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. 2022 Apr;48(3):e12787.
doi: 10.1111/nan.12787. Epub 2021 Dec 28.

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

Masashi Ogasawara  1   2 , Nobuyuki Eura  1   2   3 , Utako Nagaoka  4 , Tatsuro Sato  5 , Hajime Arahata  6 , Tomohiro Hayashi  7 , Tomoko Okamoto  8 , Yuji Takahashi  8 , Madoka Mori-Yoshimura  8 , Yasushi Oya  8 , Akinori Nakamura  9 , Rui Shimazaki  4 , Terunori Sano  10 , Theerawat Kumutpongpanich  1 , Narihiro Minami  1   2 , Shinichiro Hayashi  1   2 , Satoru Noguchi  1   2 , Aritoshi Iida  2 , Masaki Takao  10 , Ichizo Nishino  1   2
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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

Masashi Ogasawara et al. Neuropathol Appl Neurobiol. 2022 Apr.

Abstract

Aims: Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy.

Methods: We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2).

Results: The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy.

Conclusion: Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.

Keywords: CGG repeat expansion; GIPC1; LRP12; NOTCH2NLC; neuronal intranuclear inclusion disease; oculopharyngeal muscular dystrophy; oculopharyngodistal myopathy.

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References

REFERENCES

    1. Sone J, Tanaka F, Koike H, et al. Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease. Neurology. 2011;76(16):1372-1376.
    1. Sone J, Mitsuhashi S, Fujita A, et al. Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet. 2019;51(8):1215-1221.
    1. Ishiura H, Shibata S, Yoshimura J, et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet. 2019;51(8):1222-1232.
    1. Ogasawara M, Iida A, Kumutpongpanich T, et al. CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations. Acta Neuropathol Commun. 2020;8(1):204.
    1. Deng J, Yu J, Li P, et al. Expansion of GGC repeat in GIPC1 is associated with oculopharyngodistal myopathy. Am J Hum Genet. 2020;106(6):793-804.

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