The Clinical And Pathological Characteristics Of Neuronal Intranuclear Inclusion Disease

Part 1:Re-defining the clinicopathological spectrum of neuronal intranuclear inclusion diseaseBackground:Neuronal intranuclear inclusion disease(NIID)is a very rare chronic degenerative disease.Currently,its pathogenesis is not clear,its clinical manifestations and diagnostic criteria are still controversial,and there is currently no specific treatment for treatment.The rapidly increasing case reports revealed that 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 patients with NIID.The purpose of this study was to systematically evaluate the symptoms,signs,ancillary examinations,and pathological changes of different systems in patients with NIID,to confirm that NIID is a systemic inclusion body disease rather than a purely nervous system involvement.It is confirmed that NIID is a disease involving multiple systems,and systemic intranuclear inclusion body disease(SIID)may be more appropriate for this disease.The clinical and pathological profiles of NIID should be redefined.Methods:NIID patients were confirmed by examining GGC repeats in 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 proportion of different system symptoms was 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,50.0%in endocrine system.In addition,other system 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 20 NIID patients with previous surgery.The percentage of initial symptoms of NIID in different systems was listed as followings:respiratory system(37.3%)>nervous system(21.6%)>digestive system(13.7%)>urinary system(11.8%)>circulatory system(7.8%)>reproductive system(3.9%)>Locomotor system(2.0%).Median onset age in different systems was 3 years in locomotor system,28.5 years in reproductive system,30 years in digestive system,38.5 years in circulatory system,42 years in respiratory system,50 years in nervous system,and 55 years in urinary system.Conclusion:We for the first time 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.In addition,the initial symptoms and median age of onset of NIID in different systems also showed the heterogeneity of the NIID system.Part 2:Exploring a pathological detection method that can replace skin biopsyBackground and purpose:The diagnosis of NIID in the past mainly relied on autopsy.Later,it was gradually found that rectal and sural nerve biopsy could be used as antemortem pathological biopsy criteria.Still,the patient acceptance rate was low due to great traumatic nature.It was not until Prof.Sone in 2011 found that a skin tissue biopsy 10 cm above the lateral malleolus had a high positive rate that gradually became the pathologic biopsy standard for NIID.However,considering its invasive nature,this study aims to explore a non-invasive or less invasive pathological detection method.Methods:The pathological data,including previous surgical specimens of different tissues,of patients who met the diagnostic criteria of NIID were collected.Urine samples from 10 patients were collected simultaneously and prepared into paraffin sections for p62 and UB immunohistochemical staining to assess specificity and sensitivity.Results:A total of 35 tissue samples from 20 patients with previous surgery were obtained.Of all the tissues,33cases(94.3%)showed P62 and UB positivity,while only 2(5.7%)cases were negative.All the samples were of gastric tissues.Among six cases of skin biopsy pathology,5 cases(83.3%)were p62 and UB positive and 1 case(16.7%)was negative.For the patient with negative skin staining,a paraffin section of the bladder tissue was taken ten years ago and stained with p62 and UB,which showed strong positivity.A total of 10 patients’ urine samples were collected,and only 1(10%)immunohistochemical staining was positive for p62 and UB on immunohistochemical staining.Conclusions:The sensitivity of previous surgical specimens may be higher than that of previous skin biopsy tests,which can be used as a reliable and patient-friendly alternative to skin biopsy for pathological diagnosis of NIID.Although urine tissue is a simple,convenient,and harmless detection method for patients,considering its low positive rate,it is not recommended as a routine detection method.Still,it can be used as an alternative detection method for patients who do not want to undergo histopathological biopsy.Part 3:Postural tremor is also one of the early clinical phenotypes of NIIDBackground and purpose:NIID was earlier described as a neurodegenerative disease with various clinical phenotypes that mainly affects the brain,manifesting cognitive impairment,limb weakness,paresthesia,autonomic dysfunction,ataxia,Parkinson’s symptoms,epileptic seizures,episodic consciousness impairment,stroke-like episodes,and encephalitis,etc.,with a lack of specific clinical features.With the research on the genetic progress of NIID,in 2019,it was discovered that the repeat expansion of GGC trinucleotide in the NOTCH2NLC gene is an important pathogenic factor in the occurrence of NIID.A recent work from the same group showed that expanded GGC repeats in the NOTCH2NLC gene causes NIID and NIID-related diseases including parkinson’s disease,frontotemporal dementia,alzheimer disease,parkinson’s syndrome,adult brain white matter disease and ET.But as genetic studies on notch2nlc progressed,essential tremor(ET)was found to be closely related to its genes,but our clinical case suggested that ET might be merely an early manifestation of NIID rather than a true ET.The primary purpose of this section is to confirm that essential tremor-like features are only one of the early manifestations of NIID and not true ET.Methods:We collected and analyzed the clinical data of a pedigree of 16 patients who had been misdiagnosed as essential tremor(ET).The clinical data included symptoms,signs,imaging features,pathological features,and genetic analysis.Results:The proband was initially presented with typical action tremors,which improved with alcohol consumption,had a positive family history,and no significant cranial MRI abnormalities.The patient,therefore,was diagnosed with ET.As the disease progressed,the patient gradually developed memory impairment.There was a typical "ribbon sign" at the corticomedullary junction on subsequent magnetic resonance DWI sequences,and pathological biopsy of the esophagus revealed eosinophilic intranuclear inclusions positive for p62 and UB.Further testing of the FMR1 gene was performed to exclude fragile Xassociated tremor/ataxia syndrome(FXTAS),and the diagnosis of NIID was made.Following the discovery of NOTCH2NLC as the causative gene of NIID,retrospective follow-up and testing of the entire family again revealed the presence of the typical "ribbon sign " at the corticomedullary junction on magnetic resonance DWI sequences in some patients and p62 and UB positive intranuclear inclusions were observed on skin biopsy,and,finally,the diagnosis of NIID was confirmed.Conclusions:NOTCH2NLC gene is not accurately regarded as one of the pathogenic genes of ET,and postural tremor may be only one of the early clinical phenotypes of NIID.