Diagnostic indicators for adult-onset neuronal intranuclear inclusion disease

Wang, Yan; Wang, Bo; Wang, Lu; Yao, Shulin; Zhao, Jing; Zhong, Shanshan; Cong, Lu; Liu, Ling; Zhang, Jiewen; Zhang, Jun; Hong, Daojun

doi:10.5414/np301203

Cited by 36 publications

(38 citation statements)

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“…NIID has been described as a heterogeneous disease because of the variable phenotypes depending on the different patterns of central, peripheral, and autonomic nervous system involvement 6,19 . Some patients with adult‐onset NIID presented with isolated urinary disturbance at the early stage of disease, and gradually started showing parkinsonism, cerebellar ataxia, dementia, and pyramidal symptoms at the late stage of disease.…”

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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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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“…However, skin biopsy could show NIIs located in the fibroblast, adipocyte, and epithelial cells of sweat gland ducts, which greatly facilitated the antemortem diagnosis of NIID [ 102 ]. The clinical features of NIID show great heterogeneity with combinations of cognitive impairments, stroke-like symptoms, encephalitic episodes, autonomic dysfunction, limb weakness, cerebellar ataxia, parkinsonism, peripheral neuropathy, psychiatric disturbance, visual abnormalities, and other multi-system symptoms [ 57 , 119 ]. The MRI features in adult-onset NIID include diffuse white matter lesions, DWI and FLAIR hyperintensities in the corpus callosum, and DWI linear hyperintensity along the cortico-medullary junction, which are strikingly similar to those of FXTAS [ 43 , 57 ].…”

Section: Polyglycine(g) Disordersmentioning

confidence: 99%

The polyG diseases: a new disease entity

Liufu

Zheng

et al. 2022

acta neuropathol commun

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Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5’ untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

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“…[1][2][3][4] NIID is a progressive degenerative disease with intricate clinical symptoms affecting multiple systems and pathological evidence of widespread eosinophilic intranuclear inclusions in a variety of organ tissues. [5][6][7][8][9][10][11] As neuroimaging abnormalities, 12 skin biopsy 13 and genetic analysis [1][2][3][4] became widely available for the diagnosis of NIID in recent years, the number of diagnosed NIID cases increased quickly. To date, GGC repeat expansion of NOTCH2NLC has been reported to not only be responsible for typical NIID, [1][2][3][4] but also associated with a group of NOTCH2NLC-related repeat expansion disorders (NRED).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, GGC repeat expansion in the 5’untranslated region (5’UTR) of the NOTCH2NLC has been identified as the causative mutation of neuronal intranuclear inclusion disease (NIID) 1‐4 . NIID is a progressive degenerative disease with intricate clinical symptoms affecting multiple systems and pathological evidence of widespread eosinophilic intranuclear inclusions in a variety of organ tissues 5‐11 . As neuroimaging abnormalities, 12 skin biopsy 13 and genetic analysis 1‐4 became widely available for the diagnosis of NIID in recent years, the number of diagnosed NIID cases increased quickly.…”

Section: Introductionmentioning

confidence: 99%

GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy

Luan

et al. 2021

Ann Clin Transl Neurol

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Background: The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. Methods: Whole-exome sequencing (WES) and long-read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. Results: We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. Interpretation: These phenotypes enrich the class of features associated with NOTCH2NLC-related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist.

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Diagnostic indicators for adult-onset neuronal intranuclear inclusion disease

Cited by 36 publications

References 0 publications

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

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

The polyG diseases: a new disease entity

GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy

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