episodes (ELEs) group according to the associated stroke-like lesions (SLLs) findings. Clinical characteristics were compared between the SLEs group and the ELEs group among NIID patients and between NIID patients with SLEs and MELAS patients. RESULTS:Eleven (47.8%) NIID patients who manifested acute or subacute brain disorders had detectable associated SLLs and were categorized into SLEs group. SLEs patients were more likely to report fever, headache, and seizures instead of sleep disorders than ELEs patients. Four (36.4%) NIID patients with SLEs absence of diagnostic or suggestive NIID imaging features. The clinical manifestations, laboratory test results, and neuroimaging and muscle biopsy histological features of NIID patients with SLEs majorly overlapped with those of late-onset MELAS patients. Older age at the first SLE (OR [95% CI], 1.203 [1.045-1.384]), symptoms of movement disorders on admission (OR [95% CI], 9.625 [1.378-67.246]), and white matter hyperintensity in corpus callosum (OR [95% CI], 16.00 [1.542-166.46]) associated with the NIID diagnosis in patients with SLEs. INTERPRETATION:NIID patients with SLEs exhibit evident features of mitochondrial disorders. Interventions aimed at mitochondrial dysfunction might be a promising therapeutic approach for treating this disease.

Objective:To analyze the clinical, electromyographic and tremor characteristics in tremor patients with neuronal intranuclear inclusion disease (NIID).Methods:From May 2018 to April 2023, 34 patients with NIID diagnosed in the Department of Neurology, Beijing Tiantan Hospital of Capital Medical University were retrospectively included. Sixteen patients with tremor of at least one limb and (or) head were in tremor group, and 18 patients without tremor were in control group. The clinical, electromyogram and tremor data of all participants were summarized, the clinical features and electromyogram differences of the 2 groups were compared, and the tremor characteristics of patients with NIID were analyzed.Results:The proportion of female patients in the tremor group was higher than that in the non tremor group (12/16 vs 7/18, P=0.045). The proportion of upper and lower limb peripheral nerve damage in the tremor group was lower than that in the non tremor group (2/16 vs 9/18, P=0.030), with statistical significance. There was no significant difference between the 2 groups in higher cortex and autonomic nervous dysfunction. The amplitude of composite muscle action potential and sensory nerve action potential in all patients was normal or slightly decreased; some patients experienced a decrease in motor and sensory fiber conduction velocity. The proportion of motor and sensory nerve conduction velocity slowing in the non tremor group was higher than that in the tremor group [motor nerve:41.7%(30/72) vs 17.2%(11/64), χ 2=9.64, P=0.002;sensory nerve:38.9% (35/90) vs 20.0%(16/80), χ 2=7.19, P=0.007]. The number of cases of postural tremors in different parts among the 16 patients was as follows: 13 in the upper limbs, 7 in the lower limbs, and 6 in the head; static tremor: 8 cases in the upper limbs, 3 cases in the lower limbs, and 5 cases in the head. At rest, the frequency of tremors in different parts of the body was as follows: upper limb (5.3±1.1) Hz, lower limb (4.2±0.4) Hz, and head (3.9±0.6) Hz. The difference in tremor frequency among the 3 parts was statistically significant ( F=3.92, P=0.047); Pairwise comparison showed that the frequency of head tremor was lower than that of upper limb tremor, with a statistically significant difference ( P=0.020). In a postural state, tremor frequency in different parts was as follows: upper limb (5.4±0.9) Hz, lower limb (5.0±0.7) Hz, head (3.9±0.7) Hz. There was a statistically significant difference in tremor frequency among the 3 parts ( F=6.65, P=0.005). Further pairwise comparison revealed statistically significant differences in tremor frequency between the patient′s head, upper and lower limbs ( P=0.001, P=0.022). Synchronous tremor rhythm was predominant, with occasional alternations or synchronous+alternations. There was no harmonic tremor spectrum was observed. Conclusions:NIID patients with tremors were more common in female patients.The degree of peripheral nerve damage was milder than those without tremors. The site and form of tremor were diverse, with a dominant frequency of 4-6 Hz, mainly synchronous rhythm, and no harmonic spectrum. Postural tremors were common in the limbs.

The GGC repeat expansions in the NOTCH2NLC gene are associated with multiple neurodegenerative disorders. Herein, we report the clinical phenotype in a family with biallelic GGC expansions in NOTCH2NLC . Autonomic dysfunction was a prominent clinical manifestation in three genetically confirmed patients without dementia, parkinsonism, and cerebellar ataxia for > 12 years. A 7-T brain magnetic resonance imaging in two patients revealed a change in the small cerebral veins. The biallelic GGC repeat expansions may not modify the disease progression in neuronal intranuclear inclusion disease. Autonomic dysfunction-dominant may expand the clinical phenotype of NOTCH2NLC .

Background and Objectives Neuronal intranuclear inclusion body disease (NIID) is a neurodegenerative disease with highly heterogeneous clinical manifestations. The present study aimed to characterize clinical features and propose a classification system based on a large cohort of NIID in China. Methods The Chinese NIID registry was launched from 2017, and participants' demographics and clinical features were recorded. Brain MRI, skin pathologies, and the number of GGC repeat expansions in the 5′ untranslated region of the NOTCH2NLC gene were evaluated in all patients. Results In total, 223 patients (64.6% female) were recruited; the mean (SD) onset age was 56.7 (10.3) years. The most common manifestations were cognitive impairment (78.5%) and autonomic dysfunction (70.9%), followed by episodic symptoms (51.1%), movement disorders (50.7%), and muscle weakness (25.6%). Imaging markers included hyperintensity signals along the corticomedullary junction on diffusion-weighted imaging (96.6%), white matter lesions (98.1%), paravermis (55.0%), and focal cortical lesions (10.1%). The median size of the expanded GGC repeats in these patients was 115 (range, 70–525), with 2 patients carrying >300 GGC repeats. A larger number of GGC repeats was associated with younger age at onset (r = −0.329, p < 0.0001). According to the proposed clinical classification based on the most prominent manifestations, the patients were designated into 5 distinct types: cognitive impairment-dominant type (34.1%, n = 76), episodic neurogenic event-dominant type (32.3%, n = 72), movement disorder-dominant type (17.5%, n = 39), autonomic dysfunction-dominant type (8.5%, n = 19), and neuromuscular disease-dominant type (7.6%, n = 17). Notably, 32.3% of the episodic neurogenic event-dominant type of NIID has characteristic focal cortical lesions on brain MRI presenting localized cortical edema or atrophy. The mean onset age of the neuromuscular disease-dominant type was 47.2 (17.6) years, younger than the other types (p < 0.001). There was no significant difference in the sizes of GGC repeats among the patients in the 5 types (p = 0.547, Kruskal-Wallis test). Discussion This observational study of NIID establishes an overall picture of the disease regarding clinical, imaging, and genetic characteristics. The proposed clinical classification of NIID based on the most prominent manifestation divides patients into 5 types.