Assessing the <i>NOTCH2NLC</i> GGC expansion in essential tremor patients from eastern China

Yan, Yaping; Cao, Lanxiao; Gu, Luyan; Zhang, Bo; Xu, Congying; Pu, Jiali; Tian, Jun; Yin, Xinzhen; Zhang, Baorong; Guo-hua, Zhao

doi:10.1093/brain/awaa348

Cited by 15 publications

(14 citation statements)

References 10 publications

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“…Tremor has also been reported in patients with NIID at a rate of approximately 15.8%-47.5% [1,5]. Recently, Sun et al [12] [13,14,16,17], the issue of the relationship between ET and NIID in patients with the NOTCH2NLC-GGC repeat expansion also emerged [13,14]. In the present study, we believe our systematic reevaluation of these tremor-dominant patients with the NOTCH2NLC-GGC repeat expansion provides a solid conclusion for this issue.…”

Section: Re Sultssupporting

confidence: 67%

“…With increased genetic screening for the NOTCH2NLC ‐GGC repeat expansion in patients with neurological disorders, positivity for this repeat expansion was found for different phenotypes and disorders, including multiple system atrophy [6], dementia [7], leukoencephalopathy [8], Parkinson’s disease [9], and amyotrophic lateral sclerosis [10], which led to the term “ NOTCH2NLC ‐related repeat expansion disorders” being proposed [11]. The most common movement disorder, essential tremor (ET), was repeatedly reported to be associated with NOTCH2NLC ‐GGC repeat expansion, with rates of 0%–6.67% [12−18]. Among these ET patients with NOTCH2NLC ‐GGC repeat expansion (20 probands from five centers) [12−14,16,17], two East Asian patients manifested the classic clinical and radiological features of NIID at 4 and 10 years after their initial diagnosis of ET [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Neuronal intranuclear inclusion disease tremor‐dominant subtype: A mimicker of essential tremor

Yang

Cen

Wang

et al. 2021

Euro J of Neurology

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Background and purpose The GGC repeat expansion in the NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). Recently, this repeat expansion was also reported to be associated with essential tremor (ET). However, some patients with this repeat expansion, initially diagnosed with ET, were eventually diagnosed with NIID. Therefore, controversy remains regarding the clinical diagnosis of these expansion‐positive patients presenting with tremor‐dominant symptoms. This study aimed to clarify the clinical phenotype in tremor‐dominant patients who have the GGC repeat expansion in the NOTCH2NLC gene. Methods We screened for pathogenic GGC repeat expansions in 602 patients initially diagnosed with ET and systematically re‐evaluated the clinical features of the expansion‐positive probands and their family members. Results Pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in 10 probands (1.66%). Seven of these probands were re‐evaluated and found to have systemic areflexia, cognitive impairment, and abnormal nerve conduction, which prompted a change of diagnosis from ET to NIID. Three of the probands had typical hyperintensity in the corticomedullary junction on diffusion‐weighted imaging. Intranuclear inclusions were detected in all four probands who underwent skin biopsy. Conclusions The NIID tremor‐dominant subtype can be easily misdiagnosed as ET. We should take NIID into account for differential diagnosis of ET. Systemic areflexia could be an important clinical clue suggesting that cranial magnetic resonance imaging examination, or even further genetic testing and skin biopsy examination, should be used to confirm the diagnosis of NIID.

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Section: Re Sultssupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Neuronal intranuclear inclusion disease tremor‐dominant subtype: A mimicker of essential tremor

Yang

Cen

Wang

et al. 2021

Euro J of Neurology

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“…This study is of great significance, as it might reveal a new candidate genetic risk factor that underly ~6% familial patients with ET 14 . NOTCH2NLC GGC repeat expansion was later screened in Chinese,22 23 Singaporean21 and European10 12 24 patients affected by ET and found to account for 0%–6.67% ET pedigrees/patients. Nevertheless, some patients with NOTCH2NLC -ET were suspected or eventually diagnosed with NIID based on their family history, symptoms, MRI, genetic evidence, and most importantly, the positive pathological staining 10 21–23…”

Section: Notch2nlc-related Disordersmentioning

confidence: 99%

“…There were no studies investigating the NOTCH2NLC intermediate-length GGC repeat expansion in any human neurological disorders until Ma et al 28 and Shi et al 31 reported that patients with PD could harbour intermediate-length GGC expansion in NOTCH2NLC . Moreover, Ng et al 21 and Yan et al 23 have previously reported patients with ET harbouring 47–53 and 41–48 GGC repeats; however, the detailed data were not provided. Put together, it is plausible that the intermediate-length NOTCH2NLC GGC repeat expansion confers a higher risk of PD and ET in the Asian population.…”

Section: Notch2nlc-related Disordersmentioning

confidence: 99%

“…Four paralogous genes ( NOTCH2NLA , NOTCH2NLB , NOTCH2NLC and NOTCH2NLR ) have been identified, all residing in chromosome 1 54. GGC repeat expansion in the 5′ UTR of NOTCH2NLC has been found to be associated with NIID,4–8 leukoencephalopathy,33 ET,20–23 MSA,27 PD,28 31 ALS53 and OPDM,40 41 most of which are neurodegenerative disorders, suggesting a contributing role of NOTCH2NLC GGC repeat expansion in neurodegeneration. Three possible disease-causing mechanisms may underly the pathogenesis of NOTCH2NLC GGC repeat expansion: loss-of-function, RNA toxicity, and RAN toxicity.…”

Section: Potential Disease-causing Mechanisms Of Expanded Ggc Repeats In Notch2nlc Genementioning

confidence: 99%

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NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation

Fan

Shi

2021

J Med Genet

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GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC is the most common causative factor in neuronal intranuclear inclusion disease (NIID) in Asians. Such expanded GGC repeats have been identified in patients with leukoencephalopathy, essential tremor (ET), multiple system atrophy, Parkinson’s disease (PD), amyotrophic lateral sclerosis and oculopharyngodistal myopathy (OPDM). Herein, we review the recently reported NOTCH2NLC-related disorders and potential disease-causing mechanisms. We found that visual abnormalities may be NOTCH2NLC-specific and should be investigated in other patients with NOTCH2NLC mutations. NOTCH2NLC GGC repeat expansion was rarely identified in patients of European ancestry, whereas the actual prevalence of the expansion in European patients may be potentially higher than reported, and the CGG repeats in LRP12/GIPC1 are suggested to be screened in European patients with NIID. The repeat size and interruptions in NOTCH2NLC GGC expansion confer pleiotropic effects on clinical phenotype, a pure and stable ET phenotype may be an early symptom of NIID, and GGC repeats in NOTCH2NLC possibly give rise to ET. An association may also exist between intermediate-length NOTCH2NLC GGC repeat expansion and patients affected by PD and ET. NOTCH2NLC-OPDM highly resembles NOTCH2NLC-NIID, the two disorders may be the variations of a single neurodegenerative disease, and there may be a disease-causing upper limit in size of GGC repeats in NOTCH2NLC, repeats over which may be non-pathogenic. The haploinsufficiency of NOTCH2NLC may not be primarily involved in NOTCH2NLC-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with NOTCH2NLC-associated disorders.

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NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders

2021

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Assessing the NOTCH2NLC GGC expansion in essential tremor patients from eastern China

Cited by 15 publications

References 10 publications

Neuronal intranuclear inclusion disease tremor‐dominant subtype: A mimicker of essential tremor

Neuronal intranuclear inclusion disease tremor‐dominant subtype: A mimicker of essential tremor

NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation

NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders

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