Heterogenous Genetic, Clinical, and Imaging Features in Patients with Neuronal Intranuclear Inclusion Disease...

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases

Background:

• Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder.
• It stems from expanded GGC repeats in the NOTCH2NLC gene.
• Clinical presentations of NIID are highly varied, and the link between repeat length and phenotype is unclear.

Purpose of the Study:

• To investigate the genetic and clinical spectrum of NIID.
• To clarify the association between NOTCH2NLC GGC repeat length/sequence and clinical/imaging features in adult-onset NIID patients.

Main Methods:

• Genetic analysis of Japanese adult-onset NIID patients.
• Repeat-primed PCR, amplicon-length PCR, and long-read sequencing to analyze NOTCH2NLC GGC repeat expansions.
• Correlation analysis between repeat characteristics and clinical/imaging findings.

Main Results:

• All 15 patients had expanded GGC repeats in NOTCH2NLC (94–361 repeats).
• Larger GGC repeat sizes were associated with cerebellar ataxia and urinary dysfunction.
• A higher ARWMC score was observed in patients with non-glycine-type interruptions compared to pure poly-glycine expansions.

Conclusions:

• The length and sequence of GGC repeats in NOTCH2NLC play a role in modifying NIID clinical and imaging phenotypes.
• This study clarifies the genetic and clinical spectrum of NIID in Japanese patients.
• Further research is needed to fully understand the genotype-phenotype correlations in NIID.