Identification of expanded repeats in NOTCH2NLC in neurodegenerative dementias

Jiao, Bin; Zhou, Lu; Zhou, Yifei; Weng, Ling; Liao, Xinxin; Tian, Yun; Guo, Lijia; Liu, Xixi; Yuan, Zhenhua; Xiao, Xuewen; Jiang, Yaling; Wang, Xin; Yang, Qingda; Li, Chenping; Zhu, Yuan; Zhou, Lin; Zhang, Weiwei; Wang, Junling; Liu, Yu; Gu, Wenping; Yang, Jie; Xia, Jianghai; Huang, Qing; Yin, Jun; Xue, Jun; Duan, Ranhui; Tang, Beisha; Shen, Lu

doi:10.1016/j.neurobiolaging.2020.01.010

Cited by 67 publications

(43 citation statements)

References 38 publications

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“…Our study also demonstrates that inclusion criteria based on the characteristic MRI features of NIID strongly predicts the presence of NOTCH2NLC GGC repeat expansions. This compares favorably to the weak correlation of other clinical features with NOTCH2NLC GGC repeat expansion; Jiao et al and Okubo et al demonstrated NOTCH2NLC GGC repeat expansions in 0.4% and 11.9% of patients with patients with neurodegenerative dementia and leukoencephalopathy, respectively 23,24 …”

Section: Discussionmentioning

confidence: 79%

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort

Chen

Cheng

et al. 2020

Clinical Genetics

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Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5′‐untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long‐read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92‐138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26‐380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID.

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Section: Discussionmentioning

confidence: 79%

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort

Chen

Cheng

et al. 2020

Clinical Genetics

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“…Subsequently, various diseases have been associated with CGG repeat expansions in NOTCH2NLC , including multiple system atrophy (MSA), leukoencephalopathy, Alzheimer’s disease and frontotemporal dementia (AD/FTD), tremor, and retinal dystrophy, suggesting that the spectrum of NOTCH2NLC diseases is, in fact, wide (Fig. 2 s) [ 4 , 5 , 7 , 10 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations

Ogasawara

Iida²,

Kumutpongpanich

et al. 2020

acta neuropathol commun

128

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Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC. We aimed to identify and to clinicopathologically characterize patients with OPDM who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Note that 211 patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of identified patients with OPDM_NOTCH2NLC were re-reviewed. Intra-myonuclear inclusions were evaluated using immunohistochemistry and electron microscopy (EM). Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically demonstrated ptosis, ophthalmoplegia, dysarthria and muscle weakness; they myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which were diagnostic of NIID (typically on skin biopsy), in addition to rimmed vacuoles. The sample for EM was available only from one patient, which demonstrated intranuclear inclusions of 12.6 ± 1.6 nm in diameter. We identified seven patients with OPDM_NOTCH2NLC. Our patients had various additional central and/or peripheral nervous system involvement, although all were clinicopathologically compatible; thus, they were diagnosed as having OPDM and expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

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“…54 In two parallel studies, genome-wide linkage analysis first identified overlapping intervals on chromosomes 1p22.1-q21.3 and 1p13.3-23.1 and the same expansion in NOTCH2NLC was revealed by long-read sequencing. 55,56 Screening of this expansion in additional neurological disorders led to expand associated phenotypes to essential tremor (ETM6 [MIM: 618866]), 108,109 FTD and Azheimer-like dementias, 110 and multiple system atrophy. 111 Many families with NOTCH2NLC expansions are from Japan and China, suggesting a founder effect in these populations.…”

Section: Neuronal Intranuclear Inclusion Disease (Niid)mentioning

confidence: 99%

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

Depienne

Mandel

2021

The American Journal of Human Genetics

259

208

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Identification of expanded repeats in NOTCH2NLC in neurodegenerative dementias

Cited by 67 publications

References 38 publications

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort

Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort

CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations

30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?

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