Neuronal intranuclear inclusion disease caused by NOTCH2NLC gene expansion: a case report and literature review

Abstract Background Neuronal intranuclear inclusion disease (NIID) is an extremely rare, slowly progressive neurodegenerative disorder characterized by episodic neurological and psychiatric symptoms. Diagnosis is challenging due to non-specific presentations, often leading to misdiagnosis. Key diagnostic features include characteristic diffusion-weighted imaging (DWI) abnormalities, eosinophilic intranuclear inclusions on skin biopsy, and GGC repeat expansions in the NOTCH2NLC gene. Case Presentation A 56-year-old woman presented with acute onset confusion, disorientation, personality changes (inappropriate verbal outbursts), and aimless wandering. Symptoms were episodic and fluctuating. Past history included a right hemispheric ischemic stroke with residual hemiparesis, type 2 diabetes mellitus, and organophosphate poisoning. Initial admission diagnosis was "metabolic encephalopathy." Serial brain MRI+DWI over 3 years consistently showed symmetric hyperintensity on DWI along the corticomedullary junction in bilateral fronto-parieto-temporal white matter, semioval centers, and corpus callosum (ribbon sign). Cerebrospinal fluid analysis showed normal protein levels and lymphocytic pleocytosis (118.80 cells/μL). Episodic cognitive fluctuations persisted despite standard medical management. Given the characteristic DWI findings and clinical course, NIID was suspected. Genetic testing confirmed a pathogenic heterozygous NOTCH2NLC GGC repeat expansion (n=16/101 repeats). Skin biopsy and EMG were declined. Family history revealed a daughter with suspected cognitive issues. A diagnosis of NIID was confirmed. Conclusions This report details the first genetically confirmed case of NIID in our region, presenting primarily with episodic psychiatric symptoms. It highlights the diagnostic challenge and the critical role of recognizing the characteristic DWI ribbon sign and performing genetic testing for NOTCH2NLC expansions, especially in cases with unexplained episodic neuropsychiatric decline. Increased awareness and accessibility of genetic testing will likely lead to more frequent diagnosis of NIID in China.