Intranuclear inclusions in skin biopsies are not limited to neuronal intranuclear inclusion disease but can also be seen in oculopharyngodistal myopathy

Ogasawara, Masashi; Eura, Nobuyuki; Nagaoka, Utako; Sato, Tatsuro; Arahata, Hajime; Hayashi, Tomohiro; Okamoto, Tomoko; Takahashi, Yūji; Mori‐Yoshimura, Madoka; Oya, Yasushi; Nakamura, Akinori; Shimazaki, Rui; Sano, Tadahiro; Kumutpongpanich, Theerawat; Minami, Narihiro; Hayashi, Shinichiro; Noguchi, S.; Iida, Aritoshi; Takao, Masaki; Nishino, Ichizo

doi:10.1111/nan.12787

Cited by 15 publications

(10 citation statements)

References 10 publications

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“…We have recently reported that INIs in skin biopsy samples are found not only in NIID, but also in three types of OPDMs, suggesting that the underlying pathogenesis of OPDM could be identical to that of NIID, as these diseases are caused by a CGG repeat expansion. 16 In contrast, here, the frequency of the nonmuscle-INIs in muscle biopsy samples was significantly higher in OPDM_NOTCH2NLC than in OPDM_GIPC1 and OPDM_LRP12. However, the frequency of myo-INIs was similar among the subtypes of OPDM, indicating that the CGG expansions in the NOTCH2NLC gene affect a wider range of cell types, which may help differentiate OPDM_NOCTH2NLC from other OPDM subtypes in muscle pathology.…”

Section: Discussioncontrasting

confidence: 70%

Intra-myonuclear inclusions are diagnostic of oculopharyngeal muscular dystrophy

Ogasawara

Eura

Iida³

et al. 2022

Preprint

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The pathologies of oculopharyngeal muscular dystrophy (OPMD) and oculopharyngodistal myopathy (OPDM) are indistinguishable. We found that p62-positive intra-nuclear inclusions (INIs) in myonuclei (myo-INIs) were significantly more frequent in OPMD (11.4 ± 4.1%, range 5.0– 17.5%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (1–2% on average, range 0.0–3.5%, p<0.0001). In contrast, INIs in nonmuscle cells (nonmuscle-INIs) were present in OPDM, but absent in other RVMs, including OPMD. These results indicate that OPMD can be differentiated from OPDM and other RVMs by the frequent presence of myo-INIs (≥5%) and the absence of nonmuscle-INIs in muscle pathology.

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Section: Discussioncontrasting

confidence: 70%

Intra-myonuclear inclusions are diagnostic of oculopharyngeal muscular dystrophy

Ogasawara

Eura

Iida³

et al. 2022

Preprint

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“…Besides these non-specific myopathic changes, OPDM histopathology is characterized by the presence of cytoplasmic rimmed vacuoles (RVs) and typical eosinophilic nuclear inclusions (NIs), which are both p62-and ubiquitinpositive (Zhao et al, 2015;Deng et al, 2020;Saito et al, 2020;Kumutpongpanich et al, 2021;Matsubara et al, 2021;Xi et al, 2021). Of interest, these intranuclear inclusions are also observed in skin sections of individuals with OPDM cases (Ogasawara et al, 2021), and are reminiscent of the typical inclusions observed in FXTAS and NIID. Importantly, the mutations causing OPDM were recently identified as similar expansions of ~70 to 200-300 CGG repeats located within the 5′UTR of two different genes, LRP12 and GIPC1 (Ishiura et al, 2019;Deng et al, 2020;Kumutpongpanich et al, 2021;Xi et al, 2021).…”

Section: Oculopharyngodistal Myopathiesmentioning

confidence: 99%

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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“…Neuronal nuclear inclusions (NIIs) in the skin or biopsy samples of other tissues are the characteristic histopathologic findings of NIID. NIIs are not limited to NIID, but are also present in a variety of multiple neurodegenerative diseases, such as fragile X-associated tremor/ataxia syndrome (FXTAS), distal ophthalmopharyngeal myopathy, and oropharyngeal myopathy, which have overlapping clinical symptoms and similar pathological outcomes, and even have some commonalities in genetic diagnosis ( Boivin and Charlet-Berguerand, 2022 ; Ogasawara et al, 2022 ; Zhou et al, 2022 ). The existence of NIIs and the dysfunction of the ubiquitin-proteasome system (UPS) are the shared pathological features in NIID and other neurodegenerative diseases.…”

Section: Neuronal Nuclear Inclusions the Typical Pathological Changes...mentioning

confidence: 99%

Clinical and mechanism advances of neuronal intranuclear inclusion disease

Liu

et al. 2022

Front. Aging Neurosci.

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Due to the high clinical heterogeneity of neuronal intranuclear inclusion disease (NIID), it is easy to misdiagnose this condition and is considered to be a rare progressive neurodegenerative disease. More evidence demonstrates that NIID involves not only the central nervous system but also multiple systems of the body and shows a variety of symptoms, which makes a clinical diagnosis of NIID more difficult. This review summarizes the clinical symptoms in different systems and demonstrates that NIID is a multiple-system intranuclear inclusion disease. In addition, the core triad symptoms in the central nervous system, such as dementia, parkinsonism, and psychiatric symptoms, are proposed as an important clue for the clinical diagnosis of NIID. Recent studies have demonstrated that expanded GGC repeats in the 5′-untranslated region of the NOTCH2NLC gene are the cause of NIID. The genetic advances and possible underlying mechanisms of NIID (expanded GGC repeat-induced DNA damage, RNA toxicity, and polyglycine-NOTCH2NLC protein toxicity) are briefly summarized in this review. Interestingly, inflammatory cell infiltration and inflammation were observed in the affected tissues of patients with NIID. As a downstream pathological process of NIID, inflammation could be a therapeutic target for NIID.

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Intranuclear inclusions in skin biopsies are not limited to neuronal intranuclear inclusion disease but can also be seen in oculopharyngodistal myopathy

Cited by 15 publications

References 10 publications

Intra-myonuclear inclusions are diagnostic of oculopharyngeal muscular dystrophy

Intra-myonuclear inclusions are diagnostic of oculopharyngeal muscular dystrophy

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

Clinical and mechanism advances of neuronal intranuclear inclusion disease

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