Adult-onset Neuronal Intranuclear Inclusion Disease Research Articles

Clinical and genetic analysis of a patient with Neuronal intranuclear inclusion body disease characterized by cortical enhancement in the posterior brain region

To explore the clinical, imaging, and genetic characteristics of an adult patient with sporadic Neuronal intranuclear inclusion disease (NIID). A patient who had visited the First People's Hospital of Chenzhou on August 6, 2023 was selected as the study subject. Results of clinical examination, neuroimaging, and genetic testing were retrospectively analyzed along with a literature review. The number of GGC trinucleotide repeats in the 5'-untranslated region of the NOTCH2NLC gene was determined by GC-PCR. The patient had presented with episodic encephalopathy, with enhanced magnetic resonance imaging showing enhancement features of the posterior cerebral cortex during the period of acute episode. Genetic testing revealed an increased number of GGC repeats (n = 97) in the 5'- untranslated region of the NOTCH2NLC gene, which confirmed the diagnosis of NIID. Clinical attention should be paid to the enhanced MRI findings of patients with adult-onset NIID, for whom posterior cortical enhancement may be characteristic manifestation during the acute phase of encephalopathy-like episode.

Mapping macrostructural and microstructural brain alterations in patients with neuronal intranuclear inclusion disease.

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. 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. 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). 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.

Clinical and multimodal imaging features of adult-onset neuronal intranuclear inclusion disease.

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. 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. 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. 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.

Adult-onset neuronal intranuclear inclusion disease presenting with acute encephalitis-like episode and without characteristic hyperintensities on MR-DWI: a case report

Adult-onset neuronal intranuclear inclusion disease presenting with acute encephalitis-like episode and without characteristic hyperintensities on MR-DWI: a case report

Ultra-high-field 7-Tesla magnetic resonance imaging in fragile X tremor/ataxia syndrome (FXTAS).

Fragile X tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder characterized by premutation expansion of fragile X mental retardation 1 (FMR1) gene. It is a common single-gene cause of tremor, ataxia, and cognitive decline in adults. FXTAS affects the central, peripheral and autonomic nervous systems, leading to a range of neurological symptoms from dementia to dysautonomia. A characteristic imaging feature of FXTAS is symmetric T2 hyperintensity in the deep white matter of the cerebellar hemispheres and middle cerebral peduncle. However, recent studies have reported additional findings on diffusion weighted images (DWI), such as a symmetric high-intensity band-like signal at the cerebral corticomedullary junction. These findings, along with the characteristic cerebellar signal alterations, overlap with imaging findings seen in adult-onset neuronal intranuclear inclusion disease (NIID). Importantly, recent pathology studies have shown that both FXTAS and NIID can manifest intranuclear inclusion bodies, posing a diagnostic challenge and potential for misdiagnosis. We describe a 58-year-old man with FXTAS who received an erroneous diagnosis based on imaging and histopathology results. We emphasize the potential pitfalls in distinguishing NIID from FXTAS and stress the importance of genetic analysis in all cases with suspected NIID and FXTAS for confirmation. Additionally, we present the 7T MRI brain findings of FXTAS.

Adult-onset neuronal intranuclear inclusion disease related retinal degeneration: a Chinese case series.

To evaluate adult-onset neuronal intranuclear inclusion disease (NIID)-related retinopathy with guanine-guanine-cytosine repeat expansions in NOTCH2NLC. Neuro-ophthalmic evaluations, including best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP), ultrasound biomicroscopy, pupillometry, fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), Humphrey visual field, full-field electroretinography (ERG), and multifocal ERG (mf-ERG) were performed in patients with gene-proven NIID. Nine patients (18 eyes) were evaluated, with a median age of 62 years (55-68) and only one man was included in our study. Six patients presented with decreased visual acuity or night blindness, whereas the other three were asymptomatic. The visual acuity was measured from 20/200 to 20/20. Miosis was present in eight patients, four of whom had ciliary process hypertrophy and pronation, and three of whom had shallow anterior chambers. Fundus photography, FAF, and OCT showed consistent structural abnormalities mainly started from peripapillary areas and localized in the outer layer of photoreceptors and inner ganglion cell layer. ERG and mf-ERG also revealed retinal dysfunction in the corresponding regions. Patients with NIID showed both structural and functional retinopathies which were unique and different from common cone-rod dystrophy or retinitis pigmentosa. Patients with miosis may have a potential risk of an angle-closure glaucoma attack. Neuro-ophthalmic evaluations is essential for evaluating patients with NIID, even without visual symptom.

Case series of familiar adult-onset neuronal intranuclear inclusion disease

Case series of familiar adult-onset neuronal intranuclear inclusion disease

Longitudinal course of hyperintensity on diffusion weighted imaging in adult-onset neuronal intranuclear inclusion disease patients.

High signals on diffusion weighted imaging along the corticomedullary junction (CMJ) have demonstrated excellent diagnostic values for adult-onset neuronal intranuclear inclusion disease (NIID). However, the longitudinal course of diffusion weighted imaging high intensities in adult-onset NIID patients has rarely been investigated. We described four NIID cases that had been discovered using skin biopsy and NOTCH2NLC gene testing, after diffusion weighted imaging exhibiting the distinctive corticomedullary junction high signals. Then using complete MRI data from NIID patients, we analyzed the chronological diffusion weighted imaging alterations of those individuals that had been published in Pub Med. We discussed 135 NIID cases with comprehensive MRI data, including our four cases, of whom 39 had follow-up outcomes. The following are the four primary diffusion weighted imaging dynamic change patterns: (1) high signal intensities in the corticomedullary junction were negative on diffusion weighted imaging even after an 11-year follow-up (7/39); (2) diffusion weighted imagings were initially negative but subsequently revealed typical findings (9/39); (3) high signal intensities vanished during follow-up (3/39); (4) diffusion weighted imagings were positive at first and developed in a step-by-step manner (20/39). We discovered that NIID lesions eventually damaged the deep white matter, which comprises the cerebral peduncles, brain stem, middle cerebellar peduncles, paravermal regions, and cerebellar white matter. The longitudinal dynamic changes in NIID of diffusion weighted imaging are highly complex. We find that there are four main patterns of dynamic changes on diffusion weighted imaging. Furthermore, as the disease progressed, NIID lesions eventually involved the deep white matter.

Heterogenous Genetic, Clinical, and Imaging Features in Patients with Neuronal Intranuclear Inclusion Disease Carrying NOTCH2NLC Repeat Expansion.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

First case of adult onset neuronal intranuclear inclusion disease with both typical radiological signs and NOTCH2NLC repeat expansions in a Caucasian individual.

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. This case presentation includes magnetic resonance imaging (MRI) of the neurocranium, histology by skin biopsy, and long-read genome sequencing. 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. 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.

Genetic Movement Disorders Commonly Seen in Asians.

The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease-causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann-Sträussler-Scheinker disease, PLA2G6-related parkinsonism, adult-onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians.

Teaching Video NeuroImages: A Triad of Tremor, Ataxia, and Cognitive Impairment

A 67-year-old woman presented with a 2-year history of forgetfulness and unsteadiness. She scored 17 on the Montreal Cognitive Assessment. She had tremor of head and upper limbs (video 1) since early adulthood, which was diagnosed as essential tremor. Brain MRI showed leukoencephalopathy and high signal intensity along the corticomedullary junction on diffusion-weighted images (figure 1). The diagnosis of adult-onset neuronal intranuclear inclusion disease (NIID) was confirmed by skin biopsy showing eosinophilic intranuclear inclusions (figure 2).1 NIID is a clinically heterogeneous rare neurodegenerative disease.2 Its characteristic MRI pattern should prompt confirmation of the diagnosis by skin biopsy.

Neuropathological features of adult-onset neuronal intranuclear inclusion disease with fluid-attenuated inversion recovery high-intensity signals in the cerebellar paravermal area from an early stage: A case report.

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.

Unraveling rare form of adult-onset NIID by characteristic brain MRI features: A single-center retrospective review.

Adult-onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with high clinical heterogeneity. Previous studies indicated that the high-intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI) on brain MRI, known as the "ribbon sign," could serve as a strong diagnostic clue. Here we used the explorative approach to study the undiagnosed rate of adult-onset NIID in a single center in China via searching for the ribbon sign in picture archive and communication system (PACS) and report the clinical and radiological features of initially undiagnosed NIID patients. Consecutive brain MRI of 21,563 adult individuals (≥18 years) in the PACS database in 2019 from a tertiary hospital were reviewed. Of them, 4,130 were screened out using the keywords "leukoencephalopathy" and "white matter demyelination." Next, all 4,130 images were read by four neurologists. The images with the suspected ribbon sign were reanalyzed by two neuroradiologists. Those with the ribbon sign but without previously diagnosed NIID were invited for skin biopsy and/or genetic testing for diagnostic confirmation. The clinical features of all NIID patients were retrospectively reviewed. Five patients with high-intensity in the corticomedullary junction on DWI were enrolled. Three patients were previously diagnosed with NIID confirmed by genetic or pathological findings and presented with episodic encephalopathy or cognitive impairment. The other two patients were initially diagnosed with limb-girdle muscular dystrophy (LGMD) with rimmed vacuoles (RVs) and normal pressure hydrocephalus (NPH) in one each. Genetic analysis demonstrated GGC repeat expansion in the NOTCH2NLC gene of both, and skin biopsy of the first patient showed the presence of intranuclear hyaline inclusion bodies. Thus, five of the 21,563 adult patients (≥18 years) were diagnosed with NIID. The distinctive subcortical high-intensity signal on DWI was distributed extensively throughout the lobes, corpus callosum, basal ganglia, and brainstem. In addition, T2-weighted imaging revealed white matter hyperintensity of Fazekas grade 2 or 3, atrophy, and ventricular dilation. Distinctive DWI hyperintensity in the junction between the gray and white matter can help identify atypical NIID cases. Our findings highly suggest that neurologists and radiologists should recognize the characteristic neuroimaging pattern of NIID.

Sporadic adult-onset neuronal intranuclear inclusion disease without high-intensity signal on DWI and T2WI: a case report

BackgroundNeuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in cells in the central and peripheral nervous system. High-intensity signal in the corticomedullary junction on diffusion-weighted imaging (DWI) is supportive to the diagnosis of NIID. We describe a patient with sporadic adult-onset NIID but without any high-intensity signal on DWI and T2-weighted imaging (T2WI).Case presentationA 58-year-old woman without special family history developed mild persistent tremor in the right hand and deteriorated 2 years later. At 60 years of age, the patient began to conceive the bank, police and internet being deceptive, further presented apathy and confusion after two and a half years, as well as fabrication of non-existent things. Despite the treatment of antipsychotic drugs due to a diagnosis of mental disorder, the patient appeared weakness in the right limbs. Neurological examination revealed mutism, resting tremor, cogwheel-like rigidity in upper limbs, and weakness in all limbs. Brain magnetic resonance imaging displayed no cerebral atrophy initially but atrophy of frontal, temporal and parietal lobes 5 years later. No any high-intensity signal on DWI and T2WI was revealed. However, hypometabolism in the cortexes with atrophy and the right putamen nucleus were showed on 18F-fluoro-deoxy-glucose positron emission tomography/magnetic resonance. On the basis of 107 GGC repeats (normal number <40) in NOTCH2NLC gene and intranuclear inclusions with p62 immunoreactivity in the adipocyte of cutaneous sweat duct by skin biopsy, NIID was finally diagnosed. The symptomatic treatment was given but the patient had no evident improvement.ConclusionsOur case highlights that despite the lack of high-intensity signal on DWI and T2WI, NIID is still considered for patients with parkinsonism and mental impairment.

Adult-onset autosomal dominant leukodystrophy and neuronal intranuclear inclusion disease: lessons from two new Chinese families.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare genetic leukoencephalopathy caused by duplication of the lamin B1 gene (LMNB1) or LMNB1 upstream deletions. Neuronal intranuclear inclusion disease (NIID) is another leukoencephalopathy due to GGC repeat expansion in the 5'-untranslated region of the NOTCH2NLC gene. Here, we report two Chinese ADLD families with neuroimaging and clinical features mimicking NIID. We conducted detailed medical history inquiry, neurological examinations, and magnetic resonance imaging in the two families. Candidate gene sequencing and whole exome sequencing (WES) with copy number variation analysis were used to screen the genetic variations. The special points on the clinical and neuroimaging findings in the current families and differential diagnosis of ADLD with NIID are discussed. The two families presented with slowly progressive, multiple central nervous system symptoms, including spastic paraplegia, autonomic dysfunction, ataxia, deep sensory loss, and tremor. Clinical phenotypes were consistent within the family. Transient hypoglycemia and transient dilated pupils indicating autonomic dysfunctions were recorded for the first time in ADLD. Brain MRI showed band-like hyperintensities at the cortico-medullary junction on DWI, typical for NIID. Skin biopsy and genetic sequencing of the NOTCH2NCL gene did not support the diagnosis of NIID. Further whole exome sequencing (WES) identified the duplication mutation spanning the entire LMNB1 gene. The novel feature of transient hypoglycemia and dilated pupils broadens the spectrum of autonomic dysfunction in ADLD. Clinical manifestations and neuroimaging of ADLD can mimic NIID. Although ADLD is even rarer than NIID, the differential diagnosis of these two diseases should not be confused.

The clinical and neuroimaging features of sporadic adult-onset neuronal intranuclear inclusion disease.

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. 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. 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. 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.

An autopsy case of adult‐onset neuronal intranuclear inclusion disease with perivascular preservation in cerebral white matter

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by appearance of eosinophilic hyaline intranuclear inclusions. While the main symptoms of adult-onset NIID are dementia or limb weakness, some patients present with encephalitic episodes and transient neurological symptoms. The pathophysiology of these acute, transient symptoms, however, remains unknown. Here, we describe an autopsy case of adult-onset NIID with progressive dementia and transient hemiparesis. The patient was a 70-year-old man without a relevant family history, and initially presented with progressive dementia. He then exhibited transient left hemiparesis at 75 years of age and died of ureteral cancer at 77 years of age. Neuropathological examination revealed the presence of multiple areas of focal spongiosis in the subcortical white matter and patchy myelin pallor of the white matter, as in previous reports. However, perivascular areas were preserved even in the damaged white matter. In addition, dense glial fibrillary acidic protein (GFAP)-immunoreactive astrocytic processes were observed in these areas. [Correction added on 23 January 2022, after first online publication: the preceding sentence has been corrected to improve readability.] GFAP immunohistochemistry revealed decreased density and morphological abnormalities of astrocytes in the affected white matter. These pathological findings might reflect blood-brain barrier impairment and dysregulation of blood flow, which may be related to the pathophysiology of the acute, transient symptoms observed in NIID.

Upstream open reading frame with NOTCH2NLC GGC expansion generates polyglycine aggregates and disrupts nucleocytoplasmic transport: implications for polyglycine diseases.

Neuronal intranuclear inclusion disease (NIID) is neurodegenerative disease characterized by widespread inclusions. Despite the identification of GGC repeat expansion in 5'UTR of NOTCH2NLC gene in adult-onset NIIDs, its pathogenic mechanism remains unclear. Gain-of-function poly-amino-acid proteins generated by unconventional translation have been revealed in nucleotide repeat expansion disorders, inspiring us to explore the possibility of unconventional translation in NIID. Here we demonstrated that NOTCH2NLC 5'UTR triggers the translation of a polyglycine (polyG)-containing protein, N2NLCpolyG. N2NLCpolyG accumulates in p62-positive inclusions in cultured cells, mouse models, and NIID patient tissues with NOTCH2NLC GGC expansion. Translation of N2NLCpolyG is initiated by an upstream open reading frame (uORF) embedding the GGC repeats. N2NLCpolyG tends to aggregate with the increase of GGC repeat units, and displays phase separation properties. N2NLCpolyG aggregation impairs nuclear lamina and nucleocytoplasmic transport but does not necessarily cause acute death on neuronal cells. Our study suggests a similarity of pathogenic mechanisms between NIID and another GGC-repeat disease, fragile X-associated tremor ataxia syndrome. These findings expand our knowledge of protein gain-of-function in NIID, and further highlight evidence for a novel spectrum of diseases caused by aberrant polyG protein aggregation, namely the polyG diseases.

Clinical Features of Adult-Onset Neuronal Intranuclear Inclusion Disease: A Multi-Centre Study in China

Background: The full clinical spectrum of neuronal intranuclear inclusion disease (NIID) and its relationship with genotype have not been documented. We aimed to identify the clinical, neuroimaging, and genetic features of adult-onset NIID. Methods: An adult-onset NIID registry was launched in multiple centres throughout China. Clinical data, routine brain magnetic resonance imaging, and skin pathologies were evaluated. Arterial spin labelling magnetic resonance imaging and electrophysiological studies were conducted. Repeat-primed and amplicon length polymerase chain reaction were used to screen (GGC)n repeat expansions in the 5’ untranslated region of the NOTCH2NLC gene. Findings: In total, 134 adult-onset patients with NIID (66% female) from 72 clinical centres were included; 23 cases were familial. The mean age of onset was 56·9±9·4 years. The median disease duration was 4 (IQR 2–9) years. Adult-onset NIID was divided into three subtypes based on primary manifestations: dementia-dominant type (n=65), parkinsonism-dominant type (n=19), and episodic neurogenic event-dominant type (n=45). Among the patients, 90·5% presented with mild demyelinating polyneuropathy. All patients presented with high intensities along the corticomedullary junction on diffusion-weighted imaging, and 53·7% of them presented with abnormal hyperintensity in the paravermal area on T2/fluid-attenuated inversion recovery images. Cerebral blood flow in the whole brain was lower and that in globus pallidus was higher in patients with NIID than in healthy controls. (GGC) n repeat number in the 5’-untranslated region of the NOTCH2NLC gene ranged from 82 to 173 repeats. A significant inverse correlation between (GGC) n repeat number and age of onset was observed (r=–0·203, p=0·018). Interpretation: This study provides a novel classification of adult-onset NIID for clinical application. Decreased cerebral perfusion may underpin the pathogenesis of NIID and highlight the potential of perfusion modulation therapy. (GGC) n repeat number was inversely correlated with the age of onset, and the pathogenetic effect may have a cumulative effect. Funding: None Declaration of Interest: We declare no competing interests. Ethical Approval: This study was approved by the Medical Ethics Committee of Beijing Tiantan Hospital, Capital Medical University, and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from all individuals or their authorised surrogates at enrolment.