Abstract
Neuronal intranuclear inclusion disease (NIID) used to be considered as a neurodegenerative disease. Due to the availability of skin biopsy, the diagnostic efficiency of the disease has been greatly improved. Recently, researchers have successfully identified that the GGC repeat expansion in the 5′-untranslated region of the NOTCH2NLC gene is the causative mutation of NIID. Besides the typical phenotype of brain degeneration, peripheral neuropathy, and autonomic disturbance, the gene mutation is also associated with Alzheimer's disease, frontotemporal dementia, Parkinson’s disease, multiple system atrophy, essential tremor, adult leukoencephalopathy, and oculopharyngodistal myopathy. However, it still needs more studies to elucidate whether those variable NIID phenotypes can categorize into NOTCH2NLC repeat expansion related disorders. We update the discovery milestone, clinical phenotype, laboratory examinations, as well as new insight into the diagnosis and treatment of NIID. NIID is an unusual degenerative disease that can involve multiple systems, especially involves the nervous system. Originally, it is named after the pathological characteristics with extensive intranuclear eosinophilic inclusions in central and peripheral nervous tissues, as well as in multiple other organs (Sone et al., Brain 139:3170–3186, 2016). In 2019, several research teams from China and Japan have simultaneously identified that the GGC repeat expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene is the pathogenic mutation of NIID (Ishiura et al., Nat Genet 51:1222–1232, 2019; Deng et al., J Med Genet 56:758–764, 2019; Sone et al., Nat Genet 51:1215–1221, 2019; Sun et al., Brain 143:222–233, 2020; Tian et al., Am J Hum Genet 105:166–176, 2019). Since then, the number of reported NIID cases is rapidly increasing, and the spectrum of NOTCH2NLC repeat expansion related disorders is significantly broadening (Westenberger and Klein, Brain 143:5–8, 2020). However, the NIID associated with GGC repeat expansion of the NOTCH2NLC gene might be account for a part of patients, probably more frequently in the Asian population, because this expansion has not been identified in an European series with postmortem confirmed NIID cases (Chen et al., Ann Clin Transl Neurol 2020). In order to better understand of the disease, we need to revisit the current state of NIID in combination with the findings based on our experiences in recent years and update the concepts about the clinical and pathogenic progression of NIID.
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Data availability
The images used in the current study are available from the corresponding author on reasonable request.
Abbreviations
- 5′UTR:
-
5′-Untranslated region
- AD:
-
Alzheimer’s disease
- CADASIL:
-
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
- DWI:
-
Diffusion-weighted imaging
- ET:
-
Essential tremor
- FTD:
-
Frontotemporal dementia
- FXTAS:
-
Fragile X-associated tremor/ataxia syndrome
- NIHID:
-
Neuronal intranuclear hyaline inclusion disease
- NIID:
-
Neuronal intranuclear inclusion disease
- NRED:
-
NOTCH2NLC Gene-related repeat expansion disorder
- MELAS:
-
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
- MSA:
-
Multiple system atrophy
- OPDM:
-
Oculopharyngodistal myopathy
- PD:
-
Parkinson’s disease
References
Barnett JL, McDonnell WM, Appelman HD, Dobbins WO (1992) Familial visceral neuropathy with neuronal intranuclear inclusions: diagnosis by rectal biopsy. Gastroenterology 102:684–691. https://doi.org/10.1016/0016-5085(92)90121-e
Chen L, Wu L, Li S, Huang Q, Xiong J, Hong D, Zeng X (2018) A long time radiological follow-up of neuronal intranuclear inclusion disease: two case reports. Medicine 97:e13544. https://doi.org/10.1097/md.0000000000013544
Chen Z et al (2020) Neuronal intranuclear inclusion disease is genetically heterogeneous. Ann Clin Transl Neurol. https://doi.org/10.1002/acn3.51151
Cheng W et al (2018) C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat Commun 9:51. https://doi.org/10.1038/s41467-017-02495-z
Deng J et al (2019) Long-read sequencing identified repeat expansions in the 5′UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease. J Med Genet 56:758–764. https://doi.org/10.1136/jmedgenet-2019-106268
Dong H et al (2020) A case of adult-onset neuronal intranuclear inclusion disease without abnormal high-intensity signal in the corticomedullary junction in diffusion-weighted imaging. Neurol Sci. https://doi.org/10.1007/s10072-020-04385-7
Fang P et al (2020) Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy. Ann Clin Transl Neurol 7:517–526. https://doi.org/10.1002/acn3.51021
Glineburg MR, Todd PK, Charlet-Berguerand N, Sellier C (2018) Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in Fragile X tremor ataxia syndrome. Brain Res 1693:43–54. https://doi.org/10.1016/j.brainres.2018.02.006
Haltia M, Somer H, Palo J, Johnson WG (1984) Neuronal intranuclear inclusion disease in identical twins. Ann Neurol 15:316–321. https://doi.org/10.1002/ana.410150403
Hayashi K, Hamaguchi T, Sakai K, Nakamura K, Wakabayashi K, Shirasaki H, Yamada M (2019) Neuronal intranuclear inclusion disease showing blepharoptosis and positive serum anti-acetylcholine receptor antibody without myasthenia gravis. J Neurol Sci 400:119–121. https://doi.org/10.1016/j.jns.2019.03.013
Hong D, Wang Z, Zhang W, Xi J, Lu J, Luan X, Yuan Y (2011) A series of Chinese patients with desminopathy associated with six novel and one reported mutations in the desmin gene. Neuropathol Appl Neurobiol 37:257–270. https://doi.org/10.1111/j.1365-2990.2010.01112.x
Imai T, Kato B, Ohsima J, Hasegawa Y (2018) An adult onset sporadic neuronal intranuclear inclusion disease case reminiscent with Fisher syndrome. Rinsho Shinkeigaku 58:505–508. https://doi.org/10.5692/clinicalneurol.cn-001139
Ishihara T et al (2020) Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy. Neurol Genet 6:e531. https://doi.org/10.1212/nxg.0000000000000531
Ishiura H et al (2019) Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet 51:1222–1232. https://doi.org/10.1038/s41588-019-0458-z
Jiao B et al (2020) Identification of expanded repeats in NOTCH2NLC in neurodegenerative dementias. Neurobiol Aging 89:142.e1-142.e7. https://doi.org/10.1016/j.neurobiolaging.2020.01.010
Josephs KA (2011) Neuronal intranuclear inclusion disease: no longer a pain in the butt. Neurology 76:1368–1369. https://doi.org/10.1212/WNL.0b013e3182166ead
Kawarabayashi T et al (2018) Disappearance of MRI imaging signals in a patient with neuronal intranuclear inclusion disease. J Neurol Sci 388:1–3. https://doi.org/10.1016/j.jns.2018.02.038
Liang H et al (2020) Clinical and pathological features in adult-onset NIID patients with cortical enhancement. J Neurol. https://doi.org/10.1007/s00415-020-09945-7
Lieberman AP, Robitaille Y, Trojanowski JQ, Dickson DW, Fischbeck KH (1998) Polyglutamine-containing aggregates in neuronal intranuclear inclusion disease. Lancet 351:884. https://doi.org/10.1016/s0140-6736(05)70296-8
Lindenberg R, Rubinstein LJ, Herman MM, Haydon GB (1968) A light and electron microscopy study of an unusual widespread nuclear inclusion body disease a possible residuum of an old herpesvirus infection. Acta Neuropathol 10:54–73. https://doi.org/10.1007/bf00690510
Ma D et al (2020) Association of NOTCH2NLC repeat expansions with parkinson disease. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2020.3023
Malandrini A et al (1996) Neuronal intranuclear inclusion disease: polymerase chain reaction and ultrastructural study of rectal biopsy specimen in a new case. Acta Neuropathol 91:215–218. https://doi.org/10.1007/s004010050417
Morimoto S, Hatsuta H, Komiya T, Kanemaru K, Tokumaru AM, Murayama S (2017) Simultaneous skin-nerve-muscle biopsy and abnormal mitochondrial inclusions in intranuclear hyaline inclusion body disease. J Neurol Sci 372:447–449. https://doi.org/10.1016/j.jns.2016.10.042
Mosaheb S, Thorpe JR, Hashemzadeh-Bonehi L, Bigio EH, Gearing M, Cairns NJ (2005) Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease. Acta Neuropathol 110:360–368. https://doi.org/10.1007/s00401-005-1057-x
Nakamura M et al (2018) Two cases of sporadic adult-onset neuronal intranuclear inclusion disease preceded by urinary disturbance for many years. J Neurol Sci 392:89–93. https://doi.org/10.1016/j.jns.2018.07.012
Ogasawara M et al (2020) CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations. Acta Neuropathol Commun 8:204. https://doi.org/10.1186/s40478-020-01084-4
Okubo M et al (2019) GGC repeat expansion of NOTCH2NLC in adult patients with leukoencephalopathy. Ann Neurol 86:962–968. https://doi.org/10.1002/ana.25586
Qin X et al (2020) Neuronal intranuclear inclusion disease: two case report and literature review. Neurol Sci. https://doi.org/10.1007/s10072-020-04613-0
Raza HK et al (2020) Recent progress in neuronal intranuclear inclusion disease: a review of the literature. Neurol Sci 41:1019–1025. https://doi.org/10.1007/s10072-019-04195-6
Sakurai T, Harada S, Wakida K, Yoshida M, Nishida H (2016) Sporadic adult-onset neuronal intranuclear inclusion disease with the main presentation of repeated cerebellar ataxia: a case study. Rinsho Shinkeigaku 56:439–443. https://doi.org/10.5692/clinicalneurol.cn-000875
Sellier C et al (2017) Translation of expanded CGG repeats into FMRpolyG is pathogenic and May contribute to Fragile X tremor ataxia syndrome. Neuron 93:331–347. https://doi.org/10.1016/j.neuron.2016.12.016
Sone J et al (2005) Neuronal intranuclear hyaline inclusion disease showing motor-sensory and autonomic neuropathy. Neurology 65:1538–1543. https://doi.org/10.1212/01.wnl.0000184490.22527.90
Sone J et al (2011) Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease. Neurology 76:1372–1376. https://doi.org/10.1212/WNL.0b013e3182166e13
Sone J et al (2016) Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain 139:3170–3186. https://doi.org/10.1093/brain/aww249
Sone J et al (2019) Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet 51:1215–1221. https://doi.org/10.1038/s41588-019-0459-y
Sugiyama A et al (2017) MR imaging features of the cerebellum in adult-onset neuronal intranuclear inclusion disease: 8 cases. Am J Neuroradiol 38:2100–2104. https://doi.org/10.3174/ajnr.A5336
Sun QY et al (2020) Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor. Brain 143:222–233. https://doi.org/10.1093/brain/awz372
Sung JH, Ramirez-Lassepas M, Mastri AR, Larkin SM (1980) An unusual degenerative disorder of neurons associated with a novel intranuclear hyaline inclusion (neuronal intranuclear hyaline inclusion disease) a clinicopathological study of a case. J Neuropathol Exp Neurol 39:107–130. https://doi.org/10.1097/00005072-198003000-00001
Takahashi-Fujigasaki J (2003) Neuronal intranuclear hyaline inclusion disease. Neuropathology 23:351–359. https://doi.org/10.1046/j.1440-1789.2003.00524.x
Tian Y et al (2019) Expansion of human-specific GGC repeat in neuronal intranuclear inclusion disease-related disorders. Am J Hum Genet 105:166–176. https://doi.org/10.1016/j.ajhg.2019.05.013
Uchihara T, Tanaka J, Funata N, Arai K, Hattori T (2003) Influences of intranuclear inclusion on nuclear size—morphometric study on pontine neurons of neuronal intranuclear inclusion disease cases. Acta Neuropathol 105:103–108. https://doi.org/10.1007/s00401-002-0614-9
Wang R, Nie X, Xu S, Zhang M, Dong Z, Yu S (2020a) Interrelated pathogenesis? Neuronal intranuclear inclusion disease combining with hemiplegic migraine. Headache 60:382–395. https://doi.org/10.1111/head.13687
Wang Y et al (2020b) Diagnostic indicators for adult-onset neuronal intranuclear inclusion disease. Clin Neuropathol 39:7–18. https://doi.org/10.5414/np301203
Wang ZY, Guo JJ, Wang M, Wang ZX, Hong DJ, Yu XF (2020c) Adult-onset neuronal intranuclear inclusion disease mimicking Parkinson’s disease in a Chinese patient: a case report and literature reviews. Neuro Endocrinol Lett 41:155–161
Westenberger A, Klein C (2020) Essential phenotypes of NOTCH2NLC-related repeat expansion disorder. Brain 143:5–8. https://doi.org/10.1093/brain/awz404
Woulfe JM (2007) Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progress. Neuropathol Appl Neurobiol 33:2–42. https://doi.org/10.1111/j.1365-2990.2006.00819.x
Xiao F, Tian X, Wang XF (2018) Cerebral atrophy and leukoencephalopathy in a young man presenting with encephalitic episodes. JAMA Neurol 75:1563–1564. https://doi.org/10.1001/jamaneurol.2018.2333
Yadav N et al (2019) Neuronal intranuclear inclusion disease: a rare etiology for rapidly progressive dementia. Alzheimer Dis Assoc Disord 33:359–361. https://doi.org/10.1097/wad.0000000000000312
Yokoi S et al (2016) Pathological background of subcortical hyperintensities on diffusion-weighted images in a case of neuronal intranuclear inclusion disease. Clin Neuropathol 35:375–380. https://doi.org/10.5414/np300961
Zannolli R et al (2002) Hereditary neuronal intranuclear inclusion disease with autonomic failure and cerebellar degeneration. Arch Neurol 59:1319–1326. https://doi.org/10.1001/archneur.59.8.1319
Zhu Y et al (2016) Reversible splenial lesion syndrome associated with encephalitis/encephalopathy presenting with great clinical heterogeneity. BMC Neurol 16:49. https://doi.org/10.1186/s12883-016-0572-9
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The authors would appreciate the patients and their families for their enthusiasm and participation in this study.
Funding
The work was supported by the National Natural Science Foundation of China (No. 81460199), and Double thousand talents program of Jiangxi province (jxsq2019101021), Science and technology project of Jiangxi Health Committee (202110028).
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XL and DJH performed the literature search, prepared the figures, and wrote the manuscript.
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Lu, X., Hong, D. Neuronal intranuclear inclusion disease: recognition and update. J Neural Transm 128, 295–303 (2021). https://doi.org/10.1007/s00702-021-02313-3
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DOI: https://doi.org/10.1007/s00702-021-02313-3