Re-defining the clinicopathological spectrum of neuronal intranuclear inclusion disease

Background: The rapidly increasing case reports revealed that neuronal intranuclear inclusion disease (NIID) had concomitant other system symptoms besides nervous system symptoms. In this study, we systematically evaluated the symptoms, signs, auxiliary examination, and pathological changes in different systems in NIID patients. Methods:NIID patients were confirmed by examining GGC repeats in theNOTCH2NLCgene. Clinical data of NIID patients including symptoms, signs, and auxiliary examinations were collected for analysis. Ubiquitin and p62 were detected in different tissues from previous surgical samples. Results: Fifty-one NIID patients from 17 families were included in this study. Except neurological symptoms, clinical manifestations from other systems were very notable and diverse. The proportions of different system symptoms were 88.2% in nervous system, 78.4% in respiratory system, 72.5% in circulatory system, 72.5% in locomotor system, 66.7% in urinary system, 64.7% in digestive system, 61.5% in reproductive system, and 50.0% in endocrine system. In addition, other common symptoms included sexual dysfunction (43.1%), pupil constriction (56.9%), blurred vision (51.0%), and hearing loss (23.5%). Ubiquitin and p62-positive cells were found in different tissues and systems in 24 NIID patients with previous surgery. Initial symptoms of NIID and median onset age in different systems also revealed system heterogeneity of NIID. Interpretation For the first time, we systematically demonstrated that NIID is a heterogeneous and systemic neurodegenerative disease by providing clinical and pathological evidence. In addition to the nervous system, the clinical symptomatic and pathological spectrum of NIID has been extended to almost all systems.