To study the clinical, imaging, and neuropathological features of patients with neuronal intranuclear inclusion disease (NIID) and to summarize the clinical characteristics of this disease. Methods: We report the diagnosis and treatment process of a familial NIID case admitted to our hospital. We also searched our hospital database to collect an additional seven NIID clinical cases. All cases were reviewed for clinical presentation, imaging findings, neuropathology, and genetic testing. Results: The reported case initially presented with “subacute encephalitis”and head magnetic resonance imaging (MRI) revealed swelling in the left temporal, parietal, and occipital lobes of the brain tissue, leaving the clinical diagnosis unclear. Further examinations, including cerebrospinal fluid analysis and immunological tests, were conducted, followed by a brain biopsy for pathological analysis. The patient’s family history was traced, and whole-exome sequencing and dynamic gene mutation testing were performed. The brain biopsy indicated intranuclear inclusion body accumulation, and an abnormal GGC trinucleotide repeat expansion was detected in the NOTCH2NLC gene. Combining the results of the family follow-up and genetic testing, a final diagnosis of familial NIID was made. Conclusion: The clinical manifestations of NIID are highly heterogeneous. Attention should be paid to the combination of neuropathological examination and dynamic mutation gene testing to facilitate an accurate diagnosis.