scholarly journals Long-read sequencing identifies GGC repeat expansion in human-specific NOTCH2NLC associated with neuronal intranuclear inclusion disease

2019 ◽  
Author(s):  
Jun Sone ◽  
Satomi Mitsuhashi ◽  
Atsushi Fujita ◽  
Takeshi Mizuguchi ◽  
Keiko Mori ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Linkage Mapping ◽  
Clinical Manifestations ◽  
Repeat Expansion ◽  
Specific Gene ◽  
Intranuclear Inclusion ◽  
Wide Range ◽  
Long Read ◽  
Neuronal Intranuclear Inclusion ◽  
Human Specific

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult 1–8, but skin biopsy realized its ante-mortem diagnosis 9,10 and many NIID cases have been diagnosed by skin biopsy11,12. Most cases of NIID are sporadic, but several familial cases are known. Using a large NIID family, we conducted linkage mapping, found a 58.1-Mb linked-region at 1p22.1-q21.3 with a maximum logarithm of odds (LOD) score of 4.21, and successfully identified a GGC repeat expansion in the 5’ portion of NOTCH2NLC in all affected members by long-read sequencing, but not in unaffected members. We further found the similar expansions in additional 8 unrelated families with NIID as well as 39 sporadic NIID patients. Repeat-primed PCR consistently detected the GGC repeat expansion in all the familial and sporadic patients diagnosed by skin biopsy, but never in unaffected family members nor 200 controls. This shows that pathogenic changes in a human-specific gene evolutionarily generated by segmental duplication indeed causes a human disease.

scholarly journals The Value of NOTCH2NLC Gene Detection and Skin Biopsy in the Diagnosis of Neuronal Intranuclear Inclusion Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Pang ◽  
Jing Yang ◽  
Yanpeng Yuan ◽  
Yuan Gao ◽  
Changhe Shi ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Clinical Manifestations ◽  
Asian Population ◽  
Diagnostic Value ◽  
Gene Detection ◽  
Intranuclear Inclusion ◽  
Mri Findings ◽  
Corticomedullary Junction ◽  
Repeat Expansions ◽  
Neuronal Intranuclear Inclusion

The clinical manifestations of neuronal intranuclear inclusion disease (NIID) are heterogeneous, and the premortem diagnosis is mainly based on skin biopsy findings. Abnormal GGC repeat expansions in NOTCH2NLC was recently identified in familial and sporadic NIID. The comparison of diagnostic value between abnormal GGC repeat expansions of NOTCH2NLC and skin biopsy has not been conducted yet. In this study, skin biopsy was performed in 10 suspected adult NIID patients with clinical and imaging manifestations, and GGC repeat size in NOTCH2NLC was also screened by repeat primed-PCR and GC-rich PCR. We found that five cases had ubiquitin-immunolabelling intranuclear inclusion bodies by skin biopsy, and all of them were identified with abnormal GGC repeat expansions in NOTCH2NLC, among whom four patients showed typical linear hyperintensity at corticomedullary junction on DWI. Five (5/10) NIID patients were diagnosed by combination of NOTCH2NLC gene detection, skin biopsy or combination of NOTCH2NLC, and typical MRI findings. The diagnostic performance of NOTCH2NLC gene detection was highly consistent with that of skin biopsy (Kappa = 1). The unexplained headache was firstly reported as a new early phenotype of NIID. These findings indicate that NOTCH2NLC gene detection is needed to be a supplement in the diagnose flow of NIID and also may be used as an alternative method to skin biopsy especially in Asian population.

scholarly journals NOTCH2NLC CGG Repeats Are Not Expanded and Skin Biopsy Was Negative in an Infantile Patient With Neuronal Intranuclear Inclusion Disease

2020 ◽  
Vol 79 (10) ◽  
pp. 1065-1071
Author(s):  
Ivana Jedlickova ◽  
Anna Pristoupilova ◽  
Helena Hulkova ◽  
Alena Vrbacka ◽  
Viktor Stranecky ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Neurodegenerative Disorder ◽  
Brain Mri ◽  
Cerebellar Atrophy ◽  
Intranuclear Inclusion ◽  
Negative Results ◽  
Developmental Regression ◽  
Cgg Repeats ◽  
Long Read ◽  
Neuronal Intranuclear Inclusion

Abstract Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disorder categorized into 3 phenotypic variants: infantile, juvenile, and adult. Four recent reports have linked NIID to CGG expansions in the NOTCH2NLC gene in adult NIID (aNIID) and several juvenile patients. Infantile NIID (iNIID) is an extremely rare neuropediatric condition. We present a 7-year-old male patient with severe progressive neurodegenerative disease that included cerebellar symptoms with cerebellar atrophy on brain MRI, psychomotor developmental regression, pseudobulbar syndrome, and polyneuropathy. The diagnosis of iNIID was established through a postmortem neuropathology work-up. We performed long-read sequencing of the critical NOTCH2NLC repeat motif and found no expansion in the patient. We also re-evaluated an antemortem skin biopsy that was collected when the patient was 2 years and 8 months old and did not identify the intranuclear inclusions. In our report, we highlight that the 2 methods (skin biopsy and CGG expansion testing in NOTCH2NLC) used to identify aNIID patients may provide negative results in iNIID patients.

scholarly journals Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Atsuhiko Sugiyama ◽  
Takahiro Takeda ◽  
Mizuho Koide ◽  
Hajime Yokota ◽  
Hiroki Mukai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Repeat Expansion ◽  
Cerebellar Hemisphere ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Lateral Sclerosis

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. Case presentation A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. Conclusions We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

Heterozygous GGC repeat expansion of NOTCH2NLC in a patient with neuronal intranuclear inclusion disease and progressive retinal dystrophy

2020 ◽  
Vol 41 (1) ◽  
pp. 93-95 ◽  
Author(s):  
Takaaki Hayashi ◽  
Satoshi Katagiri ◽  
Kei Mizobuchi ◽  
Kazutoshi Yoshitake ◽  
Shuhei Kameya ◽  
...  
Keyword(s):  
Retinal Dystrophy ◽  
Repeat Expansion ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion

Neuronal intranuclear inclusion disease cases with leukoencephalopathy diagnosed via skin biopsy

2013 ◽  
Vol 85 (3) ◽  
pp. 354-356 ◽  
Author(s):  
J. Sone ◽  
N. Kitagawa ◽  
E. Sugawara ◽  
M. Iguchi ◽  
R. Nakamura ◽  
...  
Keyword(s):  
Skin Biopsy ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

2019 ◽  
Vol 51 (8) ◽  
pp. 1215-1221 ◽  
Author(s):  
Jun Sone ◽  
Satomi Mitsuhashi ◽  
Atsushi Fujita ◽  
Takeshi Mizuguchi ◽  
Kohei Hamanaka ◽  
...  
Keyword(s):  
Intranuclear Inclusion ◽  
Long Read ◽  
Repeat Expansions ◽  
Neuronal Intranuclear Inclusion

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

2019 ◽  
Vol 56 (11) ◽  
pp. 758-764 ◽  
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.

scholarly journals Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 222-233 ◽  
Author(s):  
Qi-Ying Sun ◽  
Qian Xu ◽  
Yun Tian ◽  
Zheng-Mao Hu ◽  
Li-Xia Qin ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Essential Tremor ◽  
Repeat Expansion ◽  
Chain Reaction ◽  
Comprehensive Strategy ◽  
Whole Exome ◽  
High Prevalence ◽  
Long Read ◽  
Polymerase Chain ◽  
Human Specific

Abstract Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5′ region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5′ region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.

scholarly journals Neuronal intranuclear inclusion disease with mental abnormality: a case report

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaosa Chi ◽  
Man Li ◽  
Ting Huang ◽  
Kangyong Tong ◽  
Hongyi Xing ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Clinical Work ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Corticomedullary Junction ◽  
Normal White Blood Cell ◽  
Neuronal Intranuclear Inclusion ◽  
The Brain

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a chronic progressive neurodegenerative disease that is characterized by the discovery of eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous systems and visceral organs. In this paper, we report a case of an adult-onset neuronal intranuclear inclusion disease presenting with mental abnormality in China. Case presentation A 62-year-old woman presented with mental abnormality and forgetfulness for 3 months before she was admitted to our hospital. There were prodromal symptoms of fever before she had the mental disorder. Encephalitis was first suspected, and the patient underwent lumbar puncture and brain magnetic resonance imaging (MRI). A cerebrospinal fluid (CSF) examination indicated normal pressure, a normal white blood cell count, and slightly elevated protein and glucose levels. Coxsackie B virus, enterovirus, and cytomegalovirus tests showed normal results. Bacterial culture and Cryptococcus neoformans test results were negative. The contrast-enhanced MRI of the brain was normal. The brain diffusion-weighted imaging (DWI) showed a symmetrically distributed strip-shaped hyperintensity signal of the corticomedullary junction in the bilateral frontal, parietal, and temporal lobes. We considered the diagnosis of the NIID, and therefore, skin biopsy was performed. The electron microscopy revealed that intranuclear inclusions in the nucleus of fibrocytes existed and were composed of filaments. Conclusions NIID is a rare neurodegenerative disease with diverse clinical manifestations. In clinical work, when a patient presents with abnormal mental behavior and exhibits hyperintensity signals on DWI images of the corticomedullary junction, it is crucial to consider the diagnosis of NIID.

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