Essential tremor as the early symptom of NOTCH2NLC gene-related repeat expansion disorder

Chen, Hao; Lu, Likui; Wang, Bin; Hua, Xiaodong; Wan, Bo; Sun, Miao; Xu, Xingshun

doi:10.1093/brain/awaa142

Cited by 28 publications

(25 citation statements)

References 13 publications

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“…Skin biopsy was regarded a useful diagnostic tool for NIID and the deposits of intranuclear inclusion in skin was a diagnostic hallmark for NIID 2 . However, our cases and other reports also showed that the presence of intranuclear inclusion in skin was later than that in other systems such as kidney and bladder or the occurrence of neurological symptoms 10,13,14 ; indicating that positive skin involvement is not necessary for the early diagnosis of NIID. In our study, some symptoms of other systems preceded the symptoms of nervous system.…”

Section: Discussionmentioning

confidence: 43%

Re‐defining the clinicopathological spectrum of neuronal intranuclear inclusion disease

Chen¹,

Wang

et al. 2020

Ann Clin Transl Neurol

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Background: The rapidly increasing case reports revealed that neuronal intranuclear inclusion disease (NIID) had concomitant other system symptoms besides nervous system symptoms. In this study, we systematically evaluated the symptoms, signs, auxiliary examination, and pathological changes in different systems in NIID patients. Methods: NIID patients were confirmed by examining GGC repeats in the NOTCH2NLC gene. Clinical data of NIID patients including symptoms, signs, and auxiliary examinations were collected for analysis. Ubiquitin and p62 were detected in different tissues from previous surgical samples. Results: Fifty-one NIID patients from 17 families were included in this study. Except neurological symptoms, clinical manifestations from other systems were very notable and diverse. The proportions of different system symptoms were 88.2% in nervous system, 78.4% in respiratory system, 72.5% in circulatory system, 72.5% in locomotor system, 66.7% in urinary system, 64.7% in digestive system, 61.5% in reproductive system, and 50.0% in endocrine system. In addition, other common symptoms included sexual dysfunction (43.1%), pupil constriction (56.9%), blurred vision (51.0%), and hearing loss (23.5%). Ubiquitin and p62-positive cells were found in different tissues and systems in 24 NIID patients with previous surgery. Initial symptoms of NIID and median onset age in different systems also revealed system heterogeneity of NIID. Interpretation: For the first time, we systematically demonstrated that NIID is a heterogeneous and systemic neurodegenerative disease by providing clinical and pathological evidence. In addition to the nervous system, the clinical symptomatic and pathological spectrum of NIID has been extended to almost all systems.

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Section: Discussionmentioning

confidence: 43%

Re‐defining the clinicopathological spectrum of neuronal intranuclear inclusion disease

Chen¹,

Wang

et al. 2020

Ann Clin Transl Neurol

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“…A limitation of our study was our inability to obtain a skin sample and MRI head images of patient B, which may provide pathological and radiological evidence to support the diagnosis of NIID. Recent studies described 3 East Asian ET patients carrying this repeat expansion and intranuclear inclusions in skin biopsy: 2 of them manifested classical clinical and radiological features of NIID 10 years after initial tremor onset, but 1 patient continued to display pure ET phenotype after 4 decades of follow‐up 18,19 . These studies illustrate the variable clinical expressivity of NIID, which may be caused by genetic factors such as GGC‐repeat length, interruptions in the repeat tracts, or other unknown modifiers.…”

Section: Discussionmentioning

confidence: 87%

“…Recent studies described 3 East Asian ET patients carrying this repeat expansion and intranuclear inclusions in skin biopsy: 2 of them manifested classical clinical and radiological features of NIID 10 years after initial tremor onset, but 1 patient continued to display pure ET phenotype after 4 decades of follow-up. 18,19 These studies illustrate the variable clinical expressivity of NIID, which may be caused by genetic factors such as GGC-repeat length, interruptions in the repeat tracts, or other unknown modifiers. Thereby, it is plausible that our patient displayed an ET phenocopy of NIID.…”

Section: Discussionmentioning

confidence: 94%

Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders

et al. 2020

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Background The objective of this study was to determine the prevalence of the GGC‐repeat expansion in NOTCH2NLC in whites presenting with movement disorders. Methods We searched for the GGC‐repeat expansion in NOTCH2NLC using repeat‐primed polymerase chain reaction in 203 patients with essential tremor, 825 patients with PD, 194 patients with spinocerebellar ataxia, 207 patients with “possible” or “probable” MSA, and 336 patients with pathologically confirmed MSA. We also screened 30,008 patients enrolled in the 100,000 Genomes Project for the same mutation using ExpansionHunter, followed by repeat‐primed polymerase chain reaction. All possible expansions were confirmed by Southern blotting and/or long‐read sequencing. Results We identified 1 patient who carried the NOTCH2NLC mutation in the essential tremor cohort, and 1 patient presenting with recurrent encephalopathy and postural tremor/parkinsonism in the 100,000 Genomes Project. Conclusions GGC‐repeat expansion in NOTCH2NLC is rare in whites presenting with movement disorders. In addition, existing whole‐genome sequencing data are useful in case ascertainment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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“…Moreover, studies of families with these mutations illustrate the important fact that ET is frequently not a stable phenotype. ET can be the initial phenotype of neuronal intranuclear inclusion disease (GGC repeat expansion in the NOTCH2NLC gene) ( 40 ) but may evolve into a more complex syndrome with dementia, parkinsonism, ataxia, convulsions, neuropathy, or autonomic dysfunction ( 41 ) ( Figure 1 ). ET may exist for years before a patient with the HTRA2 p.G399S allele develops Parkinsonism ( 38 ).…”

Section: Etiologies Of the Essential Tremor Syndromementioning

confidence: 99%

“…This flow diagram illustrates how Axis 1 and 2 classifications may change over time. This clinical scenario is based on the work of Chen et al(40). A 54-year-old Chinese man presented with a 5-year history of tremor in the head and upper limbs.…”

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confidence: 99%

Do We Belittle Essential Tremor by Calling It a Syndrome Rather Than a Disease? No

Elble

2020

Front. Neurol.

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A task force of the International Parkinson and Movement Disorder Society (MDS) recently published a tremor classification scheme that is based on the nosologic principle of two primary axes for classifying an illness: clinical manifestations (Axis 1) and etiology (Axis 2). An Axis 1 clinical syndrome is a recurring group of clinical symptoms, signs (physical findings), and possibly laboratory results that suggests the presence of at least one underlying Axis 2 etiology. Syndromes must be defined and used consistently to be of value in finding specific etiologies and effective treatments. The MDS task force concluded that essential tremor is a common neurological syndrome that has never been defined consistently by clinicians and researchers. The MDS task force defined essential tremor as a syndrome of bilateral upper limb action tremor of at least 3 years duration, with or without tremor in other locations (e.g., head, voice, or lower limbs), in the absence of other neurological signs (e.g., dystonia, parkinsonism, myoclonus, ataxia, peripheral neuropathy, and cognitive impairment). Deviations from this definition should not be labeled as essential tremor. Patients with additional questionably-abnormal signs or with signs of uncertain relevance to tremor are classified as essential tremor plus. The MDS classification scheme encourages a thorough unbiased phenotyping of patients with tremor, with no assumptions of etiology, pathology, pathophysiology, or relationship to other neurological disorders. The etiologies, pathology, and clinical course of essential tremor are too heterogeneous for this syndrome to be viewed as a disease or a family of diseases.

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Essential tremor as the early symptom of NOTCH2NLC gene-related repeat expansion disorder

Cited by 28 publications

References 13 publications

Re‐defining the clinicopathological spectrum of neuronal intranuclear inclusion disease

Re‐defining the clinicopathological spectrum of neuronal intranuclear inclusion disease

Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders

Do We Belittle Essential Tremor by Calling It a Syndrome Rather Than a Disease? No

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