The Phenotypes and Mechanisms of NOTCH2NLC-Related GGC Repeat Expansion Disorders: a Comprehensive Review

Huang, XiuRong; Tang, Beisha; Jin, Peng; Guo, Jifeng

doi:10.1007/s12035-021-02616-2

Cited by 29 publications

(36 citation statements)

References 48 publications

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“…In the period when autopsy pathology was the main diagnostic method, our understanding for the NIID was mainly limited to the nervous system ( Cao et al, 2021 ; Fan et al, 2022 ; Huang et al, 2022 ). However, with the discovery of the NIID causative gene, the understanding about the disease was already beyond the scope of the previous cognition ( Deng et al, 2019 ; Ishiura et al, 2019 ; Sone et al, 2019 ; Tian et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

Zhou

Huang²,

Huang³

et al. 2022

Front. Aging Neurosci.

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ObjectiveThe diagnosis of neuronal intranuclear inclusion disease (NIID) is currently based on CGG repeat expansion in the 5′UTR of the NOTCH2NLC gene, or p62-positive intranuclear inclusions in skin biopsy. The purpose of this study is to explore the value of non-invasive pathological findings in urine sediment cells from NIID patients.Materials and methodsTen patients with clinically suspected NIID were enrolled for skin biopsy and gene screening. Morning urine (500 ml) was collected from each patient, and cell sediment was obtained by centrifugation. Urine cytology, including Giemsa staining, p62 immunostaining, and electron microscopic examination, were conducted on cell sediment.ResultsThe main clinical symptoms of 10 patients included episodic disturbance of consciousness, cognitive impairment, tremor, limb weakness, and so on. Cerebral MRI showed that 9 patients had linear DWI high signal in the corticomedullary junction. Genetic testing found that the number of CGG repeat ranged from 96 to 158 in the NOTCH2NLC gene. Skin biopsy revealed that all patients showed p62-positive intranuclear inclusions in 18.5 ± 6.3% of the duct epithelial cells of sweat gland. In contrast, urine sediment smears revealed that only 3 patients had p62 positive intranuclear inclusions in 3.5 ± 1.2% of the sedimentary cells. Ultrastructural examinations showed that intranuclear inclusions were also identified in the cell sediment of the 3 patients.ConclusionUrine cytology may be a new and non-invasive pathological diagnosis technique for some NIID patients, although the positive rate is not as high as that of skin biopsy, which is a sensitive and reliable pathological method for NIID.

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Section: Discussionmentioning

confidence: 99%

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

Zhou

Huang²,

Huang³

et al. 2022

Front. Aging Neurosci.

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“…However, some groups showed that PD-like symptoms were the early-stage symptoms of NIID ( Chen et al, 2020b ; Yang et al, 2021 ). Therefore, PD-like symptoms are the dominant phenotypes of NIID ( Huang et al, 2021 ). Patients with familial PD or essential tremors should be considered for the diagnosis of NIID or NOTCH2NLC gene-related disorders.…”

Section: Clinical Symptoms Of Neuronal Intranuclear Inclusion Diseasementioning

confidence: 99%

“…These studies showed two aspects: on the one hand, these diseases showed similar symptoms as NIID, indicating the symptom heterogenicity of NIID; on the other hand, similar to different variants of the same gene associated with distinct genetic diseases, different lengths of GGC repeat expansion in the NOTCH2NLC gene may cause different diseases with variable phenotypes, which are already reported in some studies ( Sone et al, 2019 ; Tian et al, 2019 ). However, the association between GGC repeat size and different phenotypes is inconclusive ( Huang et al, 2021 ). Therefore, to avoid confusion, NOTCH2NLC-related repeat expansion disorders were proposed to name symptom-heterogeneous diseases associated with GGC repeat expansion in the NOTCH2NLC gene ( Westenberger and Klein, 2020 ).…”

Section: Genetic and Epigenetic Progress Of Neuronal Intranuclear Inc...mentioning

confidence: 99%

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Clinical and mechanism advances of neuronal intranuclear inclusion disease

Liu

et al. 2022

Front. Aging Neurosci.

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Due to the high clinical heterogeneity of neuronal intranuclear inclusion disease (NIID), it is easy to misdiagnose this condition and is considered to be a rare progressive neurodegenerative disease. More evidence demonstrates that NIID involves not only the central nervous system but also multiple systems of the body and shows a variety of symptoms, which makes a clinical diagnosis of NIID more difficult. This review summarizes the clinical symptoms in different systems and demonstrates that NIID is a multiple-system intranuclear inclusion disease. In addition, the core triad symptoms in the central nervous system, such as dementia, parkinsonism, and psychiatric symptoms, are proposed as an important clue for the clinical diagnosis of NIID. Recent studies have demonstrated that expanded GGC repeats in the 5′-untranslated region of the NOTCH2NLC gene are the cause of NIID. The genetic advances and possible underlying mechanisms of NIID (expanded GGC repeat-induced DNA damage, RNA toxicity, and polyglycine-NOTCH2NLC protein toxicity) are briefly summarized in this review. Interestingly, inflammatory cell infiltration and inflammation were observed in the affected tissues of patients with NIID. As a downstream pathological process of NIID, inflammation could be a therapeutic target for NIID.

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“…In addition to the similar myopathic phenotype, some genotypes may manifestant multisystem symptoms. Previous studies have identified the CGG repeat expansions in NOTCH2NLC as the disease-causing gene of NIID [19 ▪▪ ,27,38,39], which were reported associated with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, essential tremor, amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases [39–52]. In 2021, Yu et al [22 ▪▪ ] extended the spectrum of NOTCH2NLC repeat expansion-related diseases to a predominant myopathy phenotype, OPDM.…”

Section: Genotype–phenotype Correlationsmentioning

confidence: 99%

Oculopharyngodistal myopathy

Deng

Wang

2022

Current Opinion in Neurology

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Purpose of reviewOculopharyngodistal myopathy (OPDM) is a rare adolescent or adult-onset neuromuscular disease that is characterized by progressive ocular, facial, pharyngeal and distal limb muscle weakness. The rimmed vacuoles and intranuclear inclusions in myofibers constitute the pathological hallmark of OPDM. In this review, the latest findings related to the genetic, molecular and clinical features of OPDM, as well as the diagnosis and management are summarized. Recent findingsFour gene mutations, CGG repeats in the 5'-untranslated region of LRP12, GIPC1, NOTCH2NLC and RILPL1 have been reported to be disease-causing genes in OPDM, namely OPDM1, OPDM2, OPDM3 and OPDM4, accordingly. So far, limited studies have suggested that CGG repeat expansion within the pathogenic range may play a key role in the pathogenesis of OPDM with the gain-of-function mechanism at the RNA and/or protein level, while repeat expansion over a threshold limit may cause hypermethylation, leading to the transcriptional silencing of the CGG repeats in the expanded allele, which results in the existence of mild phenotype or asymptomatic carriers.

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The Phenotypes and Mechanisms of NOTCH2NLC-Related GGC Repeat Expansion Disorders: a Comprehensive Review

Cited by 29 publications

References 48 publications

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

Clinical and mechanism advances of neuronal intranuclear inclusion disease

Oculopharyngodistal myopathy

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