Assessing the <i>NOTCH2NLC</i> GGC expansion in European patients with essential tremor

Liao, Calwing; Akçimen, Fulya; Díez-Fairén, Mónica; Houle, Gabrielle; Ross, Jay P.; Schmilovich, Zoe; Spiegelman, Dan; Vuokila, Veikko; Catoire, Hélène; Meijer, Inge A.; Pástor, Pau; Rajput, Alex; Rouleau, Guy A.

doi:10.1093/brain/awaa291

Cited by 12 publications

(7 citation statements)

References 9 publications

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“…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%

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: 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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“…An almost pathognomonic magnetic resonance imaging (MRI) marker of NIID is represented by a curvilinear hyperintensity at the corticomedullary junction at diffusion weighted imaging (DWI) sequences. However, its sensitivity is limited 2 .By employing long-read sequencing (LRS), repeat-primed polymerase chain reaction (RP-PCR) and GC-rich PCR, the screening of NOTCH2NLC GGC repeat expansions has been rapidly extended to a variety of neurological disorders, including oculopharyngodistal myopathy (OPDM) 9,10 , Parkinson's disease (PD) [11][12][13][14][15][16] , essential tremor (ET) 14,[17][18][19][20][21][22] , multiple system atrophy (MSA) 14,23,24 , spinocerebellar ataxia (SCA) 5,14 , dementia [i.e., Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia (VaD)] 5,25,26 , hereditary spastic paraplegia (HSP) 27 , peripheral neuropathy 5,28-30 , adult leukoencephalopathy [31][32][33][34] , and specifically cerebral small vessel disease 35 . However, the results of these studies have been spurious, so that the pathogenic role of NOTCH2NLC in neurological disorders beyond NIID is still debated.…”

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confidence: 99%

NOTCH2NLC GGC repeats are not expanded in Italian amyotrophic lateral sclerosis patients

Manini

Gagliardi

Meneri

et al. 2023

Sci Rep

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Repeat expansions in genes other than C9orf72 and ATXN2 have been recently associated with Amyotrophic Lateral Sclerosis (ALS). Indeed, an abnormal number of GGC repeats in NOTCH2NLC has been recently reported in 0.7% of sporadic ALS patients from mainland China. This finding was not confirmed in an ALS cohort of subjects from Taiwan. As the involvement of expanded NOTCH2NLC alleles in ALS is debated, we addressed this point by evaluating NOTCH2NLC repeat expansions in an Italian cohort of ALS patients. A screening analysis of NOTCH2NLC GGC repeats was performed by repeat-primed polymerase chain reaction (RP-PCR) in a cohort of 385 probable/definite ALS Italian patients. Mean age at onset was 60.5 years (SD 13.7), and 60.9% were males. Sporadic cases were 357 (92.7%), and most patients had a spinal onset (71.8%). None of our patients showed the typical sawtooth tail pattern on RP-PCR, thus excluding abnormal repeat expansion in NOTCH2NLC. Overall, we suggest that NOTCH2NLC expanded alleles might be absent or at least extremely rare in ALS Italian patients. Further investigations in larger cohorts with different ethnic backgrounds are required to support the involvement of NOTCH2NLC in ALS.

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“…To date, most studies regarding NOTCH2NLC GGC repeat expansion came from the Japanese and Chinese populations [7][8][9]22 but rarely identified in European individuals. 21,23,24 Our study had several limitations. We acknowledged that intranuclear inclusion detected in cutaneous blood vessel is not sufficient to support the causality between NOTCH2NLC mutation and cSVD.…”

Section: Discussionmentioning

confidence: 95%

“…To date, most studies regarding NOTCH2NLC GGC repeat expansion came from the Japanese and Chinese populations 7–9,22 but rarely identified in European individuals. 21,23,24…”

Section: Discussionmentioning

confidence: 99%

NOTCH2NLC GGC Repeat Expansion in Patients With Vascular Leukoencephalopathy

Liao

Wei

Chang

et al. 2023

Stroke

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BACKGROUND: Neuronal intranuclear inclusion disease (NIID), caused by GGC (guanine-guanine-cytosine) repeat expansion in NOTCH2NLC , has several clinical and radiological features akin to cerebral small vessel disease (cSVD). The present study tested the hypothesis that NOTCH2NLC GGC expansion may contribute to cSVD. METHODS: One hundred and ninety-seven unrelated patients with genetically unsolved vascular leukoencephalopathy without NOTCH3 , HTRA1 , and mitochondrial m.3243A>G mutations and 730 healthy individuals were screened for NOTCH2NLC GGC repeat expansion using repeat-primed polymerase chain reaction, fragment analysis, Southern blot analysis, or nanopore sequencing with Cas9 (CRISPR associated protein 9)-mediated enrichment. The clinical and neuroimaging features of the patients were compared between individuals with and without NOTCH2NLC GGC repeat expansion. RESULTS: Six of the 197 (3.0%) patients with unsolved vascular leukoencephalopathy and none of the controls carried the GGC repeat expansion ( P =0.00009). Skin biopsy of 1 patient revealed eosinophilic, ubiquitin-positive, and p62-positive intranuclear inclusions in the cells of sweat gland and capillary, providing pathologic evidence for the involvement of small vessels in NIID. For the 6 patients, gait disturbance and cognitive decline were common manifestations with a median onset age of 65 (59–69) years. They all had multiple neuroimaging features suggestive of cSVD, including diffuse white matter hyperintensities, lacunes, and enlarged perivascular space in all 6 patients, cerebral microbleeds in 5, and old intracerebral hemorrhage in 4. Four patients had linear hyperintensity in the corticomedullary junction on diffusion-weighted imaging—the characteristic neuroimaging feature of NIID. There was no difference in the severity of cSVD imaging features between the patients with and without the GGC expansion but more pronounced brain atrophy in the patients with the GGC expansion. CONCLUSIONS: NOTCH2NLC GGC repeat expansion accounted for 3% of genetically unsolved Taiwanese vascular leukoencephalopathy cases after excluding participants with cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). NIID should be considered in patients manifesting cSVD, especially in those with characteristic neuroimaging feature of NIID.

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Assessing the NOTCH2NLC GGC expansion in European patients with essential tremor

Cited by 12 publications

References 9 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 GGC repeats are not expanded in Italian amyotrophic lateral sclerosis patients

NOTCH2NLC GGC Repeat Expansion in Patients With Vascular Leukoencephalopathy

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