The pathogenesis of NIID remains unknown. Immunohistochemistry showed that intranuclear inclusions were positive for ubiquitin and ubiquitin-related proteins, including p62, SUMO1, FUS, MYO6 and OPTN-C protein5,12,13,16,17, suggesting that the ubiquitin-proteasome system in the nucleus may play a role in NIID. In addition, some intranuclear inclusion bodies were found to stain positive for anti-polyglutamine antibodies and anti-ataxin3 antibodies4,13. However, this may be the result of cross-reactivity. No CAG repeat amplification was observed in NIID18.
NIID is a rare chronic progressive neurodegenerative disease with variable clinical features, mainly manifesting as cognitive impairment, limb weakness, sensory abnormalities, autonomic dysfunction, ataxia, Parkinson's symptoms, epilepsy, seizure disorder, stroke-like seizures, and encephalitis-like seizures, etc. It is often considered a heterogeneous disease, and in the past, autopsy was required to confirm the diagnosis of the disease, so that patients were more difficult to diagnose during their lifetime. In the past, autopsy was required to confirm the diagnosis of the disease, so the patients were more difficult to diagnose during their lifetime. Currently, the diagnosis can be confirmed by typical imaging changes, skin pathology biopsy and genetic testing.
The pathophysiological mechanisms of NIID are unclear. In patients with NIID, intranuclear inclusion bodies are frequently present in morphologically essentially normal neurons, and their pathological significance is unknown. Even when extensive intranuclear inclusion bodies are present on pathological examination, they are not necessarily accompanied by neuronal degeneration and loss. Intranuclear inclusion bodies are not necessarily cytotoxic. Intranuclear inclusion bodies in NIID contain some proteins of the ubiquitin-proteasome protein degradation system, such as ubiquitin and p62, whose formation is associated with dysfunction of the ubiquitin-proteasome protein degradation system. It has been suggested that intranuclear inclusion body formation in NIID may have a similar pathophysiological pathway to polyglutamine disease, and is a neurodegenerative disease caused by amplification of genes specific for trinucleotide repeats (cytosine-adenine-guanine, encoding glutamine)11,18.
In 2003, Takahashi-Fujigasaki classified NIID into infantile, adolescent, and adult forms according to the age of onset and into epidemic and familial forms according to the mode of inheritance1. In this case, there is no history of similar disease in the family, so we consider disseminated adult neuronal intranuclear inclusion disease. Disseminated NIID most often starts at the age of 51–76 years, and the duration of the disease varies from 1 to 19 years. The symptoms are diverse and can be divided into three groups of symptoms: central nervous system, peripheral nerve, and autonomic nerve involvement2. The symptoms of CNS involvement include: dementia (94.7%), which is the first and core symptom; ataxia (52.8%); episodic disorders of consciousness (39.5%), which vary in severity and last from a few hours to several days; behavioral abnormalities (26.3%), which manifest as irritability, slurred speech, disuse disorder, and addiction to gambling; and subacute encephalitis-like manifestations (21%), which manifest as fever, headache, vomiting, etc. manifested as fever, headache, vomiting, impaired consciousness, and inactive mutism signs in late stages; others such as tonicity (23.7%), tremor (18.4%), and generalized tonic seizures (13.2%). Peripheral nerve involvement manifested: sensory impairment (28.6%), mild hypoesthesia, terminal limb numbness; decreased muscle strength (27%), mild decrease in muscle strength of distal extremities. Autonomic nerve involvement manifested: pupillary constriction (94.4%), bladder dysfunction (urinary incontinence; 33.8%), vomiting (15.8%), and syncope (8.1%). The clinical presentation of familial NIID is similar to that of the disseminated type, but the proportion of symptoms occurring is slightly different and can be divided into 2 subgroups according to their symptoms: the dementia group and the limb weakness group. The age of onset of dementia is over 40 years old, with dementia as the first and core symptom, which may be accompanied by mild autonomic dysfunction and subclinical peripheral neuropathy; the limb weakness group: The age of onset is 16–39 years old, with lower limb weakness as the first symptom, and sensory impairment and autonomic dysfunction gradually appear. Dementia with white matter lesions may appear in the course of the disease up to about 20 years19.
Imaging studies have their characteristic features: (1) White matter abnormal signals. Diffuse symmetrical and patchy hyperintense lesions are common in the subcortical white matter area beside the lateral ventricles (mainly in the frontoparietal lobe) on T2WI and T2-FlairWI, and may also be present in areas such as the brainstem, cerebellum, and corpus callosum; (2) cerebellar atrophy or demyelinating changes in the cerebellar white matter area; and (3) DWI characteristic features: curvilinear hyperintensity along the corticomedullary junction, which we call silk or diaper distribution.
In 2011, Japanese scholar Sone et al found that acidophilic and transparent inclusions were also observed in the nuclei of sweat gland cells, adipocytes, and fibroblasts in skin biopsy specimens from NIID patients. The composition and structural features of these bodies are consistent with those of intranuclear inclusion bodies of neurons, thus confirming that skin biopsy can be effective in the diagnosis of NIID14. Sone et al. recommended that the best area for skin biopsy is 10 cm above the outer ankle. This area is considered to have a moderate density of fat and sweat gland cells in the skin. In this patient, the skin pathology was taken in accordance with the optimal area for skin biopsy recommended by Sone et al.
Prof. Shen Lu and Prof. Tang Beisha's team identified the causative gene on chromosome 1p13.3-q23.1 by chain analysis of a five-generation family with myasthenia gravis phenotype NIID, and after whole-exome sequencing (WES) did not find the suspected causative mutation, long read long sequencing (LRS) identified the human-specific NOTCH2NLC gene within the interval with abnormal GGC repeat amplification associated with this family. sequencing (LRS) identified an aberrant repeat amplification of GGC within the human-specific NOTCH2NLC gene in the interval associated with this family. Further abnormal GGC repeats (≥ 66) at the 5' end of the NOTCH2NLC gene were identified by RP-PCR and GC-PCR in other NIID families (40 patients) and in patients with disseminated NIID3. This study revealed for the first time internationally that the pathogenesis of neuronal intranuclear inclusion body disease is associated with abnormal GGC repeat amplification in the NOTCH2NLC gene, thus identifying the NOTCH2NLC gene as the causative gene of NIID for the first time in the world.
For adult NIID, the following disorders need to be distinguished primarily: (1) Fragile X-associated tremor/ataxia syndrome (FXTAS), a rare genetic neurodegenerative disorder manifesting mainly as cerebellar ataxia. typical MRI features of FXTAS are FLAIR, T2WI symmetrical high signal foci in the cerebellar midfoot and total cerebellar atrophy, deep peri-lateral ventricular brain White matter lesions, which may appear as high signal foci in the corpus callosum compression. FMR1 gene testing and skin biopsy may be useful for differentiation. (2) Binswanger's disease, a cerebral small vessel disease with chronic progressive dementia as the main manifestation, is characterized by varying degrees of brain atrophy and ventricular enlargement, with symmetrical distribution of crescentic long T1 and long T2 signals in the deep cerebral white matter around the lateral ventricles, and common infarcts in the basal ganglia, thalamus and brainstem. In contrast, patients with NIID had almost no foci of lacunar cerebral infarction in the basal ganglia, thalamus, and central hemi-oval region.
There is no specific treatment for NIID, and no method has been found for the disappearance of intranuclear inclusion bodies or neurological recovery. Symptomatic management may delay the development of some symptoms (e.g., seizures, dementia, Parkinson's syndrome)20, but none of them can stop the course of the disease. NIID, due to its multiple heterogeneities, produces a large number of associated complications, which can manifest in completely different ways. Therefore, we propose to define a term NIID-related diseases (NIIDRD), which includes NIID and other related neurodegenerative diseases caused by human-specific GGC repeat sequence expansions NOTCH2NLC.