<i>NOTCH2NLC</i>-related disorders: the widening spectrum and genotype-phenotype correlation.

Abstract

GGC repeat expansion in the 5' untranslated region of <i>NOTCH2NLC</i> is the most common causative factor in neuronal intranuclear inclusion disease (NIID) in Asians. Such expanded GGC repeats have been identified in patients with leukoencephalopathy, essential tremor (ET), multiple system atrophy, Parkinson's disease (PD), amyotrophic lateral sclerosis and oculopharyngodistal myopathy (OPDM). Herein, we review the recently reported <i>NOTCH2NLC</i>-related disorders and potential disease-causing mechanisms. We found that visual abnormalities may be <i>NOTCH2NLC</i>-specific and should be investigated in other patients with <i>NOTCH2NLC</i> mutations. <i>NOTCH2NLC</i> GGC repeat expansion was rarely identified in patients of European ancestry, whereas the actual prevalence of the expansion in European patients may be potentially higher than reported, and the CGG repeats in <i>LRP12</i>/<i>GIPC1</i> are suggested to be screened in European patients with NIID. The repeat size and interruptions in <i>NOTCH2NLC</i> GGC expansion confer pleiotropic effects on clinical phenotype, a pure and stable ET phenotype may be an early symptom of NIID, and GGC repeats in <i>NOTCH2NLC</i> possibly give rise to ET. An association may also exist between intermediate-length <i>NOTCH2NLC</i> GGC repeat expansion and patients affected by PD and ET. <i>NOTCH2NLC</i>-OPDM highly resembles <i>NOTCH2NLC</i>-NIID, the two disorders may be the variations of a single neurodegenerative disease, and there may be a disease-causing upper limit in size of GGC repeats in <i>NOTCH2NLC</i>, repeats over which may be non-pathogenic. The haploinsufficiency of <i>NOTCH2NLC</i> may not be primarily involved in <i>NOTCH2NLC</i>-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with <i>NOTCH2NLC</i>-associated disorders.