NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders

Cao, Lanxiao; Yan, Yaping; Zhao, Guohua

doi:10.1007/s10072-021-05498-3

Cited by 22 publications

(20 citation statements)

References 52 publications

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“…Furthermore, there is increasing report of various acute symptoms of the central nervous system associated with NIID, including stroke-like episodes, migraine-like attack, epileptic seizures and/or encephalitic episodes; as well as evidences of clinical manifestations from other systems ( Chen H. et al, 2020 ). Overall, these recent clinical observations suggest that NIID covers a much larger-than-previously-thought spectrum of clinical manifestations potentially extending to almost all systems (review in Cao Y. et al, 2021 ; Cao L. et al, 2021 ; Fan et al, 2022 ).…”

Section: Neuronal Intranuclear Inclusion Diseasementioning

confidence: 84%

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

Boivin

Charlet‐Berguerand

2022

Front. Genet.

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Microsatellites are repeated DNA sequences of 3–6 nucleotides highly variable in length and sequence and that have important roles in genomes regulation and evolution. However, expansion of a subset of these microsatellites over a threshold size is responsible of more than 50 human genetic diseases. Interestingly, some of these disorders are caused by expansions of similar sequences, sizes and localizations and present striking similarities in clinical manifestations and histopathological features, which suggest a common mechanism of disease. Notably, five identical CGG repeat expansions, but located in different genes, are the causes of fragile X-associated tremor/ataxia syndrome (FXTAS), neuronal intranuclear inclusion disease (NIID), oculopharyngodistal myopathy type 1 to 3 (OPDM1-3) and oculopharyngeal myopathy with leukoencephalopathy (OPML), which are neuromuscular and neurodegenerative syndromes with overlapping symptoms and similar histopathological features, notably the presence of characteristic eosinophilic ubiquitin-positive intranuclear inclusions. In this review we summarize recent finding in neuronal intranuclear inclusion disease and FXTAS, where the causing CGG expansions were found to be embedded within small upstream ORFs (uORFs), resulting in their translation into novel proteins containing a stretch of polyglycine (polyG). Importantly, expression of these polyG proteins is toxic in animal models and is sufficient to reproduce the formation of ubiquitin-positive intranuclear inclusions. These data suggest the existence of a novel class of human genetic pathology, the polyG diseases, and question whether a similar mechanism may exist in other diseases, notably in OPDM and OPML.

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Section: Neuronal Intranuclear Inclusion Diseasementioning

confidence: 84%

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

Boivin

Charlet‐Berguerand

2022

Front. Genet.

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“…In the period when autopsy pathology was the main diagnostic method, our understanding for the NIID was mainly limited to the nervous system ( Cao et al, 2021 ; Fan et al, 2022 ; Huang et al, 2022 ). However, with the discovery of the NIID causative gene, the understanding about the disease was already beyond the scope of the previous cognition ( Deng et al, 2019 ; Ishiura et al, 2019 ; Sone et al, 2019 ; Tian et al, 2019 ).…”

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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“…′ UTR region of the human-specific NOTCH2NLC gene is the genetic underpinning of NIID (8,9). While the number of GGC repeats normally does not exceed 40, patients with NIID typically present with a minimum of 60 repeats (6,10).…”

Section: Discussionmentioning

confidence: 99%

Case report: Two siblings with neuronal intranuclear inclusion disease exhibiting distinct clinicoradiological findings

et al. 2022

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Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by the presence of eosinophilic hyaline intranuclear inclusions. Owing to its widely varying clinical manifestations, NIID is frequently misdiagnosed or overlooked. However, a characteristic high-intensity corticomedullary junction signal on diffusion-weighted imaging (DWI) is often indicative of NIID. In this study, we described the case of two sisters with NIID who presented with distinct symptoms and imaging data. The younger sister showed symptoms similar to those of mitochondrial encephalopathy, with a reversible high-intensity signal from the cortex on T2 and DWI. The elder sister showed a characteristic high-signal “ribbon sign” in the corticomedullary junction on DWI. Skin biopsy confirmed that both had neuronal intranuclear inclusion. Two years later, the younger sister also developed the characteristic high-signal “ribbon sign” in the corticomedullary junction on DWI. This case study provides new insights into the complexity of NIID. The findings suggest that patients with this condition, including those belonging to the same family, may exhibit varying clinical and imaging features at different times.

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NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders

Cited by 22 publications

References 52 publications

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

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

Case report: Two siblings with neuronal intranuclear inclusion disease exhibiting distinct clinicoradiological findings

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