| BackgroundNeuronal intranuclear inclusion disease(NIID)is a rare neurodegenerative disease characterized by the presence of eosinophilic hyaluronic acid nucleus inclusion bodies in multi-system tissue cells.The clinical manifestations of NIID are extremely heterogeneous and lack specificity.The typical MRI manifestations is linear hyperintensity in the corticomedullary junction on diffusion-weighted imaging(DWI).Whereas,recent research reported that not all of the NIID patients carried the typical DWI features,which makes it very difficult to distinguish NIID from other neurological diseases.The diagnosis requires an autopsy.Before 2011,researchers reported about 40 cases of NIID diagnosed by autopsy or rectal and sural nerve biopsy globally.However,among these diagnostic methods,autopsy is lagging,and rectal biopsy and sural nerve biopsy are too harmful to patients,which makes the diagnosis of NIID difficult during the lifetime.In 2011,Japanese scholar Sone and others discovered ubiquitin-positive nuclear inclusion bodies in skin tissue cells,which greatly improved the diagnostic efficiency of NIID.With the continuous deepening of research,subsequent studies have found that similar nuclear inclusion bodies are also found in the skin tissue cells of patients with certain trinucleotide duplication diseases(such as FXTAS,OPML and OPDM),and their clinical and MRI manifestations are also very similar to NIID,which makes the diagnostic reliability of skin biopsy decreased.Further research found that the pathogenic gene of FXTAS is FMR1,and the pathogenic genes of OPDM and OPML are LRP12 and LOC642361/NUTM2B-AS1 respectively.This finding confirms that the pathogenic genes of these trinucleotide duplication diseases are not the same.In 2019,Chinese and Japanese researchers found that the abnormal repetitive amplification of the NOTCH2NLC gene GGC may be related to the pathogenesis of adult NIID.Subsequent reports pointed out that abnormal repetitive amplification of the NOTCH2NLC gene GGC was also found in some patients with PD,ET or unexplained leukoencephalopathy,but subsequent skin biopsies of patients who tested positive for the NOTCH2NLC gene found characteristic Nuclear inclusion bodies.The purpose of this study is to initially explore the diagnostic correlation of abnormal GGC amplification of NOTCH2NLC gene,nuclear inclusions found in skin biopsy and characteristic MRI findings,and their role in the pre-mortal diagnosis of NIID.ObjectiveThe purpose of this study is to initially explore the GGC abnormal amplification of the NOTCH2NLC gene,the correlation between nuclear inclusions found in skin biopsy and the characteristic MRI diagnosis,and focus on the role of the GGC abnormal amplification of the NOTCH2NLC gene in the diagnosis of NIID.MethodsA collection of 11 patients who were diagnosed as NIID patients through clinical manifestations and MRI imaging manifestations in the Department of Neurology of the First Affiliated Hospital of Zhengzhou University from July 1,2019 to August 30,2020.Perform a skin biopsy to detect the presence of ubiquitin-positive nuclear inclusion bodies to diagnose NIID,and perform CGG repeats of the FMR1 gene to exclude fragile X tremor/ataxia syndrome,and diagnose NIID based on the diagnostic procedure of Japanese scholar Sone in 2016.Repetitive primer polymerase chain reaction(RP-PCR)was used to detect the GGC repetitions in the NOTCH2NLC gene of 11 suspected patients,and the GGC abnormal repetitions≥ 66 were the standard diagnosis of abnormal mutations.Finally,compare the two diagnosis results,summarize and analyze the clinical manifestations,imaging manifestations,skin biopsy results and genetic results of confirmed NIID patients,and analyze the correlation and consistency of the three diagnostic methods using Kappa consistency analysis and Fisher’s precise probability method.ResultsAmong the 11 suspected adult NIID patients,6 showed ubiquitin-positive nuclear inclusions in skin biopsies,and 5 of them showed typical linear hyperintensity at the cortex-medullary junction of DWI.The 6 patients with ubiquitin-positive nuclear inclusion bodies all had less than 45 FMRI CGG repeats,31,30,30,31,25,and 33,respectively.According to sone’s diagnosis process in 2016,5 cases of adult NIID were diagnosed in this study.In addition,genetic testing of 6 patients with positive skin biopsy showed that the amplification of NOTCH2NLC GGC repeats ranged from 66 to 170.Therefore,6 patients were diagnosed with NIID through NOTCH2NLC genetic testing.1.General demographic and clinical characteristics.There are 6 confirmed NIID patients,including 2 males and 4 females.4 patients had acute or subacute onset,and 2 patients had chronic onset,with a course of 24-0.3(7.36±10.11)months.2 cases had family history(2/6,33.3%),four cases were sporadic cases(4/6,66.6%).There is no significant difference in clinical manifestations between the two.The clinical manifestations are extremely heterogeneous.Autonomic dysfunction is the most common(6/6,100%).Autonomic dysfunction includes sweating abnormalities(4/6,66.6%)and pupil contraction abnormalities(3/6,50%),gastrointestinal symptoms(3/6,50%),postural dizziness(2/6,33.3%)and abnormal bladder function are visible(2/6,33.3%);followed by headache(5/6,83.3%)and dementia(4/6,66.6%);It peripheral neuropathy(3/6,50%),muscle weakness(2/6,33.3%),Parkinson’s syndrome(2/6,33.3%)and disturbance of consciousness(1/6,16.7%)can also be seen.2.Imaging performance.On MRI images of 6 patients diagnosed with NIID,5 patients showed typical DWI epithelial medulla junction hyperintensity(5/6),6 patients all showed bilateral ventricular white matter lesions(6/6)and 5 patients showed enlarged ventricles(5/6);2 cases of T2 FLAIR showed obvious pons hyperintensity(2/6);1 case of T2 FLAIR had symmetrical hyperintensity in the cerebellar midfoot(1/6).The sensitivity of a typical DWI high intensity signal is 5/6(83.3%),the specificity is 5/5(100%),the positive predictive value is 5/5(100%),and the negative predictive value is 5/6(83.3%).3.Skin biopsy and genetic testing.The positive rate of HE staining for eosinophilic inclusions in the skin biopsy of 6 patients with confirmed NIID was 100%(6/6),the positive rate of ubiquitin was 100%(6/6),and the positive rate of electron microscope was 33.3%(2/6).Extended GGC repeats were found in one NOTCH2NLC allele of each NIID patient,which were 128,170,66,105,103,and 14,respectively.Among the 6 confirmed NIID cases,the positive rate of abnormal GGC duplication in NOTCH2NLC was 100%(6/6).The sensitivity,specificity,positive predictive value and negative predictive value of skin biopsy and NOTCH2NLC GGC repeat amplification were 5/5(100%),respectively.4.Analysis of correlation and consistency between skin biopsy and genetic testing.The three diagnostic methods of NIID were compared through Fisher’s exact probability method and Kappa consistency analysis.Repeated amplification of NOTCH2NLC GGC was completely consistent with skin biopsy(P=0.004,K=1),and typical DWI features showed high consistency with them(P=0.031,K=0.82).ConclusionThe GGC abnormal repetitive mutation of NOTCH2NLC gene has strong consistency with the characteristic nuclear inclusion bodies that are positive for ubiquitin found on skin biopsy.Therefore,we preliminarily believe that NOTCH2NLC genetic testing should become an important step in the process of diagnosing NIID before death.Then,considering the invasiveness of skin biopsy and the limitations of clinical acceptance,NOTCH2NLC genetic testing may be able to replace skin biopsy as a premortem diagnosis NIID is an important method,especially for Asian people.But it still needs a larger sample of clinical studies to confirm. |
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