NOTCH2NLC-related disorders: the widening spectrum and genotype–phenotype correlation

Abstract

GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC 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 NOTCH2NLC-related disorders and potential disease-causing mechanisms. We found that visual abnormalities may be NOTCH2NLC-specific and should be investigated in other patients with NOTCH2NLC mutations. NOTCH2NLC 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 LRP12/GIPC1 are suggested to be screened in European patients with NIID. The repeat size and interruptions in NOTCH2NLC 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 NOTCH2NLC possibly give rise to ET. An association may also exist between intermediate-length NOTCH2NLC GGC repeat expansion and patients affected by PD and ET. NOTCH2NLC-OPDM highly resembles NOTCH2NLC-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 NOTCH2NLC, repeats over which may be non-pathogenic. The haploinsufficiency of NOTCH2NLC may not be primarily involved in NOTCH2NLC-related disorders and a toxic gain-of-function mechanism possibly drives the pathogenesis of neurodegeneration in patients with NOTCH2NLC-associated disorders.

Clinical features ofNOTCH2NLC-related neuronal intranuclear inclusion disease

“…More than 400 cases of NIID have been reported worldwide, most of which were in East Asia. [23][24][25] Little evidence is available from large-sample studies. We investigated clinical features of 247 NIID-affected Han Chinese patients with NOTCH2NLC GGC repeat expansions in multiple centres within China.…”

Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

“…In the period when autopsy pathology was the main diagnostic method, our understanding for the NIID was mainly limited to the nervous system ( Cao et al, 2021 ; Fan et al, 2022 ; Huang et al, 2022 ). However, with the discovery of the NIID causative gene, the understanding about the disease was already beyond the scope of the previous cognition ( Deng et al, 2019 ; Ishiura et al, 2019 ; Sone et al, 2019 ; Tian et al, 2019 ).…”

“…At present, it was believed that the number of CGG repeat in NOTCH2NLC was less than 40 in the normal controls. The number of CGG repeat between 41 and 60 was intermediate and might be associated with a few Parkinson’s disease or essential tremor ( Fan et al, 2022 ). The number of CGG repeat more than 60 was pathogenic, and the typical phenotype of NIID usually had about 120 repeats.…”

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

“…Furthermore, there is increasing report of various acute symptoms of the central nervous system associated with NIID, including stroke-like episodes, migraine-like attack, epileptic seizures and/or encephalitic episodes; as well as evidences of clinical manifestations from other systems (Chen H. et al, 2020). Overall, these recent clinical observations suggest that NIID covers a much larger-than-previously-thought spectrum of clinical manifestations potentially extending to almost all systems (review in Cao L. et al, 2021;Fan et al, 2022).…”