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.

The Value of NOTCH2NLC Gene Detection and Skin Biopsy in the Diagnosis of Neuronal Intranuclear Inclusion Disease

“…At present, most researchers believe that GGC repeat expansions in NOTCH2NLC as the causative mutations for NIID. In previously reported 143 NIID patients who underwent skin biopsy and NOTCH2NLC gene detection at the same time, we found that there was a high degree of consistency between skin biopsy and NOTCH2NLC gene detection in the remaining patients, except for one patient whose skin biopsy was negative and was carrier of an expansion of NOTCH2NLC GGC repeats ( 12 ). Recent studies have shown that abnormal GGC amplification in NOTCH2NLC can also occur in Parkinson's disease (PD), Alzheimer's disease (AD), unexplained white matter disease, multiple system atrophy (MSA), and essential tremor (ET) ( 5 , 11 , 13 , 14 ).…”

GGC Repeat Expansion in the NOTCH2NLC Gene Is Associated With a Phenotype of Predominant Motor–Sensory and Autonomic Neuropathy

“…The underlying mechanism of dry cough might be interpreted as follows. (1) Irritating dry cough was reported to be as an initial symptom that accounted for 51% of NIID patients in a cohort study ( Chen et al, 2020 ). Based on the findings that intranuclear inclusions were found in multiple organs including the lungs ( Sone et al, 2005 ), it could be assumed that intranuclear inclusions could possibly exist in the trachea and bronchia, which might be related to the dysfunction of the airway.…”

Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases

“…Moreover, individuals with NIID with atypical presentation, such as essential tremors, multiple-systems atrophy, and amyotrophic lateral sclerosis, and various acute symptoms, including stroke-like episodes, epileptic seizures, and/or encephalitic episodes, have also been reported ( Sone et al., 2016 ; Fang et al., 2020 ; Li et al., 2020 ; Sun et al., 2020 ; Yuan et al., 2020 ). As a consequence of these diverse ages of onset and clinical presentations, NIID diagnosis is most often confirmed by the widespread presence of characteristic eosinophilic intranuclear inclusions in neurons and glial cells in the central and peripheral nervous systems and in various other tissues ( Chen et al., 2020a , Liu et al., 2008 , Sone et al., 2005 , Sone et al., 2011 , Sone et al., 2014 ). These intranuclear inclusions are immunoreactive for various markers of the proteasomal and autophagic degradation pathways, including ubiquitin, sumo, and p62 ( Pountney et al., 2003 ; Mori et al., 2012 ; Nakamura et al., 2014 ; Sone et al., 2016 ).…”