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Background and Objectives: NOTCH2NLC -related neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease with characteristic white matter lesions (WMLs) visible on MRI. However, the distribution of WMLs and their clinical correlations remain poorly understood in NIID. This study aims to investigate the spatial and temporal distribution of WMLs in the brain of patients with NOTCH2NLC -related NIID., Methods: We retrospectively evaluated patients diagnosed with NOTCH2NLC -related NIID in Zhongshan Hospital, Fudan University. Detailed clinical information, including retrospective MRI data, was collected. Spatial distribution of WMLs with fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) hyperintensities was quantified, and the relationship between WML distribution and clinical presentations was analyzed by the Fisher exact test. The volume of whole-brain WMLs was quantified using ITK-SNAP software. The relationship between phenotypes and WML volume was analyzed by the Student t test, Mann-Whitney test, or correlation analysis. WML development patterns were summarized based on the longitudinal observation of MRI characteristics., Results: This study evaluated 45 patients with NOTCH2NLC -related NIID, with a median age of 66 years (range 55-82 years) and consisting of 30 women. Patients exhibited diverse clinical manifestations, with cognitive decline, autonomic dysfunction, and tremor being the 3 most frequent presentations. Severe WMLs were observed in 43 patients, with FLAIR hyperintensities predominantly in the corona radiata, centrum semiovale, and other brain regions. The presence of DWI hyperintensities was common in the corticomedullary junction (91.1%) and corpus callosum (53.3%). Analysis showed significant correlations between FLAIR hyperintensity volume and both age ( r = 0.312, p = 0.042) and Montreal Cognitive Assessment scores ( r = -0.371, p = 0.048). Longitudinal MRI retrospection in 7 patients over an average of 9.6 ± 2.9 years revealed 3 gradually progressed WML patterns: periventricular-subcortical, periventricular-dominant, and corticomedullary junction-dominant. In addition, 3 patients experienced rapid WML expansion associated with mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS)-like episodes., Discussion: Our analysis revealed the radiologic characteristics and spatial distribution of WMLs and demonstrated significant correlations between FLAIR hyperintensity volume and age/cognitive levels in NIID. Long-term retrospection revealed 3 types of gradual WML expansion patterns while MELAS-like episodes cause rapid WML aggravation. Although results should be confirmed in a larger cohort, these insights enhance understanding of NIID's clinical-radiologic relationships and pathogenesis.

Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by the presence of inclusions within the nuclei of various cell types. The clinical manifestations of patients with NIID are diverse. Here, we present the case of a patient with NIID whose clinical presentation and magnetic resonance features closely resembled those of hydrocephalus., Case Presentation: The patient was 71-year-old woman with no significant family history. Seven years previously, she began to experience tremors in both hands, which occurred at rest and while holding objects; this was accompanied by urinary incontinence. Four years previously, she developed weakness in both lower limbs, an unstable gait, and dizziness. Over the past year, she noticed stiffening at the root of her tongue, cognitive decline, and slower reaction times compared to her previous state. Upon admission, cranial magnetic resonance imaging (MRI) revealed hydrocephalus-like changes. A cerebrospinal fluid drainage test returned negative results. The patient presented with tremors and urinary incontinence. Physical examination indicated pupillary constriction, and electromyography suggested peripheral neuropathy. Genetic testing revealed 91 GGC repeats in the NOTCH2NLC gene, indicating abnormal expansion. The final diagnosis was NIID. We provided symptomatic treatment for the tremor and cognitive impairment, but there was no significant improvement in the clinical symptoms., Conclusions: Our case suggests that when a patient presents with clinical symptoms and MRI findings resembling hydrocephalus, the possibility of NIID should be considered, especially in the presence of tremors and autonomic symptoms., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained from the patient to publish her case, and approval for this study was provided by the Research Ethics Committee of The Second Hospital of Liaocheng. Consent for publication: Written informed consent for publication of this Case Report was obtained from the patient. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The expansion of GGC repeats within NOTCH2NLC leads to translation of the uN2CpolyG protein, the primary pathogenic factor in neuronal intranuclear inclusion disease (NIID). The aim of this study was to explore the deposition of uN2CpolyG as an amyloid in the vessel wall, leading to uN2CpolyG cerebral amyloid angiopathy-related cerebral microbleeds (CMBs). A total of 97 patients with genetically confirmed NIID were enrolled in this study. We analysed the presence of CMBs using susceptibility-weighted imaging sequences and compared general clinical information, cerebrovascular risk factors, stroke history, antiplatelet medication use and MRI features between NIID patients with and without CMBs. We also performed haematoxylin and eosin, Perl's, Congo red and Thioflavin S staining, ubiquitin, p62 and uN2CpolyG immunostaining on brain tissue obtained from four NIID patients. A total of 354 CMBs were detected among 41 patients with NIID, with nearly half located in the deep brain, one-third in the lobes and ∼20% in the infratentorial area. No significant differences in cerebrovascular disease risk factors or history of antiplatelet drug use were observed between patients with and without CMBs. However, patients with CMBs had suffered a higher incidence of previous ischaemic and haemorrhagic stroke events. This group also had a higher incidence of recent subcortical infarcts and a higher proportion of white matter lesions in the external capsule and temporal pole. Conversely, patients without CMBs showed higher detection of high signals at the corticomedullary junction on diffusion-weighted imaging and more pronounced brain atrophy. Haematoxylin and eosin staining showed blood vessel leakage and haemosiderin-laden macrophage clusters, and Prussian blue staining revealed iron deposition in brain tissue. CMBs occurred more frequently in small vessels lacking intranuclear inclusions, and extensive degeneration of endothelial cells and smooth muscle fibres was observed mainly in vessels lacking inclusions. Congo red-positive amyloid deposition was observed in the cerebral vessels of NIID patients, with disordered filamentous fibres appearing under an electron microscope. Additionally, the co-localization of Thioflavin S-labelled amyloid and uN2CpolyG protein in the cerebral vascular walls of NIID patients further suggested that uN2CpolyG is the main pathogenic protein in this form of amyloid angiopathy. In conclusion, we reviewed patients with GGC repeat expansion of NOTCH2NLC from a new perspective, providing initial clinical, neuroimaging and pathological evidence suggesting that uN2CpolyG might contribute to a distinct type of cerebral amyloid angiopathy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Neuronal Intranuclear Inclusion Disease (NIID) is a neurodegenerative disease affecting the central and peripheral nerves. We aimed to assess the pathophysiological features of peripheral nerve dysfunction in NIID., Methods: We observed six unrelated NIID patients through clinical records, nerve conduction studies, and multiple measures of motor nerve excitability. Additionally, we reviewed one NIID patientt who underwent a nerve biopsy. Control measures were obtained from 22 age-matched normal subjects., Results: The NIID patients exhibited mild conduction slowing and distinct nerve excitability abnormalities, including a significant decrease in excitability through hyperpolarizing threshold electrotonus (TE) and increased overshoots in both depolarizing and hyperpolarizing conditions. Histopathology revealed thinly myelinated fibers and axonal degeneration. Mathematical modeling suggested that reduced leak conductance was the key factor contributing to the observed excitability changes., Conclusions: The findings indicate that NIID involves a complex interplay of axonal degeneration and myelin dysfunction, leading to unique peripheral nerve excitability changes. These results provide new insights into the pathophysiology of NIID., Significance: Nerve excitability testing offers insight into particular axonal excitability abnormalities especially combined with histopathologic studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: 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., Methods: 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., Results: 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% were female. Among these patients, 85.9% exhibited peripheral neuropathy. Specifically, 19 patients (24.4%) presented with symptomatic peripheral neuropathy, with 17 of these individuals demonstrating sensorimotor polyneuropathy. Additionally, 48 patients (61.5%) exhibited subclinical peripheral nerve damage. Segmental motor conduction studies indicated that both distal and proximal nerve segments were uniformly affected. F-wave latency prolongation was observed in 84.6% of tibial nerves, demonstrating high sensitivity (66/67) and specificity (11/11) for detecting peripheral neuropathy in NIID. The severity of peripheral neuropathy was stratified into four levels, with approximately two-thirds of cases presenting with pure demyelination and one-third displaying a combination of demyelination and axonal degeneration. Severe axonal damage was exclusively identified in the neuromuscular disease-dominant subtype of NIID. Importantly, male patients exhibited more pronounced peripheral nerve damage compared to female patients., Conclusions: This study identified a significant prevalence of peripheral neuropathy in NIID, exhibiting a spectrum of severity ranging from mild demyelination to severe axonal damage. Prolongation of F-wave latency emerged as a sensitive marker for the detection of peripheral nerve impairment. Furthermore, the findings underscore the potential influence of gender in the pathophysiology of NIID, warranting further investigation., Competing Interests: Declarations. Conflicts of interest: The authors have no competing interest to report that are relevant to the content of this manuscript., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

A male in his 20s presented with episodic headache and subsequently developed episodic unilateral weakness, dysphasia and encephalopathy. These paroxysmal episodes persisted over time with the development of background cognitive impairment and neuropsychiatric symptoms. MRI surveillance demonstrated progressive T2 hyperintensity with focal cortical oedema correlating to symptoms observed during clinical episodes.Genetic testing for hemiplegic migraine, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes along with exome sequencing and high-density microarray did not reveal a cause for the clinical phenotype. The diagnosis of neuronal intranuclear inclusion disease (NIID) was confirmed by the detection of large guanine-guanine-cytosine repeat expansion in the Notch 2 N-terminal-like C gene using long-read nanopore sequencing.NIID is a genetic neurodegenerative disease, more common in Asian populations. It can present with a varied neurological phenotype, including an episodic event type that can mimic hemiplegic migraine and encephalopathy. This case report highlights the importance of considering NIID in cases of paroxysmal headache and encephalopathy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease with a characteristic pathological feature of eosinophilic hyaluronan inclusions in the nervous system and internal organs. The identification of GGC-repeat expansions in the Notch 2 N-terminal like C (NOTCH2NLC) gene facilitates the accurate diagnosis of NIID. Due to its rareness and high clinical heterogeneity, the diagnosis of NIID is often delayed or missed. Here, we report a case of NIID mimicking autoimmune encephalitis. A 55-year-old Chinese man presented with fever, headache, recurrent seizures, and weakness in the upper and lower left limbs. Brain MRI revealed diffuse T2/ FLAIR-hyperintense lesions in the bilateral basal ganglia, corpus callosum, and periventricular white matter, with swelling of the right temporal, frontal, and parietal cortices accompanied by meningeal enhancement. Abnormally high signal lesions were observed in the corticomedullary junction in diffusion-weighted imaging (DWI). The infectious or autoimmune disease screening of central nervous system using CSF was normal. The test of GGC-repeat expansion in the NOTCH2NLC gene by capillary electrophoresis indicated GGC repeats (48 and 110 GGC repeats), which supported the diagnosis of NIID. After treatment with glucocorticoid, the clinical symptoms of this patient improved significantly. In the literature, 12 cases of NIID presenting with encephalitis-like attacks were identified, most of which were recurrent, accompanied by progressive symptoms such as dementia, Parkinsonism symptoms, migraine, or dysuria. In this case, there was a single encephalitis-like episode without other progressive symptoms. In patients with encephalitis-like symptoms, NIID should be considered, especially when no other evidence of infection is found, as demonstrated in this case. In addition, long-term monitoring of disease progression is also very important., Competing Interests: Declarations. Ethics approval and consent to participate: Written informed consent was obtained from the legal guardians of the patient. This study was approved by the Research Ethics Committee of Peking University Shenzhen Hospital. Consent for publication: Written informed consent for publication of this case report was obtained from the patient. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

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., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: This study aimed to analyze the clinical and multimodal imaging manifestations of adult-onset neuronal intranuclear inclusion disease (NIID) patients and to investigate NIID-specific neuroimaging biomarkers., Methods: Forty patients were retrospectively enrolled from the Qilu Hospital of Shandong University. We analyzed the clinical and imaging characteristics of 40 adult-onset NIID patients and investigated the correlation between these characteristics and genetic markers and neuropsychological scores. We further explored NIID-specific alterations using multimodal imaging indices, including diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and brain age estimation. In addition, we summarized the dynamic evolution pattern of NIID by examining the changes in diffusion weighted imaging (DWI) signals over time., Results: The NIID patients' ages ranged from 31 to 77 years. Cognitive impairment was the most common symptom (30/40, 75.0%), while some patients (18/40, 45.0%) initially presented with episodic symptoms such as headache (10/40, 25.0%). Patients with cognitive impairment symptoms had more cerebral white matter damage (χ2 = 11.475, P = 0.009). The most prevalent imaging manifestation was a high signal on DWI in the corticomedullary junction area, which was observed in 80.0% (32/40) of patients. In addition, the DWI dynamic evolution patterns could be classified into four main patterns. Diffusion tensor imaging (DTI) revealed extensive thinning of cerebral white matter fibers. The estimated brain age surpassed the patient's chronological age, signifying advanced brain aging in NIID patients., Conclusions: The clinical manifestations of NIID exhibit significant variability, usually leading to misdiagnosis. Our results provided new imaging perspectives for accurately diagnosing and exploring this disease's neuropathological mechanisms., Competing Interests: Declarations Ethical information This study has been approved by the Institutional Review Board and has therefore been approved performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study protocols were approved by the Medical Ethics Committee of the Qilu Hospital of Shandong University. Informed consent Informed consent was obtained from all individual participants included in the study. Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024. The Author(s).)

Background: The expansion of GGC repeats (typically exceeding 60 repeats) in the 5' untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson's disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored., Methods: Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs., Results: Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex., Conclusions: Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consents were obtained from patients. The use of human samples in this study was properly assessed and approved by SingHealth Centralised Institutional Review Board (2017/2602). Animals were maintained under institutional guidelines, and all protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the National Neuroscience Institute (NNI) and Tan Tock Seng Hospital. Consent for publication: Not applicable. Competing interests: The authors report no competing interests., (© 2024. The Author(s).)

Rationale: Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease with various manifestations and high heterogeneity. Clinical characteristics, imaging, skin biopsy, and genetic testing are necessary for its diagnosis. Electromyography may also be a useful tool for diagnosing NIID. In this study, we report a patient with motor and sensory nerve demyelination changes accompanied by axonal damage., Patient Concerns: A 64-year-old woman was admitted to our department with gradually worsening forgetfulness for over a year. After 6 years of follow-up, the symptoms progressively deteriorated., Diagnoses: Cerebrospinal fluid analysis revealed increased protein levels. Brain magnetic resonance imaging showed characteristic "ribbon-like" high signals in the corticomedullary junction area on diffusion-weighted imaging. High-intensity signals in the white matter were also observed on T2 and fluid-attenuated inversion recovery imaging. Electromyography revealed multiple peripheral nerve damage and conduction changes, including motor and sensory nerve demyelination changes, accompanied by axonal damage. Skin biopsy revealed inclusion bodies with strong positive staining for P62 and ubiquitin antibodies in the nuclei of sweat gland cells, adipocytes, and fibroblasts. Genetic testing indicated that the number of GGC repeats in NOTCH2NLC alleles were 14 and 134, respectively. Consequently, the patient was diagnosed with NIID., Interventions: Currently, no effective treatment is available to delay the progression of the disease., Lessons: We report a case of NIID with subclinical peripheral neuropathy, although the patient did not experience sensory symptoms such as numbness in the extremities. Electromyography can be used to detect subclinical peripheral nerve damage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

To summarize the characteristics of urinary system symptoms in 11 patients with neuronal intranuclear inclusion disease (NIID), in order to improve the understanding of the disease. A retrospective analysis was performed on 15 patients with NIID of the First Affiliated Hospital of Zhengzhou University, which were enrolled between January, 2020 and December, 2022. All of them were confirmed by NOTCH2NLC gene and pathology. GGC repeated expansion mutationof NOTCH2NLC gene, the pathogenic gene of NIID, was detected by gene test, and eosinophilic intranuclear inclusions were detected by skin pathological biopsy. 4/15 patients started with urinary symptoms, 11/15 patients with NIID combined with different degrees of urinary system symptoms, manifested as frequent urination, weak urination, incontinence and other neurogenic bladder symptoms, and the serious patients due to long-term urinary retention, secondary ureteral dilation, hydronephrosis, even renal failure, some patients with urinary system symptoms may be earlier than other systems.

Rationale: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with highly variable clinical manifestations, making diagnosis challenging. Recent advancements in genetic and pathological testing, such as the identification of GGC repeat expansions in the NOTCH2NLC gene, have improved diagnostic accuracy, but familial cases remain underreported., Patient Concerns: This report details 3 cases of familial adult-onset NIID in 2 sisters and 1 brother. The older sister experienced episodic encephalopathy and autonomic dysfunction for over 40 years, while the younger sister presented similar symptoms 5 years ago. The brother also developed episodic encephalopathy 5 years ago. Brain diffusion-weighted imaging (DWI) for all 3 patients revealed hyperintensity at the corticomedullary junction and corpus callosum. Skin biopsies from the older sister and brother confirmed the presence of p62 antibody-positive intranuclear inclusion bodies in sweat gland cells and fibroblasts. Genetic testing showed 146 and 133 GGC repeats in the NOTCH2NLC gene in the older sister and brother, respectively., Diagnoses: All 3 patients were diagnosed with NIID based on clinical, radiological, and genetic findings., Interventions: The patients received hormonal therapy, circulation-enhancing treatments, and rehydration therapy during acute episodes., Outcomes: All 3 patients showed significant improvement in symptoms following treatment, with a return to baseline function after hospital discharge., Lessons: Proper management of NIID includes prompt recognition of symptoms, adequate rest, and avoidance of triggers such as fatigue, infections, and stress, which may reduce the frequency of episodic attacks. Early diagnosis and targeted symptomatic treatment are essential for improving patient outcomes., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background : Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder characterized by the formation of intranuclear inclusions in cells. Adult-type NIID usually develops in elderly patients with various clinical manifestations and is sometimes accompanied by ocular symptoms. A case of adult-onset NIID with early and unique manifestations, including a progressive corneal defect and retinal changes, which are concerning at a young age, is reported. Case Presentation : A 29-year-old woman with adult sporadic NIID presented to our department with a progressive corneal disorder. Her neurological symptoms started at the age of 22 years, and she was diagnosed with NIID by skin biopsy and genetic testing. Ocular examination revealed bilateral corneal superficial punctate keratitis, right corneal opacity, decreased vision, nocturnal lagophthalmos, and early retinal changes. Corneal nerve fiber atrophy was detected by in vivo confocal microscopy. With a Cochet-Bonnet aesthesiometer, the progression of NIID and decreased corneal sensation were confirmed. Findings consistent with neurotrophic keratitis and keratoconjunctivitis due to nocturnal lagophthalmos were both suggested as being complications of her underlying NIID. Treatment with punctal plugs, sodium hyaluronate eye drops, diquafosol sodium eye drops, systemic and local antivirals, and local steroid medications resulted in the gradual improvement in the irregularity and opacity of the epithelium. Conclusions: NIID may lead to neurotrophic keratopathy due to impairment of the corneal sensory nerves. Nocturnal lagophthalmos is a remarkable finding in a case of NIID. The findings in the present case highlight the complex and multifaceted nature of NIID, with neurological and ocular manifestations requiring a multidisciplinary approach to management.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder represented by eosinophilic intranuclear inclusions (EIIs) and GGC/CGG repeat expansion in the NOTCH2NLC gene. We report here two adult cases of NIID, genetically confirmed, with manifestation of encephalopathy-like symptoms and address the histopathologic findings obtained by brain biopsies, with a focus on "astrocytic" intranuclear inclusions (AIIs). Case 1 presented with paroxysmal restlessness, vertigo, or fever and was later involved in severe dementia and tetraparesis. Case 2 presented with forgetfulness and then with paroxysmal fever and headache. In both cases, delimited areas with gadolinium enhancement on magnetic resonance imaging and corresponding hyperperfusion were detected, leading to brain biopsies of the cortex. On histology, Case 1 showed an abnormal lamination, where the thickness of layers was different from usual. Both neurons and astrocytes showed some dysmorphologic features. Notably, astrocytes rather than neurons harbored EIIs. Case 2 showed a cortex, where neurons tended to be arrayed in a columnar fashion. Astrocytes showed some dysmorphologic features. Notably, much more astrocytes than neurons harbored EIIs. By a double-labeling immunofluorescence study for p62/NeuN and p62/glial fibrillary acidic protein, the predominance of AIIs was confirmed in both cases. Considering the physiological functions of astrocytes for the development and maintenance of the cortex, the encephalopathy-like symptoms, dynamic change of cerebral blood flow, and cortical dysmorphology can reasonably be explained by the dysfunction of EII-bearing astrocytes rather than EII-bearing neurons. This study suggests the presence of a subtype of NIID where AIIs rather than "neuronal" intranuclear inclusions are likely a key player in the pathogenesis of NIID, particularly in cases with encephalopathy-like symptoms. The importance of AIIs ("gliopathy") should be more appreciated in future studies of NIID., (© 2024 The Authors. Neuropathology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Neuropathology.)

Objectives: Neuronal intranuclear inclusion disease (NIID) exhibited significant clinical heterogeneities. However, the clinical features, radiographic changes, and prognosis of patients with encephalitis-like NIID have yet to be systematically elucidated., Methods: Clinical data including medical history, physical examination, and laboratory examinations were collected and analyzed. Skin and sural nerve biopsies were conducted on the patient. Repeat-primed PCR (RP-PCR) and fluorescence amplicon length PCR (AL-PCR) were used to detect the expansion of CGG repeat. We also reviewed the clinical and genetic data of NIID patients with cortical enhancement., Results: A 54-year-old woman presented with encephalitis-like NIID, characterized by severe headache and agitative psychiatric symptoms. The brain MRI showed cortical swelling in the temporo-occipital lobes and significant enhancement of the cortical surface and dura, but without hyperintensities along the corticomedullary junction on diffusion-weighted image (DWI). A biopsy of the sural nerve revealed a demyelinating pathological change. The intranuclear inclusions were detected in nerve and skin tissues using the p62 antibody and electron microscopy. RP-PCR and AL-PCR unveiled the pathogenic expansion of CGG repeats in the NOTCH2NLC gene. A review of the literature indicated that nine out of the 16 patients with cortical lesions and linear enhancement exhibited encephalitis-like NIID., Conclusion: This study indicated that patients with encephalitis-like NIID typically exhibited headache and excitatory psychiatric symptoms, often accompanied by cortical edema and enhancement of posterior lobes, and responded well to glucocorticoid treatment. Furthermore, some patients may not exhibit hyperintensities along the corticomedullary junction on DWI, potentially leading to misdiagnosis., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events., Methods: Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis., Results: ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case., Conclusions: This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by the expansion of GGC trinucleotide repeats in NOTCH2NLC gene. Despite identifying uN2CpolyG, a toxic polyglycine (polyG) protein translated by expanded GGC repeats, the exact pathogenic mechanisms of NIID remain unclear. In this study, we investigated the role of polyG by expressing various forms of NOTCH2NLC in mice: the wild-type, the expanded form with 100 GGC repeats (either translating or not translating into uN2CpolyG), and the mutated form that encodes a pure polyG without GGC-repeat RNA and the C-terminal stretch (uN2CpolyG-dCT). Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and resulted in neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathologic lesions such as white-matter lesions, microgliosis, and astrogliosis. In contrast, expressing GGC-repeat RNA alone was non-pathogenic. Through bulk and single-nuclei RNA sequencing, we identified common molecular signatures linked to the expression of uN2CpolyG and uN2CpolyG-dCT, particularly the upregulation of inflammation and microglia markers, and the downregulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients using positron emission tomography, correlating with levels of white-matter atrophy. Furthermore, microglia ablation ameliorated neurodegenerative phenotypes and transcriptional alterations in uN2CpolyG-expressing mice but did not affect polyG inclusions. Together, these results demonstrate that polyG is crucial for the pathogenesis of NIID and highlight the significant role of microglia in polyG-induced neurodegeneration., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Neuronal intranuclear inclusion disease (NIID) is a rare complex neurodegenerative disorder presents with various radiological features. The study aimed to investigate the structural abnormalities in NIID using multi-shell diffusion MR., Materials and Methods: Twenty-eight patients with adult-onset NIID and 32 healthy controls were included. Volumetric and diffusion MRI measures, including volume, fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) of six brain structures, including cortex, subcortical GM, cerebral WM, cerebellar GM and WM, and brainstem, were obtained and compared between NIID and healthy controls. Associations between MRI measures and clinical variables were investigated., Results: Brain lesions of NIID included corticomedullary junction lesions on DWI, confluent leukoencephalopathy, lesions on callosum, cerebellar middle peduncle, cerebellar paravermal area and brainstem, and brain atrophy. Compared to healthy controls, NIID showed extensive volume loss of all the six brain regions (all p < 0.001); lower FA in cerebral WM (p < 0.001); higher MD in all WM regions; lower ODI in cortex (p < 0.001); higher ODI in subcortical GM (p < 0.001) and brainstem (p = 0.016); lower ICVF in brainstem (p = 0.001), and cerebral WM (p < 0.001); higher ISOVF in all the brain regions (p < 0.001). Higher MD of cerebellar WM was associated with worse cognitive level as evaluated by MoCA scores (p = 0.011)., Conclusions: NIID patients demonstrated widespread brain atrophy but heterogeneous diffusion alterations. Cerebellar WM integrity impairment was correlated with the cognitive decline. The findings of the current study offer a sophisticated picture of brain structural alterations in NIID., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pathogenic variants in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature: ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts, and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified 4 compounds that activate VCP primarily by increasing D2 ATPase activity, where pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that impaired nuclear proteostasis may contribute to MSP, and that VCP activation may be a potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.

Neuronal intranuclear inclusion disease, caused by a GGC repeat expansion in the 5'-untranslated region of NOTCH2NLC, is a rare neurodegenerative condition with highly variable clinical manifestations. In recent years, the number of reported cases have increased dramatically in East Asia. We report the first four genetically confirmed cases of neuronal intranuclear inclusion disease in New Zealand, all having Polynesian ancestry (three New Zealand Māori and one Cook Island Māori). Phenotypically, they resemble cases reported from recent large East Asian cohorts., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS., Case Presentation: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week., Conclusions: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis., (© 2024. The Author(s).)

Objective: To observe the radiological characteristics of Neuronal Intranuclear Inclusion Disease (NIID) on lesion locations and diffusion property using quantitative imaging analysis., Methods: Visual inspection and quantitative analyses were performed on MRI data from 31 retrospectively included patients with NIID. Frequency heatmaps of lesion locations on T2WI and DWI were generated using voxel-wise analysis. Gray matter volume (GMV), white matter volume (WMV) and diffusion property of apparent diffusion coefficient (ADC) values of patients were voxel-wisely compared with healthy controls. Moreover, the ADC values within the DWI-detected lesion were compared with those within the adjacent cortical gray matter and white matter. Voxel-based lesion symptom mapping (VLSM) techniques, were used to determine the relationship between DWI lesion location and disease durations., Results: By visual inspection on the imaging findings, we proposed an "cockscomb flower sign" for describing the radiological feature of DWI hyperintensity within the corticomedullary junction. A "T2WI-DWI mismatch of spatial distribution" pattern was also revealed with visual inspection and frequency heatmaps, for describing the feature of a wider lesion distribution covering white matter shown on T2WI than that on DWI. Voxel-based morphometry comparison revealed that wildly reduced GMV and WMV, both the lesion areas detected by DWI and T2WI demonstrated ADC increase in patients. Furthermore, the ADC values within the DWI-detected lesion were intermediate between the adjacent cortex and the deep white matter with highest ADC. VLSM analysis revealed that frontal lobe, parietal lobe and internal capsule damage were associated with higher NIID durations., Conclusion: NIID features with "cockscomb flower-like" DWI hyperintensity in area of corticomedullary junction, based on a "T2WI-DWI mismatch of spatial distribution" of lesion locations. The pathological substrate of corticomedullary junction hyperintensity on DWI, can not be explained as diffusion restriction. These typical radiological features of brain MRI would be helpful for diagnosis of NIID., Competing Interests: Declaration of Competing Interest We have no conflict of Interest with co-authors., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background and Purpose: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN., Methods: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection., Results: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN., Conclusions: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

CGG repeat expansion in NOTCH2NLC is the genetic cause of neuronal intranuclear inclusion disease (NIID). Previous studies indicated that the CGG repeats can be translated into polyglycine protein (N2CpolyG) which was toxic to neurons by forming intranuclear inclusions (IIs). However, little is known about the factors governing polyG IIs formation as well as its molecular pathogenesis. Considering that neurogenetic disorders usually involve interactions between genetic and environmental stresses, we investigated the effect of stress on the formation of IIs. Our results revealed that under hyperosmotic stress, N2CpolyG translocated from the cytoplasm to the nucleus and formed IIs in SH-SY5Y cells, recapitulating the pathological hallmark of NIID patients. Furthermore, N2CpolyG interacted/ co-localized with an RNA-binding protein FUS in the IIs of cellular model and NIID patient tissues, thereby disrupting stress granule formation in cytoplasm under hyperosmotic stress. Consequently, dysregulated expression of microRNAs was found both in NIID patients and cellular model, which could be restored by FUS overexpression in cultured cells. Overall, our findings indicate a mechanism of stress-induced pathological changes as well as neuronal damage, and a potential strategy for the treatment of NIID., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background and Purpose: Neuronal intranuclear inclusion disease (NIID) poses a diagnostic challenge because of its diverse clinical manifestations. Detection of intranuclear inclusions remains the primary diagnostic criterion for NIID. Skin biopsies have traditionally been used, but concerns exist regarding postoperative complications and scarring. We sought to investigate the diagnostic utility of labial salivary gland biopsy, a less invasive alternative., Methods: This study included a total of 19 patients and 11 asymptomatic carriers who underwent labial gland biopsies, while 10 patients opted for skin biopsies. All these individuals were confirmed to have pathogenic GGC repeat expansions in the NOTCH2NLC gene. The control group comprised 20 individuals matched for age and sex, all with nonpathogenic GGC repeat expansions, and their labial gland tissue was sourced from oral surgery specimens., Results: Labial gland biopsies proved to be a highly effective diagnostic method in detecting eosinophilic intranuclear inclusions in NIID patients. The inclusions showed positive staining for p62 and ubiquitin, confirming their pathological significance. The presence of uN2CpolyG protein in the labial gland tissue further supported the diagnosis. Importantly, all patients who underwent lip gland biopsy experienced fast wound healing without any noticeable scarring. In contrast, skin biopsies led to varying degrees of scarring and one instance of a localized infection., Conclusion: Labial salivary gland biopsy emerged as a minimally invasive, efficient diagnostic method for NIID, with rapid healing and excellent sensitivity., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with variable clinical phenotypes. There is a considerable delay in the definite diagnosis, which primarily depends on postmortem brain pathological examination. Although CGG repeat expansion in the 5'-untranslated region of NOTCH2NLC has been identified as a disease-associated variant, the pathological diagnosis is still required in certain NIID cases. Intranuclear inclusions found in the skin tissue of patients with NIID dramatically increased its early detection rate. Skin biopsy, as a minimally invasive method, has become widely accepted as a routine examination to confirm the pathogenicity of the repeat expansion in patients with suspected NIID. In addition, the shared developmental origin of the skin and nerve system provided a new insight into the pathological changes observed in patients with NIID. In this review, we systematically discuss the role of skin biopsy for NIID diagnosis, the procedure of skin biopsy, and the pathophysiological mechanism of intranuclear inclusion in the skin., (© 2023 Japanese Dermatological Association.)

Background: The discovery of skin intranuclear inclusions and GGC repeat expansion of NOTCH2NLC has greatly promoted the diagnosis of neuronal intranuclear inclusion disease (NIID). With highly heterogeneous clinical manifestations, NIID patients tend to be underdiagnosed at early stages., Methods: This study comprehensively studied clinical manifestations, magnetic resonance imaging (MRI), and peripheral nerve conduction in 24 NIID and 166 other neurodegenerative disease (ND) subjects. The nomogram was plotted using the "rms" package, and the t-distributed stochastic neighbor embedding algorithm was performed. Associations between skin intranuclear inclusions and NOTCH2NLC GGC repeats were further analyzed., Results: The clinical, MRI, and peripheral nerve conduction features seriously overlapped in NIID and ND patients; they were assigned variables according to their frequency and specificity in NIID patients. A nomogram that could distinguish NIID from ND was constructed according to the assigned variables and cutoff values of the above features. The occurrence of skin intranuclear inclusions and NOTCH2NLC GGC repeats ≥ 60 showed 100% consistency, and intranuclear inclusion frequency positively correlated with NOTCH2NLC GGC repeats. A hierarchical diagnostic flowchart for definite NIID was further established., Conclusion: We provide a novel nomogram with the potential to realize early identification and update the diagnostic flowchart for definitive diagnosis. Moreover, this is the first study to define the association between skin pathology and NOTCH2NLC genetics in NIID., (© 2023. Fondazione Società Italiana di Neurologia.)

Background and Purpose: Adult onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with a heterogeneous clinical presentation that can mimic stroke and various forms of dementia. To date, it has been described almost exclusively in Asian individuals., Methods: This case presentation includes magnetic resonance imaging (MRI) of the neurocranium, histology by skin biopsy, and long-read genome sequencing., Results: A 75-year-old Caucasian female presented with paroxysmal encephalopathy twice within a 14-month period. Brain MRI revealed high-intensity signals at the cerebral corticomedullary junction (diffusion-weighted imaging) and the paravermal area (fluid-attenuated inversion recovery), a typical distribution observed in adult onset NIID. The diagnosis was corroborated by skin biopsy, which demonstrated eosinophilic intranuclear inclusion bodies, and confirmed by long-read genome sequencing, showing an expansion of the GGC repeat in exon 1 of NOTCH2NLC., Conclusions: Our case proves adult onset NOTCH2NLC-GGC-positive NIID with typical findings on MRI and histology in a Caucasian patient and underscores the need to consider this diagnosis in non-Asian individuals., (© 2023 European Academy of Neurology.)

Background: Neuronal intranuclear inclusion disease (NIID) is a great imitator with a broad spectrum of clinical manifestations that include dementia, parkinsonism, paroxysmal symptoms, peripheral neuropathy, and autonomic dysfunction. Hence, it may also masquerade as other diseases such as Alzheimer's disease, Parkinson's disease, and Charcot-Marie-Tooth disease. Recent breakthroughs on neuroimaging, skin biopsy, and genetic testing have facilitated the diagnosis. However, early identification and effective treatment are still difficult in cases of NIID., Objective: To further study the clinical characteristics of NIID and investigate the relationship between NIID and inflammation., Methods: We systematically evaluated the clinical symptoms, signs, MRI and electromyographical findings, and pathological characteristics of 20 NIID patients with abnormal GGC repeats in the NOTCH2NLC gene. Some inflammatory factors in the patients were also studied., Results: Paroxysmal symptoms such as paroxysmal encephalopathy, stroke-like episodes, and mitochondrial encephalomyopathy lactic acidosis and stroke (MELAS)-like episode were the most common phenotypes. Other symptoms such as cognitive dysfunction, neurogenic bladder, tremor, and vision disorders were also suggestive of NIID. Interestingly, not all patients showed apparent diffusion-weighted imaging (DWI) abnormality or intranuclear inclusions, while abnormal GGC repeats of NOTCH2NLC were seen in all patients. And fevers were noticed in some patients during encephalitic episodes, usually with increasing leukocyte counts and neutrophil ratios. Both IL-6 (p = 0.019) and TNF-α (p = 0.027) levels were significantly higher in the NIID group than in normal controls., Conclusion: Genetic testing of NOTCH2NLC may be the best choice in the diagnosis of NIID. Inflammation might be involved in the pathogenesis of NIID., (© 2023. Fondazione Società Italiana di Neurologia.)

Nuclear morphology of carcinoma cells is critical for the pathological diagnosis of papillary thyroid carcinoma (PTC). However, three-dimensional architecture of PTC nuclei is still elusive. In this study, we analyzed the three-dimensional ultrastructure of PTC nuclei using serial block-face scanning electron microscopy which takes advantage of the high-throughput acquisition of serial electron microscopic images and three-dimensional reconstruction of subcellular structures. En bloc-stained and resin-embedded specimens were prepared from surgically removed PTCs and normal thyroid tissues. We acquired two-dimensional images from serial block-face scanning electron microscopy and reconstructed three-dimensional nuclear structures. Quantitative comparisons showed that the nuclei of carcinoma cells were larger and more complex than those of normal follicular cells. The three-dimensional reconstruction of carcinoma nuclei divided intranuclear cytoplasmic inclusions into "open intranuclear cytoplasmic inclusions" connecting to cytoplasm outside the nucleus and "closed intranuclear cytoplasmic inclusions" without that connection. Cytoplasm with abundant organelles was observed in open inclusions, but closed inclusions contained fewer organelles with or without degeneration. Granules with a dense core were only observed in closed inclusions. Our observations suggested that open inclusions originate from nuclear invaginations, and disconnection from cytoplasm leads to closed inclusions., (© 2023 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Frontotemporal lobar degeneration (FTLD) is a group of disorders characterized by degeneration of the frontal and temporal lobes, leading to progressive decline in language, behavior, and motor function. FTLD can be further subdivided into three main subtypes, FTLD-tau, FTLD-TDP and FTLD-FUS based which of the three major proteins - tau, TDP-43 or FUS - forms pathological inclusions in neurons and glia. In this report, we describe an 87-year-old woman with a 7-year history of cognitive decline, hand tremor and gait problems, who was thought to have Alzheimer's disease. At autopsy, histopathological analysis revealed severe neuronal loss, gliosis and spongiosis in the medial temporal lobe, orbitofrontal cortex, cingulate gyrus, amygdala, basal forebrain, nucleus accumbens, caudate nucleus and anteromedial thalamus. Tau immunohistochemistry showed numerous argyrophilic grains, pretangles, thorn-shaped astrocytes, and ballooned neurons in the amygdala, hippocampus, parahippocampal gyrus, anteromedial thalamus, insular cortex, superior temporal gyrus and cingulate gyrus, consistent with diffuse argyrophilic grain disease (AGD). TDP-43 pathology in the form of small, dense, rounded neuronal cytoplasmic inclusion with few short dystrophic neurites was observed in the limbic regions, superior temporal gyrus, striatum and midbrain. No neuronal intranuclear inclusion was observed. Additionally, FUS-positive inclusions were observed in the dentate gyrus. Compact, eosinophilic intranuclear inclusions, so-called "cherry spots," that were visible on histologic stains were immunopositive for α-internexin. Taken together, the patient had a mixed neurodegenerative disease with features of diffuse AGD, TDP-43 proteinopathy and neuronal intermediate filament inclusion disease. She met criteria for three subtypes of FTLD: FTLD-tau, FTLD-TDP and FTLD-FUS. Her amnestic symptoms that were suggestive of Alzheimer's type dementia are best explained by diffuse AGD and medial temporal TDP-43 proteinopathy, and her motor symptoms were likely explained by neuronal loss and gliosis due to tau pathology in the substantia nigra. This case underscores the importance of considering multiple proteinopathies in the diagnosis of neurodegenerative diseases., (© 2023. The Author(s).)

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative condition. Skin biopsies taken from the lower leg were reported to be a standard diagnostic procedure for NIID; however, no studies have addressed the optimal skin biopsy locations. We retrospectively analyzed 12 cases in which skin biopsies were performed for diagnosing NIID. We collected clinical information including age, sex, skin biopsy site, the presence of nuclear inclusion bodies, the results of p62 immunostaining, the final diagnosis from the department of neurology, and the presence of abnormal GGC repeats in the NOTCH2NLC gene. Four of the 12 cases had a final diagnosis of NIID. One of the four cases was biopsied from the lower leg, whereas the other three cases were biopsied from the abdomen or thigh. Biopsy specimens of the four definite NIID cases revealed the average rates of nuclear inclusion body-positive cells in adipocytes, sweat gland cells, and fibroblasts to be 13.2%, 10.3%, and 6.3%, respectively. GGC repeat abnormalities in the NOTCH2NLC gene were observed in two of the four cases. The present study indicates that sites with ample subcutaneous fat tissue could be promising for diagnostic skin biopsies for NIID., (© 2023 Japanese Dermatological Association.)

A 75-year-old man presented with headache and disturbance of consciousness. Magnetic resonance imaging revealed edema localized mainly in the cortex and linear contrast enhancement. A brain biopsy revealed numerous astrocytes with inclusion, and genetic testing demonstrated prolonged GGC repeats in NOTCH2NLC. The present case provided two novel insights into the mechanism underlying encephalopathy associated with neuronal intranuclear inclusion disease. First, the histological findings at a site with contrast enhancement on magnetic resonance imaging did not demonstrate any organic association, such as the presence of inflammation or ischemic changes. Second, the imaging and cerebrospinal fluid findings demonstrated increased cerebral blood flow and opening of the blood-brain barrier, indicating the cause of the cerebral swelling.

Neuronal intranuclear inclusion disease (NIID) is a rare but probably underdiagnosed neurodegenerative disorder due to pathogenic GGC expansions in the NOTCH2NLC gene. In this review, we summarize recent developments in the inheritance features, pathogenesis, and histopathologic and radiologic features of NIID that subvert the previous perceptions of NIID. GGC repeat sizes determine the age of onset and clinical phenotypes of NIID patients. Anticipation may be absent in NIID but paternal bias is observed in NIID pedigrees. Eosinophilic intranuclear inclusions in skin tissues once considered pathological hallmarks of NIID can also present in other GGC repeat diseases. Diffusion-weighted imaging (DWI) hyperintensity along the corticomedullary junction once considered the imaging hallmark of NIID can frequently be absent in muscle weakness and parkinsonism phenotype of NIID. Besides, DWI abnormalities can appear years after the onset of predominant symptoms and may even disappear completely with disease progression. Moreover, continuous reports of NOTCH2NLC GGC expansions in patients with other neurodegenerative diseases lead to the proposal of a new concept of NOTCH2NLC-related GGC repeat expansion disorders (NRED). However, by reviewing the previous literature, we point out the limitations of these studies and provide evidence that these patients are actually suffering from neurodegenerative phenotypes of NIID., (© 2023. Fondazione Società Italiana di Neurologia.)

Neuronal intranuclear inclusion disease (NIID) is a clinically complex neurological disorder that appears sporadically or autosomally. Expansions of intronic GGC trinucleotide repeats in the NOTCH2 N-terminal-like C (NOTCH2NLC) gene cause NIID. In this study, to clarify the clinical characteristics useful for the differential diagnosis of NIID, clinical data of neurological examination, neuroimaging, and nerve conduction studies of six NIID patients diagnosed by pathological or genetic investigations were analyzed. Clinically useful characteristics for diagnosing NIID include general hyporeflexia, episodic disturbance of consciousness, sensory disturbance, miosis, and dementia. Furthermore, neuroimaging findings, such as leukoencephalopathy in T2-weighted magnetic resonance imaging and a linear high intensity of subcortical U-fibers in diffusion-weighted imaging (DWI), as well as decreased motor nerve conduction velocity, are especially important biomarkers for NIID. However, it is necessary to remember that these features may not always be present, as shown in one of the cases who did not have a DWI abnormality in this study. This study also investigated whether expanded GGC repeats were translated into polyglycine. Immunohistochemical analysis using a custom antibody raised against putative C-terminal polypeptides followed by polyglycine of uN2CpolyG revealed that polyglycines were localized in the intranuclear inclusions in skin biopsy specimens from all six patients, suggesting its involvement in the pathogenesis of NIID., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear., Patient Concerns: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence., Diagnoses, Interventions, and Outcomes: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed., Conclusion: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The retinal pathology of genetically confirmed neuronal intranuclear inclusion disease (NIID) is yet unknown. We report the ocular findings in four NIID patients with NOTCH2NLC GGC repeat expansion to investigate the pathology of retinopathy. All four NIID patients were diagnosed by skin biopsy and NOTCH2NLC GGC repeat analysis. Ocular findings in patients with NIID were studied using fundus photographs, optical coherence tomographic images (OCT), and full-field electroretinograms (ERGs). The histopathology of the retina was studied on autopsy samples from two cases with immunohistochemistry. All patients had an expansion of the GGC repeat (87-134 repeats) in the NOTCH2NLC. Two patients were legally blind and had been diagnosed with retinitis pigmentosa prior to the diagnosis of NIID and assessed with whole exome sequencing to rule out comorbidity with other retinal diseases. Fundus photographs around the posterior pole showed chorioretinal atrophy in the peripapillary regions. OCT showed thinning of the retina. ERGs showed various abnormalities in cases. The histopathology of autopsy samples showed diffusely scattered intranuclear inclusions throughout the retina from the retinal pigment epithelium to the ganglion cell layer, and optic nerve glial cells. And severe gliosis was observed in retina and optic nerve. The NOTCH2NLC GGC repeat expansion causes numerous intranuclear inclusions in the retina and optic nerve cells and gliosis. Visual dysfunction could be the first sign of NIID. We should consider NIID as one of the causes of retinal dystrophy and investigate the GGC repeat expansion in NOTCH2NLC., (© 2023. The Author(s).)

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., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: Neuronal intranuclear inclusion disease (NIID), caused by GGC (guanine-guanine-cytosine) repeat expansion in NOTCH2NLC , has several clinical and radiological features akin to cerebral small vessel disease (cSVD). The present study tested the hypothesis that NOTCH2NLC GGC expansion may contribute to cSVD., Methods: One hundred and ninety-seven unrelated patients with genetically unsolved vascular leukoencephalopathy without NOTCH3 , HTRA1 , and mitochondrial m.3243A>G mutations and 730 healthy individuals were screened for NOTCH2NLC GGC repeat expansion using repeat-primed polymerase chain reaction, fragment analysis, Southern blot analysis, or nanopore sequencing with Cas9 (CRISPR associated protein 9)-mediated enrichment. The clinical and neuroimaging features of the patients were compared between individuals with and without NOTCH2NLC GGC repeat expansion., Results: Six of the 197 (3.0%) patients with unsolved vascular leukoencephalopathy and none of the controls carried the GGC repeat expansion ( P =0.00009). Skin biopsy of 1 patient revealed eosinophilic, ubiquitin-positive, and p62-positive intranuclear inclusions in the cells of sweat gland and capillary, providing pathologic evidence for the involvement of small vessels in NIID. For the 6 patients, gait disturbance and cognitive decline were common manifestations with a median onset age of 65 (59-69) years. They all had multiple neuroimaging features suggestive of cSVD, including diffuse white matter hyperintensities, lacunes, and enlarged perivascular space in all 6 patients, cerebral microbleeds in 5, and old intracerebral hemorrhage in 4. Four patients had linear hyperintensity in the corticomedullary junction on diffusion-weighted imaging-the characteristic neuroimaging feature of NIID. There was no difference in the severity of cSVD imaging features between the patients with and without the GGC expansion but more pronounced brain atrophy in the patients with the GGC expansion., Conclusions: NOTCH2NLC GGC repeat expansion accounted for 3% of genetically unsolved Taiwanese vascular leukoencephalopathy cases after excluding participants with cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). NIID should be considered in patients manifesting cSVD, especially in those with characteristic neuroimaging feature of NIID.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine-adenine-guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34-year-old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair-dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action-related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26-year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine-immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine-positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP., (© 2022 The Authors. Neuropathology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Neuropathology.)

Objective: GGC repeat expansions in the human-specific NOTCH2NLC gene have been reported as the cause of neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of cognitive impairment in NIID and cerebral small vessel disease (CSVD), both diseases have white matter hyperintensity on T2-fluid-attenuated inversion recovery sequences of brain MRI, and white matter hyperintensity is a primary neuroimaging marker of CSVD on MRI. Therefore, we hypothesised that the GGC repeat expansions might also contribute to CSVD. To further investigate the relationship between NOTCH2NLC GGC repeat expansions and CSVD, we performed a genetic analysis of 814 patients with the disease., Methods: We performed a comprehensive GGC repeat expansion screening in NOTCH2NLC from 814 patients with sporadic CSVD. Their Fazekas score was greater than or equal to 3 points. Repeat-primed PCR and fluorescence amplicon length analyses were performed to identify GGC repeat expansions, and whole-exome sequencing was used to detect any pathogenic mutation in previously reported genes associated with CSVD., Results: We identified nine (1.11%) patients with pathogenic GGC repeat expansions ranging from 41 to 98 repeats. The minor allele frequency of expanded GGC repeats in NOTCH2NLC was 0.55%., Conclusion: Our findings suggest that intermediate-length and longer-length GGC repeat expansions in NOTCH2NLC are associated with sporadic CSVD. This provides new thinking for studying the pathogenesis of CSVD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Given the variable nature of clinical manifestations, neuronal intranuclear inclusion disease (NIID) is regarded as a heterogeneous disease which is challenging to diagnose early. To the present, progressive supranuclear palsy (PSP)-like symptoms have never been listed in the performance of NIID., Case Presentation: A 58-year-old man presented with progressive Parkinsonism and postural instability for 3 years. Initially, he was considered as probable PSP due to vertical supranuclear gaze palsy, postural instability, and hummingbird sign. No high-intensity signal on diffusion-weighted imaging (DWI) was revealed. Eventually, the diagnosis was revised to NIID by Notch 2 N-terminal like C (NOTCH2NLC) GGC repeat expansions and skin biopsy showing intranuclear eosinophilic inclusions in the vesicles and ductal epithelial cells of sweat glands., Conclusion: Even if the typical high-intensity along the corticomedullary junction (CMJ) on DWI is lacking, clinicians should be alert to the possibility of NIID when PSP-like symptoms develop. This case report offers new features of NIID and expands its clinical spectrum., (© 2023. Fondazione Società Italiana di Neurologia.)

Neuronal intranuclear inclusion disease (NIID) is a neurological disorder characterized by eosinophilic intranuclear inclusions (INI) in systemic organs and various cell types. High-intensity signals along the corticomedullary junction on diffusion-weighted imaging and presence of cellular p62-INI in skin biopsy are known indicators for NIID. Furthermore, GGC repeat expansion in NOTCH2NLC is a characteristic genetic alteration in patients with NIID. This report presents the clinical and detailed pathological features of a male older adult with NIID. We also confirmed the presence of fluid-attenuated inversion recovery high-intensity signals in the cerebellar paravermal area, showing similar pathological changes in high-intensity signals along the corticomedullary junction on diffusion-weighted imaging.

Background: Neuronal intranuclear inclusion disease (NIID) is a rare slowly progressive neurodegenerative disorder that is characterized pathologically by the presence of eosinophilic intranuclear inclusions. NIID is a heterogeneous disease with diverse clinical manifestations, making diagnosis difficult. Here, we analyzed the clinical, pathological, and radiological features of Chinese NIID patients to improve our understanding of NIID., Methods: A total of 17 patients with sporadic NIID were recruited from the Ruijin Hospital Database between 2014 and 2021. Clinical patient information and brain MRI data were collected. All of the patients underwent standard skin biopsy procedures., Results: The average age of onset for symptoms was 60.18 years, and the average duration of illness was 4.06 years. All patients were diagnosed with NIID due to the presence of intranuclear inclusions confirmed by skin biopsy. Tremor was the most common initial symptom. The average ages at onset and at diagnosis were both lower in patients with tremor than in patients without tremor. NIID may be a systemic disease that affects multiple organs, for one patient had a history of chronic renal insufficiency for more than 10 years. In addition to high-intensity U-fibers signals on diffusion-weighted imaging, there were several other MRI findings, such as focal leukoencephalopathy and cortical swelling. Encephalitic episodes followed by reversible leukoencephalopathy was another important imaging feature of NIID., Conclusion: The clinical manifestations of NIID are highly variable. Tremor may be the most common initial symptom in certain cohorts. Encephalitic episodes followed by reversible asymmetric leukoencephalopathy may also indicate this disease.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Ubiquitin- and p62-positive intranuclear inclusions are the pathological hallmark of NIID. Targeted immunostaining studies have identified several other proteins present in these inclusions. However, the global molecular changes within nuclei with these inclusions remained unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in a NIID patient with CGG repeat expansion in NOTCH2NLC to discover candidate proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins was confirmed via immunofluorescence in autopsy brain samples from three patients with genetically confirmed NIID. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A2/B1, hnRNP A3, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than in those without, which were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. Although larger studies are needed to validate our results, these proteomic data may form the basis for understanding the pathophysiology of NIID., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)