NIID is a neurodegenerative disorder caused by GGC repeat expansions in the 5’-untranslated region of the NOTCH2NLC gene. Early diagnosis is challenging due to highly variable clinical presentations, including cognitive decline, leukoencephalopathy, acute encephalitis-like episodes, parkinsonism, tremor, ataxia, peripheral neuropathy, retinopathy, oculopharyngodistal myopathy, and amyotrophic lateral sclerosis (ALS).

To enhance understanding of the phenotypic spectrum, clinical distribution, and MRI features of neuronal intranuclear inclusion disease (NIID).

The cohort included 28 men and 59 women, with a mean age of symptom onset of 60 ± 9.8 years (range: 21–78). The average expanded GGC repeat size was 113.8 ± 26.7 (range: 66–223). Skin biopsies from five patients revealed eosinophilic, p62-positive intranuclear inclusions. Initial clinical presentations included cognitive decline (30.2%), acute encephalitis-like episodes (3.9%), tremor/bradykinesia/ataxia (25.6%), and peripheral neuropathy (9.3%). Prior to genetic confirmation, 63 patients (72.4%) were diagnosed with NIID and 24 patients (27.6%) had alternative diagnoses, including cerebral small vessel disease (7 patients), Parkinson's disease (5 patients), Charcot-Marie-Tooth disease (3 patients), cerebellar ataxia (3 patients), ALS (1 patient), and mitochondrial disease (1 patient). MRI showed subcortical and periventricular white matter hyperintensities (WMH) in 87.2% of patients. WMH of the paravermis was observed in 53.5%, and middle cerebellar peduncle involvement was noted in 23.3%. Diffusion-weighted imaging (DWI) revealed curvilinear hyperintensities at the corticomedullary junction in 72.4% of patients.

This study highlights the broad clinical spectrum of NIID. MRI, particularly DWI, is crucial for identifying NIID-specific features. Increased awareness of NIID across a wide range of clinical syndromes and recognition of these MRI features may promote earlier diagnosis and lead to improved management.