<scp><i>NOTCH2NLC</i></scp> Intermediate‐Length Repeat Expansion and Parkinson's Disease in Patients of European Descent

Yau, Wai Yan; Sullivan, Roisin; Rocca, Clarissa; Calì, Elisa; Vandrovcová, Jana; Wood, Nicholas W.; Houlden, Henry

doi:10.1002/ana.26003

Cited by 8 publications

(8 citation statements)

References 4 publications

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“…Only six other works have performed NOTCH2NLC screening in patients of European descent, and specifically 2 in PD, 2 in ET, 1 in combined movement disorders, and 1 in adult leukoencephalopathy 11,14,15,19,33 . Out of a total of 38,820 European patients, only 2 were found to carry pathogenic NOTCH2NLC GGC repeat expansions (frequency 6.0 × 10 -5 ).…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

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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“…In Reply We appreciate the interest shown by Yau and colleagues for our recent article . They have previously highlighted an absence of abnormal NOTCH2NLC GGC repeat expansions in a sample of White patients with PD …”

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confidence: 81%

Questions on NOTCH2NLC Repeat Expansions in Parkinson Disease—Reply

Tan

2021

JAMA Neurol

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“…Taken together, evidence suggests that the intermediate-length GGC repeat expansion in NOTCH2NLC and a low frequency of GGA interruptions may be associated with PD instead of the parkinsonism-dominant NIID. Yau and co-workers identified no expansion carrier in European PD cohort,10 13 highlighting further the rareness of NOTCH2NLC GGC repeat expansion in the European population.…”

Section: Notch2nlc-related Disordersmentioning

confidence: 94%

“…So far, the only two European patients with NIID (diagnosed with the European NIID criteria proposed by Chen and co-workers9) harbouring NOTCH2NLC GGC repeat expansion were identified both in the Ukrainian population using in silico screening of whole-genome sequencing data in a large population cohort (50 544 patients in total),9 10 suggesting distinct genetic architecture of Asian and European patients with NIID. In addition, NOTCH2NLC GGC repeat expansion was found extremely rare in European patients with leukoencephalopathy,11 essential tremor (ET),12 Parkinson’s disease (PD),13 spinocerebellar ataxia10 and multiple system atrophy (MSA),10 suggesting the geographical heterogenicity of NOTCH2NLC GGC repeat expansion. The variable frequency of NOTCH2NLC GGC repeat expansion worldwide is similar to the GGGGCC repeat expansion in C9ORF72 .…”

Section: Notch2nlc-related Disordersmentioning

confidence: 99%

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 Intermediate‐Length Repeat Expansion and Parkinson's Disease in Patients of European Descent

Cited by 8 publications

References 4 publications

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

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

Questions on NOTCH2NLC Repeat Expansions in Parkinson Disease—Reply

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

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