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

Abstract

The NOTCH2NLC gene 5' untranslated region (UTR) GGC repeat expansion mutations were identified as a genetic contributor of neuronal intranuclear inclusion disease (NIID) in 2019. Since then, the number of reported cases with NOTCH2NLC GGC repeat expansion in Asian and European populations has increased rapidly, indicating that the expanded mutation not only leads to the onset or progression of the NIID, but also may play an important role in multiple progressive neurological disorders, including Parkinson's disease, essential tremor, multiple system atrophy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, leukoencephalopathy, and oculopharyngodistal myopathy type 3. Nevertheless, the underlying pathogenic mechanism of the NOTCH2NLC 5' UTR region GGC repeat expansion in these disorders remains largely unknown. This review aims to present recent breakthroughs on this mutation and improve our knowledge of a newly defined spectrum of disease: NOTCH2NLC-related repeat expansion disorder.

Keywords: Essential tremor; GGC repeat; NOTCH2NLC; Neuronal intranuclear inclusion disease; Parkinson’s disease.