Adult-onset neuronal intranuclear inclusion disease mimicking Fragile X-associated tremor-ataxia syndrome in ethnic Chinese patients

AbstractThe presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

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Long-read sequencing identified repeat expansions in the 5′UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106268 ◽

2019 ◽

Vol 56 (11) ◽

pp. 758-764 ◽

Cited By ~ 18

Author(s):

Jianwen Deng ◽

Muliang Gu ◽

Yu Miao ◽

Sheng Yao ◽

Min Zhu ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Electron Microscopic Observation ◽

Chinese Patients ◽

Sweat Glands ◽

Adult Onset ◽

Intranuclear Inclusion ◽

Electron Microscopic ◽

Juvenile Onset ◽

Long Read ◽

Neuronal Intranuclear Inclusion

BackgroundNeuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients.MethodsFifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.ResultsOur patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5′UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases.ConclusionOur findings provided evidence that confirmed the GGC repeated expansion in the 5′UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.

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FXTAS is difficult to differentiate from neuronal intranuclear inclusion disease through skin biopsy: a case report

BMC Neurology ◽

10.1186/s12883-021-02425-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Megumi Toko ◽

Tomohiko Ohshita ◽

Takashi Kurashige ◽

Hiroyuki Morino ◽

Kodai Kume ◽

...

Keyword(s):

Genetic Analysis ◽

Skin Biopsy ◽

Trinucleotide Repeat ◽

Late Onset ◽

Fragile X ◽

Brain Mri ◽

Intranuclear Inclusion ◽

Neuronal Intranuclear Inclusion ◽

Cerebellar Peduncle ◽

Ataxia Syndrome

Abstract Background Both fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID. Case presentation The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID. Conclusions For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.

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NOTCH2NLC-linked neuronal intranuclear inclusion body disease and fragile X-associated tremor/ataxia syndrome

Brain ◽

10.1093/brain/awaa210 ◽

2020 ◽

Vol 143 (8) ◽

pp. e69-e69

Author(s):

Adeline S L Ng ◽

Zheyu Xu ◽

Zhiyong Chen ◽

Yi Jayne Tan ◽

Weng Khong Lim ◽

...

Keyword(s):

Inclusion Body ◽

Fragile X ◽

Intranuclear Inclusion ◽

Neuronal Intranuclear Inclusion ◽

Inclusion Body Disease ◽

Ataxia Syndrome

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Genetic and Pathological Characteristic Patterns of a Family With Neuronal Intranuclear Inclusion Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa142 ◽

2020 ◽

Vol 79 (12) ◽

pp. 1293-1302

Author(s):

Shugang Zhang ◽

Qixing Gong ◽

Di Wu ◽

Yun Tian ◽

Lu Shen ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Fragile X ◽

Cerebrovascular Diseases ◽

Pathological Examination ◽

Positive Staining ◽

Intranuclear Inclusion ◽

Cgg Repeats ◽

Genetic Features ◽

Neuronal Intranuclear Inclusion ◽

Ataxia Syndrome

Abstract Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder. This study aimed to investigate clinical, imaging, genetic, and dermatopathological characteristics of a family with adult-onset NIID. The proband was a 62-year-old woman with 3 brothers and 2 sisters. Of these, 4 had symptoms of paroxysmal visual field defect, extrapyramidal symptoms, dysautonomia, emotional changes, and cognitive dysfunction. Genetic examination revealed no abnormality related to cerebrovascular diseases. More than 200 CGG repeats of FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) whereas repeats of the proband were found 29 times, which excluded FXTAS. Quantitative reverse transcription polymerase chain reaction (PCR) and GC-rich-PCR identified an expanded GGC repeat (with ∼100 repeats) in the 5′ region of NOTCH2NLC in the patient and her 2 younger brothers. Pathological examination found eosinophilic intranuclear inclusions inside adipocytes, fibrocytes, and sweat gland cells. Immunohistochemistry and immunofluorescence staining revealed positive staining for ubiquitin and p62. The detailed pathological and genetic features of this NIID family provide a valuable contribution to the existing knowledge base of this rare disorder.

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