Lindenberg et al. reported this disease for the first time in 1968 by autopsy and named it neuronal intranuclear inclusion disease (NIID), which is characterized by the presence of extensive eosinophilic hyaline intranuclear inclusions in neurons and visceral organ cells11. NIID can be categorised into sporadic and familial types by genetic background, as categorized by age of onset in the previous study: infantile, juvenile, and adult forms12. Muscle weakness was the most common initial symptom in familial cases (40%), while dementia was the most prominent in sporadic cases (7.40%)2. It is now proposed that NIID can be divided into four subgroups based on initial presentation and predominant symptoms: dementia-dominant, movement disorder-dominant, muscle weakness-dominant and paroxysmal symptom-dominant2. The incidence of NIID is unclear, but most cases have been reported in two countries, Japan and China. Adult-onset NIID occurs at a range of 51 to 76 years, and the average age of onset is 63 years in sporadic cases4. The average disease duration is 5 years in sporadic cases and 15 years in familial cases. In both sporadic and familial cases, the incidence of female patients appears to be higher than that of males13.
As the clinical spectrum of NIID has been enriched, it has been discovered that NIID is not only characterized by central nervous system symptoms such as cognitive impairment and movement disorders but also with the involvement of paroxysmal symptoms, autonomic dysfunction, bladder dysfunction, etc2. NIID is a systemic neurodegenerative disease that affects more than one system besides the nervous system. Hao Chen's team conducted a clinical genealogical study with 51 NIID patients from 17 families and found that in addition to neurological symptoms, the clinical manifestations of other systems are very obvious and diverse, and can also involve the respiratory system, circulatory system, locomotor system, urinary system, gastrointestinal system, reproductive system, and endocrine system14. Our case has experienced recurrent nausea, vomiting, and abdominal discomfort for almost 5 years. However, the NIID clinical spectrum does not typically include symptoms such as nausea or vomiting, as reported by Yun Tian and co-authors who statistically analyzed the clinical symptoms of 247 patients showing that only 36 (14.6%) patients presented with nausea and vomiting2. The prevalence of nausea and vomiting as primary symptoms was even lower. It is believed that autonomic dysfunction is associated with periodic nausea and vomiting15,16. The patients' development of urinary retention in the late stages of the disease corroborates this view, but the patients did not have other symptoms such as postural hypotension and profuse sweating, which we hypothesized might be due to the insufficient follow-up period. We observe that the initial clinical symptoms of the patient are frequently associated with other systems, and the diagnosis is only confirmed in the neurology department after the nervous system is involved. It seems to us that a long history of involvement with multiple systems could be a clue to NIID1. Additionally, we should be alerted to symptoms from other systems, as neurologic symptoms are often more advanced than those of other systems. The increasing number of cases and expanding clinical spectrum of NIID suggest that the incidence of NIID may be underreported.
Due to the high clinical heterogeneity of NIID, it has been difficult to obtain a definitive antemortem diagnosis in the past, leading to the introduction of skin biopsy tests. Adipocytes, fibroblasts, and sweat gland cells in NIID skin biopsy samples had the same pathological characteristics as neuronal cells. Haematoxylin and eosin (HE) staining indicated eosinophilia and positive for ubiquitin and anti-P62 antibodies1,17.
The clinic frequently utilizes the distinctive imaging features of NIID to provide important indications for initial screening. Hyperintense signals were detected in the corticomedullary junction on diffusion-weighted images of the head when NIID was either sporadic or familial, according to the study18. A team recently analyzed cerebellum MRI images of patients with NIID and concluded that the characteristic MRI manifestation of FLAIR hyperintense signals in the paranormal area and middle cerebellar peduncle is based on their study18. The patient in case 1 showed an abnormal signal in the middle cerebellar peduncle on both DWI and FLAIR. Research comparing MR imaging and pathologic findings found that diffuse myelin pallor without spongiosis and pathologic spongiotic alterations were connected with FLAIR hyperintense signals in the white matter and DWI hyperintense signals along the corticomedullary junction, respectively. X-fragile chromosome syndrome has images that are similar, and it's not easy to differentiate it from NIID in terms of clinical presentation and pathologic features19,20. The NOTCH2NLC gene was found to have a CGG repeat expansion in genetic analysis of patients with suspected imaging of NIID, distinguishing it from the FMR1 gene in X-brittle chromosome disease2.
In recent years, it has been reported that NOTCH2NLC GGC repeat expansions have been detected in patients with other neurodegenerative diseases, and the concept of "NOTCH2NLC-related GGC repeat expansion disorders (NRED)" has been proposed2,21. In addition, a study conducted on 247 NIID patients found that the size of GGC repeats was negatively linked to age of onset, but not to the severity of the disease2. There is a correlation between the size of the GCC repeat sequence and the clinical phenotype: when carrying > 200 GGC repeats in NIID, the patients usually present with a muscle weakness–dominant phenotype; and 100–200 GGC repeats cause a dementia-dominant phenotype2,10,13. The exact pathological mechanism of NIID is not known and its status as a nucleotide repeat amplification disease may be associated with DNA damage, RNA toxicity, and downstream abnormally encoded proteotoxicity like other nucleotide repeat amplification diseases23–26.
Currently, the treatment for NIID is primarily symptomatic and supportive, with the aim of alleviating symptoms and enhancing patients' quality of life. However, there is a need for further research into specific treatments for the disorder. Negative MRI can be observed in NIID patients as the number of reported cases increases, and ubiquitin-positive and P62-positive eosinophilic inclusion bodies have decreased specificity27. Therefore, we should be more aggressive in NIID patients with NOTCH2NLC genetic testing and skin biopsy, as well as long-term MR follow-up.