GGC Repeat Expansion of
            <i>NOTCH2NLC</i>
            in Taiwanese Patients With Inherited Neuropathies

Liao, Yi‐Chu; Chang, Fu; Huang, Han-Hung; Chen, Ting-Bing; Chou, Yi‐Chieh; Hsu, Sanford P.C.; Jih, Kang-Yang; Liu, Yihong; Hsiao, Cheng-Tsung; Fukukda, Hiromi; Mizuguchi, Takeshi; Lin, Kon‐Ping; Lin, Chou-Ching K.; Matsumoto, Naomichi; Kennerson, Marina; Lee, Yi‐Chung

doi:10.1212/wnl.0000000000013008

Cited by 27 publications

(35 citation statements)

References 20 publications

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“…Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterised by highly variable clinical manifestations and multiple systematic involvements 1 2. Clinical manifestations vary and include cognitive dysfunction,3 peripheral neuropathy,4 5 dyskinesia,6–8 paroxysmal symptoms9 10 and autonomic dysfunction 4. Widespread distribution of eosinophilic intranuclear inclusions has been observed in the central and peripheral nervous systems, and visceral organs 2.…”

Section: Introductionmentioning

confidence: 99%

Clinical features ofNOTCH2NLC-related neuronal intranuclear inclusion disease

Tian

Zhou

Gao

et al. 2022

J Neurol Neurosurg Psychiatry

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BackgroundAbnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China.MethodsPatients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.ResultsIn the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=−0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.ConclusionsNIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

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Section: Introductionmentioning

confidence: 99%

Clinical features ofNOTCH2NLC-related neuronal intranuclear inclusion disease

Tian

Zhou

Gao

et al. 2022

J Neurol Neurosurg Psychiatry

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“…Second, all patients in this cohort showed varying degrees of peripheral neuropathy. Some patients had no clinical symptoms of peripheral neuropathy, but electrophysiological studies exhibited that there were length-dependent sensorimotor demyelinating neuropathy, mainly characterized by mild NCV reduction and latency delay ( Liao et al, 2022 ). Demyelinating impairment in these patients was more extensive and severe than axonal impairment, which might partly explain the absence of obvious neuropathy symptoms in some NIID cases.…”

Section: Discussionmentioning

confidence: 99%

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

Zhou

Huang²,

Huang³

et al. 2022

Front. Aging Neurosci.

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ObjectiveThe diagnosis of neuronal intranuclear inclusion disease (NIID) is currently based on CGG repeat expansion in the 5′UTR of the NOTCH2NLC gene, or p62-positive intranuclear inclusions in skin biopsy. The purpose of this study is to explore the value of non-invasive pathological findings in urine sediment cells from NIID patients.Materials and methodsTen patients with clinically suspected NIID were enrolled for skin biopsy and gene screening. Morning urine (500 ml) was collected from each patient, and cell sediment was obtained by centrifugation. Urine cytology, including Giemsa staining, p62 immunostaining, and electron microscopic examination, were conducted on cell sediment.ResultsThe main clinical symptoms of 10 patients included episodic disturbance of consciousness, cognitive impairment, tremor, limb weakness, and so on. Cerebral MRI showed that 9 patients had linear DWI high signal in the corticomedullary junction. Genetic testing found that the number of CGG repeat ranged from 96 to 158 in the NOTCH2NLC gene. Skin biopsy revealed that all patients showed p62-positive intranuclear inclusions in 18.5 ± 6.3% of the duct epithelial cells of sweat gland. In contrast, urine sediment smears revealed that only 3 patients had p62 positive intranuclear inclusions in 3.5 ± 1.2% of the sedimentary cells. Ultrastructural examinations showed that intranuclear inclusions were also identified in the cell sediment of the 3 patients.ConclusionUrine cytology may be a new and non-invasive pathological diagnosis technique for some NIID patients, although the positive rate is not as high as that of skin biopsy, which is a sensitive and reliable pathological method for NIID.

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“…To date, studies that screened for the NOTCH2NLC GGC repeat expansion in clinically diagnosed PD patients have only identified five patients with the pathogenic repeat expansion and 19 patients with the intermediate repeat expansion (Table 1) [10,11]. Questions have arisen about the role of the NOTCH2NLC GGC repeat expansion in not only PD but also other diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, essential tremor, multiple system atrophy, Charcot−Marie−Tooth disease, and oculopharyngodistal myopathy [4–9]. Further studies are required to reveal specific phenotypes, which include clinical, neuroimaging, and pathological characteristics of patients with the NOTCH2NLC GGC repeat expansion.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, GGC repeat expansion in the NOTCH2NLC gene has been identified as the genetic cause of NIID [1]. Because of its heterogeneous clinical spectrum, the GGC repeat expansion in the NOTCH2NLC gene has been reported in cohorts of clinically diagnosed Alzheimer's disease, amyotrophic lateral sclerosis, essential tremor, multiple system atrophy, Charcot−Marie−Tooth disease, and oculopharyngodistal myopathy [4][5][6][7][8][9]. Parkinsonism could be present as a common motor symptom, paralleled with other main clinical features, in both pathologically and genetically diagnosed NIID patients [2].…”

Section: Introductionmentioning

confidence: 99%

The role of NOTCH2NLC in Parkinson's disease: A clinical, neuroimaging, and pathological study

Liu

Yang

Zhang

et al. 2022

Euro J of Neurology

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Background and purpose Recently, the pathogenic and intermediate GGC repeat expansion in NOTCH2NLC was detected in Parkinson's disease (PD). However, detailed clinical, neuroimaging, and pathological information of clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC remains scarce. Thus, we aimed to elucidate the clinical, neuroimaging, and pathological characteristics of PD patients carrying the pathogenic GGC repeat expansion in NOTCH2NLC. Methods The NOTCH2NLC GGC repeat expansion was screened in 941 sporadic PD patients and 244 unrelated probands. Comprehensive assessments were performed in three PD patients with pathogenic GGC repeat expansion in NOTCH2NLC. The repeat expansion length was estimated using CRISPR/Cas9‐based targeted long‐read sequencing. Results The three patients (two PD patients from Family 1 and one sporadic PD) carrying the pathogenic NOTCH2NLC expansion were reconfirmed with a diagnosis of clinically established PD. Although they lacked the typical neuronal intranuclear inclusion disease (NIID) magnetic resonance imaging (MRI) feature, the typical PD pattern of striatal dopamine transporter loss was detected. Notably, all three patients presented with systemic areflexia, and other secondary causes of polyneuropathy were excluded. Skin biopsy showed intranuclear inclusions and an absence of phosphorylated alpha‐synuclein deposition in the skin nerve fibers of all three patients. Conclusions Although these clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC were hardly distinguishable from idiopathic PD based on clinical course and neuroimaging features, the pathological findings indicated that their phenotype was a PD phenocopy of NIID. Systemic areflexia may be an important and unique clinical clue suggesting further genetic testing and skin biopsy examination to confirm the diagnosis of NIID in patients presenting with a PD phenocopy.

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GGC Repeat Expansion of NOTCH2NLC in Taiwanese Patients With Inherited Neuropathies

Cited by 27 publications

References 20 publications

Clinical features ofNOTCH2NLC-related neuronal intranuclear inclusion disease

Clinical features ofNOTCH2NLC-related neuronal intranuclear inclusion disease

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

The role of NOTCH2NLC in Parkinson's disease: A clinical, neuroimaging, and pathological study

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