Re-defining the clinicopathological spectrum of neuronal intranuclear inclusion disease

Abstract

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 the NOTCH2NLC gene. 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.

Figure 1

GGC repeats in the NOTCH2NLC gene from patients with NIID and control subjects. The peripheral blood samples were collected and DNA was extracted. Repeat‐primed PCR was performed to examine the GGC repeats in the NOTCH2NLC gene.

Figure 2

Typical features of MRI in patients with NIID. A representative case (case 45, A–H) shows the typical imaging manifestations showed T1 low signals (red arrows) and high signals in T2, FLAIR, and ADC axial images involving the corticomedullary junction of frontal lobe, parietal lobe, occipital lobe, temporal lobe, and corpus callosum (A–D). DWI shows ribbon signs imaging manifestations involving the corticomedullary junction, accompanied by cerebral atrophy, mainly in the temporal lobe and hippocampus (E–H). Another representative case (case 46, I–L) showed bilateral high signal intensity in the medial part of the cerebellar hemisphere immediately beside the vermis (the paravermal area, I) and in the middle cerebellar peduncle (red arrows, J) as well as the atrophy of the cerebellum (yellow arrows, J). DWI axial images showed no obvious abnormality in the cerebellum (K); however, obvious high signal intensity was found along the corticomedullary junction (L).

Figure 3

Positive immunostaining of anti‐p62 and anti‐ubiquitin in different tissues. The tissue samples obtained from the previous surgery in patients with NIID were stained with anti‐p62 and anti‐Ubiquitin antibodies. Immunohistochemical staining in nervous (A–D), circulatory (E–H), digestive (I–P), urinary (Q–T), reproductive (U–X), respiratory (Y and Z) systems, and skin tissues (a and b).

Figure 4

A representative case (patient 6) showed an intranuclear inclusion (black arrow) near a nucleolus (white arrow) in rectum tissues under an electron microscope.

Figure 5

The diagram showed the percentages of initial symptoms from different systems. Initial symptoms in the total 51 patients with NIID were summarized.