Neuronal intranuclear inclusion disease: recognition and update.J Neural Transm (Vienna). 2021 03; 128(3):295-303.JN
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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