Current advances in neuronal intranuclear inclusion disease

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder linked to pathogenic GGC repeat expansions in the NOTCH2NLC gene.
• Previous understanding of NIID's inheritance, pathogenesis, and diagnostic features is being revised by recent research.

Purpose of the Study:

• To review and synthesize recent advancements in understanding NIID, focusing on inheritance, pathogenesis, and histopathologic/radiologic features.
• To critically evaluate the diagnostic criteria and proposed new disease concepts related to NOTCH2NLC GGC repeat expansions.

Main Methods:

• Literature review of recent studies on NIID and NOTCH2NLC GGC repeat expansions.
• Analysis of inheritance patterns, clinical phenotypes, and diagnostic findings (histopathology, neuroimaging).

Main Results:

• GGC repeat size influences NIID onset and clinical presentation; paternal bias is noted, but anticipation may be absent.
• Eosinophilic intranuclear inclusions and specific diffusion-weighted imaging (DWI) findings are not exclusive to NIID and can be variable.
• NOTCH2NLC GGC repeat expansions in patients with other neurodegenerative diseases are re-evaluated as potential NIID phenotypes, challenging the concept of distinct NREDs.

Conclusions:

• The diagnostic hallmarks of NIID, including specific inclusions and imaging findings, require re-evaluation due to their presence in other conditions and variability.
• The spectrum of NIID is broader than previously recognized, encompassing phenotypes initially attributed to other neurodegenerative diseases or proposed as new entities like NREDs.
• Accurate diagnosis of NIID necessitates a comprehensive assessment beyond traditional hallmarks, considering the evolving understanding of GGC repeat expansion disorders.