GGC Repeat Expansion of <i>NOTCH2NLC</i> in Adult Patients with Leukoencephalopathy

Okubo, Masaki; Doi, Hiroshi; Fukai, Ryoko; Fujita, Atsushi; Mitsuhashi, Satomi; Hashiguchi, Shunta; Kishida, Hitaru; Ueda, Naohisa; Morihara, Keisuke; Ogasawara, Akihiro; Kawamoto, Yuko; Takahashi, Tatsuya; Takahashi, Keita; Nakamura, Hajime; Kunii, Misako; Tada, Mikiko; Katsumoto, Atsuko; Fukuda, Hiromi; Mizuguchi, Takeshi; Miyatake, Satoko; Miyake, Noriko; Suzuki, Junichiro; Ito, Yasuhiro; Sone, Jun; Sobue, Gen; Takeuchi, Hideyuki; Matsumoto, Naomichi; Tanaka, Fumiaki

doi:10.1002/ana.25586

Cited by 101 publications

(103 citation statements)

References 11 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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“…Recent studies revealed a broadened clinical spectrum of adult‐onset NIID. GGC repeat expansion was not only identified in typical adult‐ or juvenile‐onset NIID patients 4 but also observed in Alzheimer disease (AD), 3 Parkinson disease (PD), 3 adult leukoencephalopathy, 25 and essential tremor (ET), 26 implicating that GGC repeat expansions in the NOTCH2NLC gene could partly contribute to the pathological process of multiple neurodegenerative diseases, including MSA, AD, PD, ET, and leukoencephalopathy. Therefore, we also agree to define a term NIID‐related disorders (NIIDRD), 3 which include NIID and other related neurodegenerative diseases caused by the GGC repeat expansion, although it might be a misdiagnosis in nature.…”

Section: Discussionmentioning

confidence: 99%

Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy

Yao

et al. 2020

Ann Clin Transl Neurol

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Objective: Trinucleotide GGC repeat expansion in the 5'UTR of the NOTCH2NLC gene has been recognized as the pathogenesis of neuronal intranuclear inclusion disease (NIID). Previous studies have described that some NIID patients showed clinical and pathological similarities with multiple system atrophy (MSA). This study aimed to address the possibility that GGC repeat expansion in NOTCH2NLC might be associated with some cases diagnosed as MSA. Methods: A total of 189 patients with probable or possible MSA were recruited to screen for GGC repeat expansion in NOTCH2NLC by repeatprimed PCR (RP-PCR). In addition, long-read sequencing (LRS) was performed for all patients with RP-PCR-positive expansion, five patients with RP-PCR-negative expansion, and five controls on the Nanopore platform. Skin biopsies were performed on two patients with GGC expansion. Results: Five of 189 patients (2.6%) were found to have GGC expansion in NOTCH2NLC. LRS results identified that the five patients had GGC expansion between 101 and 266, but five patients with RP-PCR-negative expansion and five controls had GGC expansion between 8 and 29. Besides the typical symptoms and signs of MSA, patients with GGC expansion might have longer disease duration, severe urinary retention, and prominent cognitive impairment. In the skin samples from the patients with GGC expansion, typical p62-postive but alpha-synuclein-negative intranuclear inclusions were found in fibroblasts, adipocyte and ductal epithelial cells of sweat glands. Conclusion: Trinucleotide GGC repeat expansion in NOTCH2NLC could be observed in patients with clinically diagnosed MSA. Adult-onset NIID should be considered as a differential diagnosis of MSA.

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“…Satoko Miyatake, MD, PhD, 2 Noriko Miyake, MD, PhD, 2 Jun Sone, MD, PhD, 3,4 Gen Sobue, MD, PhD , 4,5,6 Hideyuki Takeuchi, MD, PhD, 1 Naomichi Matsumoto, MD, PhD, 2 and Fumiaki Tanaka, MD, PhD 1 We appreciate the interest shown by Dr Yau and colleagues in our recent publication. 1 We read their letter with great interest, which explains that neuronal intranuclear inclusion disease (NIID) is rare in European leukoencephalopathy, in striking contrast to our results in Japanese leukoencephalopathy.…”

Section: Author Contributionsmentioning

confidence: 95%

“…We read with interest that Okubo et al identified GGC repeat expansion in NOTCH2NLC as the most frequent genetic cause of adult onset leukoencephalopathy in Japan. 1 After the initial discovery of the causative mutation for neuronal intranuclear inclusion disease (NIID), 2,3 all additional reported NIID patients with this mutation are East Asians. Adult onset genetic leukodystrophy is clinically and radiologically heterogeneous, making definitive diagnosis challenging.…”

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confidence: 99%