Case Review: An unusual presentation of amyotrophic lateral sclerosis-like symptoms in confirmed adult-onset neuronal intranuclear inclusion disease

Case Review: An unusual presentation of amyotrophic lateral sclerosis-like symptoms in confirmed adult-onset neuronal intranuclear inclusion disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Case Review: An unusual presentation of amyotrophic lateral sclerosis-like symptoms in confirmed adult-onset neuronal intranuclear inclusion disease Siyuan Liu, Kang Wang, Xiaoqun Ba, Fang Ji, Jianfang Zhang, Jiajia Zhou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7790975/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Neuronal intranuclear inclusion disease (NIID) is defined via the presence of histopathologic eosinophilic hyaline intranuclear inclusion within not only the central and peripheral nervous system, but also the autonomic system as well as several visceral organs and dermal cells. The presence of these intranuclear inclusions produces a gradually progressive neurodegenerative disease characterized by a GGC repeat in the 5’ end of the Notch 2 N-terminal like C ( NOTCH2NCL ) gene. The primary types of clinical manifestation of NIID are exhibited by muscle weakness, dementia, and parkinsonism type. With NIID attaining a high heterogeneity in terms of clinical presentation, it is often easily misdiagnosed with other diseases including amyotrophic lateral sclerosis (ALS). Similar to NIID, ALS may also arise through the mutation of the NOTCH2NCL gene, leading to an extended GGC repeat and can coexist with NIID as reported by two cases. With this being mentioned, it can be hypothesized that ALS may contribute to a special phenotype of NIID and may attain comparable clinical attributes upon clinical diagnosis. Case presentation: In this case review, although the clinical presentation was highly indicative towards ALS, the patient was confirmed NIID via genetic analysis and skin biopsy. This can be further attributed to the absence of sensory and autonomic nerve impairment during the preliminary manifestation, and physical examination with upper motor neuron signs as well as the lack of hyper-intensive signals in the corticomedullary junctions in DWI. Conclusion: This review aims to provide insights towards the differential diagnosis of NIID with diseases exhibiting similar manifestation such as ALS. Neuronal intranuclear inclusion disease Amyotrophic lateral sclerosis NOTCH2NCL gene Autonomic nerve Amyotrophy Figures Figure 1 Figure 2 Background Neuronal Intranuclear Inclusion Disease (NIID), is a rare chronic progressive neurodegenerative disease that can be defined by the presence of histopathologic eosinophilic hyaline intranuclear inclusions within not only both central and peripheral nervous system, but also the autonomic nervous system, visceral organs, and dermal cells 1 , 2 , 3 , 4 . The etiology of NIID may be either sporadic or familial, where the first reported NIID case can be dated back to 1968 and until 2011, only 40 NIID-affected individuals have been identified via post-mortem brain biopsy 3 . Whilst the pathogenesis of NIID still remains indefinite, the identification of an extended GGC repeat can be located at the 5’ end of the Notch 2 N-terminal like C ( NOTCH2NLC ) via long-read genome sequencing (LRS) of the dermal tissue obtained during biopsy 3 , 4 . This enabled the clarification of the hereditary basis of NIID 3 , 4 . Although both sporadic and familial NIID have been reported in previous studies, the onset of NIID can vary greatly and is commonly categorized into three subgroups depending primarily on the age of onset: infant, juvenile, and adult forms 3 . The clinical manifestations of adult-onset familial NIID are highly heterogenous where the diagnosis of NIID can also be classified into dementia-dominant (NIID-D), muscle weakness-dominant (NIID-W), with or without parkinsonism-dominant (NIID-P) type 5 . By inferring to these types of manifestations, there are a plethora of symptoms of NIID that may be exhibited, including dementia, peripheral neuropathy, autonomic dysfunction, cerebellar ataxia, parkinsonism, stroke like episodes, disturbance of consciousness, and encephalitic episodes 5 , 6 . However, when the patient is presented with limb atrophy and bilaterally positive Babinski sign, without dementia and Diffuse Weighted Imaging (DWI) abnormalities in the corticomedullary junction, it is hard to differentiate from amyotrophic lateral sclerosis (ALS), as autonomic dysfunction in ALS patients is increasingly recognized (e.g., urinary urgency and incontinence) 7 . ALS, is a fatal neurodegenerative disease which involves the damage of both upper motor neuron (UMN) and lower motor neuron (LMN) functions, thereby affecting the bulbar, cervical, thoracic, or lumbar segments 7 . While the clinical manifestations of ALS may vary to a certain degree, the most prevalent is weakness and atrophy of the proximal limb muscles 7 , 8 . However, 25%-30% of cases may be presented as dysarthria, dysphagia, dysphonia, and less frequently, displayed as dyspnea 7 . According to the dissimilar onset and spread, ALS can be divided into 16 phenotypes, with the phenotype of bulbar and spinal cord-onset being the most common presentations. The less frequent presentations are flail arm and leg syndrome, primary lateral sclerosis, progressive muscular atrophy, respiratory onset, hand hemiplegia 7 . With the low life expectancy of ALS, the phenotypes of flail arm and leg contributes to the best prognosis. However, when ALS patients exhibit flail arm syndrome (FAS) in the absence of autonomic dysfunction, it is difficult to differentiate from NIID. The identification of GGC repeat within the NOTCH2NLC gene is also interestingly observed in specific patients with a clinical diagnosis of ALS.Thus, we can infer that ALS-like manifestation may be the special phenotype of NIID and has the potential to coexist with NIID due to specific part(s) of the pathophysiology ALS shares with NIID 9 . Thus far, there are only a handful of cases of NIID with clinical manifestation of ALS 9 , 10 , 11 . In our case review, a patient was reported to have confirmed NIID, coexisting with symptoms and signs of ALS in conjunction with observable characteristics of FAS, a variant phenotype of ALS. However, as the disease course established for over 5 years, the patient had gradually developed autonomic and respiratory dysfunctions. Case presentation A 53-year-old female patient was admitted to our hospital on October 7, 2022, due to weakness of limbs for more than 10 years and had difficulty in urination for more than 3 years. The patient experienced difficulty in lifting heavy objects 10 years ago and developed weakness of both upper limbs which had gradually aggravated. 6 years ago, the patient was unable to lift both upper limbs, accompanied by proximal muscle atrophy, with no abnormalities whilst walking on flat surfaces. When she went to a local hospital for diagnosis, she was suspected of possible FAS. Gradually, she was experiencing lower limb weakness. At the time of admission, the patient was completely inadequate to lift the proximal ends of upper limbs and would fall upon climbing up stairs and stated that she could only walk on flat surfaces. Additionally, the patient began to experience urination difficulty with an increase in frequency and urgency 3 years ago, which has been progressively deteriorating. Half a year ago, upon walking for a prolonged duration, she felt chest tightness with no chest pain and is often alleviated by rest. She had denied family history of neuromuscular disorders. Physical examination of the patient indicated muscle weakness in all limbs with grade I for proximal muscle strength, grade III for distal muscle strength of both upper limbs and grade IV for both proximal and distal muscles of both lower limbs. Bilateral deltoid, biceps, and triceps had significantly atrophied with slight atrophy in the first dorsal interosseus muscle. Fasciculations were not observed in the tongue and in all extremity muscles. All limbs’ deep tendon reflexes were brisk. Babinski’s signs were positive bilaterally with bilateral Hoffman’s sign being negative. The patient had normal cognitive function with a score of 29 in min-mental state examination (MMSE), with normal cranial nerve function and normal sensory nerve test. Magnetic resonance imaging (MRI) of the brain portrayed no significant abnormalities in the corticomedullary junction in T1-weighted, T2-weighted, diffuse weighted imaging (DWI) and Fluid attenuated inversion recovery (FLAIR) sequence (seen in Fig. 1 ). MRI of the cervical spinal cord indicated two short line-like high-intensity signals in the T2-weighted imaging at the level of C1 and C2 vertebrae, suggesting potential spinal cord degeneration (seen in Fig. 1 ). The Nerve conduction examination has shown a slightly reduced motor conduction velocity (MCV) in almost all tested motor nerves (seen in Table 1 ), while compound muscle action potential (CMAP) partly decreased and distal latencies prolonged only in the right median and right peroneal nerve. The ratio and latency of F-waves were normal in all tested motor nerves. The damage to sensory nerves was less severe than that to motor nerves, with a slight reduction of conduction velocity in both bilateral median and ulnar nerves coupled with decreased sensory nerve action potentials in both the left sural and superficial peroneal nerves (seen Table 1 ). Additionally, the needle electromyogram (EMG) study indicated that there were no abnormal insertional activity and spontaneous discharge unit in the tested muscles. However, with normal interference patterns, partial muscle latencies of motor unit potential (MUP) were extended to varying degrees, and all muscle amplitudes were enhanced. (seen in Table 2 ). Table 1 Nerve Conduction study results of the patient’s Extremities. Motor nerve Sensory never Never Latency (ms) MVC (m/s) CMAP (mV) F-wave latency (ms) Never SCV (m/s) SNAP (µV) R Median 4.5↑ 40.3 ↓ 5.1↓ 33.1 R Median 44.6 ↓ 10.9 L median 4.0 43.6 8.4↓ 33.1 L median 47.9↓ 20.4 R Ulnar 2.7 44.2 ↓ 8.5 (> 4.7) 32.3) R Ulnar 44.7↓ 12.7 L Ulnar 2.7 43.3↓ 9.0↓ 33.4 L Ulnar 48.6↓ 9.5 R Peroneal 5.4↑ 38.2↓ 1.3 (> 0.7) R Sural 46 15.4 L Tibial 4.7 34.7↓ 15.9 58.0 L Sural 40 7.5↓ R Tibial 5.1 35.5↓ 12.2 61.5 R Superficial peroneal 40.4 25.8 L Perineal 4.8 36.4↓ 0.3↓ L Superficial peroneal 44 10.1↓ R: right, L: left, MCV: motor conduction velocity, CMAP: compound muscle action potential, SCV: sensory conduction velocity ,SNAP: sensory nerve action potential. Table 2 Needle Electromyogram results of the patient. MUP Muscle Latency Amplitude Interference R 1st dorsal interosseous Normal increased Normal R abductor policis brevis Normal increased Normal R deltoid Prolonged increased Normal R sternocleidomastoid Prolonged increased Normal R Trapezius increased Normal R T9 parasternal Prolonged increased Normal L Tibialis anterior Prolonged increased Normal L Vastus medialis Normal increased Normal Furthermore, the urodynamic test revealed that the residual urine volume was more than 100 milliliters (ml), and the bladder detrusor muscles were overactive with obstruction in the lower urinary tract. Computed tomography (CT) scans of the chest were shown to be normal. The Pulmonary function test revealed that there was a decrease in the forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1), with a diminished rate of FEV1. Furthermore, all values of the forced expiratory volume curve had similarly decreased. The patient exhibited weak and unsustainable exhalation with a diminished maximum ventilation volume. It is also important to note that there was a decrease in both carbon monoxide diffusion capacity and specific diffusion capacity, which was made prevalent via lung diffusion testing. As the patient exhibited both UMN and LMN impairment with the autonomic nerves, as well as subclinical sensory and respiratory function abnormalities, it is evident that this is not a typical motor neuron disease or peripheral neuropathy. Considering the significant abnormal autonomic functions, a genetic test was conducted in which it revealed two abnormal repeated sequence of NOTCH2NLC gene, 21 and 97 times, respectively. The site of 97 repeated units were identified as the pathogenic genes. The patient’s parents expired due to natural causes and her daughter had rejected for genetic test. Further skin biopsy was thus proceeded and indicated endodermal interstitial collagen fiber hyperplasia with eosinophilic and p62-positive intranuclear inclusions in dermal cells (seen in Fig. 2 ). In essence, the patient was diagnosed with NIID, and no special treatments were provided. Skin biopsy was conducted and indicated endodermal interstitial collagen fiber hyperplasia with eosinophilic and p62-positive intranuclear inclusions in dermal cells, ultimately confirming the diagnosis of NIID. Discussion and conclusion The patient in our case review displayed an onset of progressive muscle weakness, originating from the bilateral proximal upper limbs to distal upper limbs and lower limbs. The weakness and atrophy present in the bilateral proximal upper limb were more severe than other muscles, giving the impression of “person-in-the-barrel”, also known as FAS. FAS is known as the atypical ALS with significantly better prognosis than typical ALS. The neurological examination also indicated UMN and LMN abnormality without sensory dysfunctions. Thus, ALS should be considered as a differential diagnosis. The patient was clinically diagnosed with bladder dysfunction more than 5 years after the clinical onset, casting doubt on the ALS diagnosis. However, the clinical presentation of respiratory dysfunction, supported the possibility of ALS as the diagnosis. Nerve conduction study indicated a reduction in both MCV and SCV, suggesting clinical dysfunction of motor nerves and subclinical dysfunction of sensory nerves. Needle EMG showed chronic denervation in the absence of active denervation, together, with subclinical dysfunction of sensory nerves and significant autonomic nerves impairment, ALS may be excluded as the diagnosis. Hence, the patient was arranged for both a gene test and skin biopsy, ultimately confirming the diagnosis of NIID. Adult-onset NIID exhibits a plethora of clinical presentations which can fall under three distinctive categories depending on the manifestations, including NIID-D, NIID-M, and NIID-P 6 . Less common symptoms of NIID were leukoencephalopathy, paroxysmal symptoms, movement disorders, autonomic dysfunction, essential tremors, or cognitive impairment. These symptoms can overlap and occur simultaneously. Due to the variable clinical manifestations and multiple systematic involvements, occasionally it can be difficult to diagnose, let alone to be differentiated from other diseases such as ALS and peripheral neuropathy. In our patient, there was a coexistence of NIID-M and autonomic dysfunction. The patient displayed profound muscle atrophy and weakness, particularly in the proximal upper limbs with slight deterioration of the lower limbs. This is demonstrated to be distinct from earlier researches, which indicated that NIID-M frequently initiated from lower limb weakness and is more severe when compared to upper limbs 12 , 13 . Reports have also shown that patients with NIID-M not only predominantly portrayed signs of distal lower limb weakness coupled with deterioration, but also had mild dementia coupled with distally prevailing sensory impairments 12 , 13 . It is important to note that it is rare to observe muscle weakness in the proximal upper limbs. As previously reported, clinical and subclinical peripheral neuropathies were common in more than 40% NOTCH2NLC -related NIID cases in patients from China 12 . This study coincided with our case where the patient had normal cognition in conjunction with subclinical sensory impairment. Autonomic dysfunction was also frequently observed (ranging from 20% to 40%) in NIID patients and the incidence rate can be positively correlated with the duration of the disease 12 . Our patient exhibited bladder dysfunction 7 years after the onset of the disease, which may be due to the pathology of intranuclear inclusions as well as diffuse inflammatory cell infiltration as indicated via the bladder biopsy report. Further urodynamic test demonstrated bladder dysfunction, including both detrusor overactivity and decreased bladder sensation, as well as a large post-void residual urine. However, the manifestation of UMN dysfunction and pulmonary function impairment displayed in our case made the diagnosis of NIID more perplex. It has been reported that NIID patients typically exhibits muscle atrophy, negative pathologic reflex as well as a reduction in tendon reflex response 1 , 2 , 13 . However, our patient displayed not only hyperreflexia in all extremities, but also portrayed bilaterally positive Babinski’s sign. Although the patient was presented with a mild spinal cord degeneration in the cervical spinal cord, it is not adequate enough to explain the damage of both LMN and UMN. With this being mentioned, a differential diagnosis between NIID and ALS should be made clear for which they attain similar characteristics upon clinical examinations. Through the conduction of Nerve Conduction Test, Needle EMG and Neuroimaging, it has played an essential role in our differential diagnosis of NIID. The decrease and reduction in MCV, SCV, CAMP, and SNAP reported via nerve conduction test were commonly observed in NIID-M patient. In ALS, however, these values should generally be normal or near normal and can be excluded when MCV is observed to be lower than 70% with distal motor latencies over 30% of the lower and upper limit of normal values. Abnormalities within the sensory nerve conduction test without entrapment syndromes and coexisting peripheral nerve disease can also exclude ALS as the diagnosis 15 . It should also be noted that needle EMG portraying chronic denervation was not frequently observed in the patients with NIID whilst respiratory dysfunction was always seen in ALS, and only reported in four NIID patients 10 , 11 , 16 , 17 , However, recent studies discovered that NIID may coexist with ALS or ALS-like symptoms and has been observed in two patients, both of which had respiratory dysfunction and expired due to respiratory failure or pneumonia 6 , 9 . Interestingly, neuronal intranuclear protein inclusions 10 , 11 and NOTCH2NCL gene mutation 18 , 19 , 20 may be detected in ALS patients. As reported, the time required for respiratory support therapy in NIID patients with ALS ranged from 5 to 22 months and passed away 1.5 to 4.5 years after onset 6 . In contrast, NIID patients with ALS-like presentation required 48 months of respiratory support and expired 15 years after onset 9 . Thus, NIID patients with ALS-like symptoms may contribute to a special phenotype where respiratory dysfunction is prevalent whilst the prognosis may be related to the degree of similarity to ALS. Thus, our patient whom had been diagnosed with NIID with clinical similarity to ALS, though not laboratory supported, displayed respiratory dysfunction 10 years after onset and did not require respiratory support. Similar to NIID, ALS may also arise from an extended GGC repeat in the NOTCH2NCL gene, suggesting the comparable clinical manifestations 9 . Yuan et al 20 identified four (0.73%) of the 545 ALS patients harboring the GGC repeat expansions, and the sizes of the expanded repeats in these four ALS patients were 44, 54, 96, and 143, respectively. Another study revealed the distribution of the GGC repeat sizes in the ALS patients did not differ from healthy people. The sizes of the GGC repeats ranged from 7 to 36 in the ALS patients and 4 to 46 in the controls 18 . Therefore, the role of NOTCH2NLC GGC repeat expansion in ALS remains uncertain, although having a profound effect on NIID development. The number of GGC repeats in NOTCH2NLC -related NIID ranged from 66 to 517. The NOTCH2NLC GGC repeat size in NIID-W patients were longer (median 155.00) compared to other types. GGC repeat number is also negatively correlated with the age of the patient at disease onset, i.e., the larger the repeat size, the younger the onset age 12 . Our patient had a repeat size of 97 times which correlated with the age of disease onset at 43. The presence of GGC abnormal repeat expansions in the 5′ region of NOTCH2NLC gene, results in a polyglycine-containing protein, uN2CpolyG expression. This protein in a mice model produced locomotor alterations, neuronal cell loss, and premature death of the animal 19 . By delving into this case, few limitations were present. Firstly, the sphincter EMG was not examined and was unable to make sure the autonomic nervous function was impaired. Secondly, though NIID can be diagnosed, there is no effective treatment, where the only option is to control the symptoms, namely muscle weakness and atrophy, impaired consciousness, and sensory impairments via medications prescribed 14 . Lastly, our patient required a prolonged duration of follow-up observation. By controlling such aspects, it aims to improve one’s quality of life and can be accomplished via levodopa and phenytoin followed by carbamazepine for patients with NIID-P and NIID with seizures, respectively 14 . Recently, however, different therapeutic strategies have been put forth for NIID such as CRISPR-based therapy, anti-sense oligonucleotide therapy, small molecule RNA drugs, and RNA interference 21 . Although promising, it attains high possibility leading to out-of-target therapy as well as low specificity 14 . Thus, it is possible to target the NOTCH2NLC genes or the protein uN2CpolyG for a promising treatment in the future. Abbreviations NIID Nuronal Intranuclear Inclusion Disease LRS Long-read Genome Sequencing NIID-D Nuronal Intranuclear Inclusion Disease Dementia-Dominant NIID-W Nuronal Intranuclear Inclusion Disease Muscle Weakness-Dominant NIID-P Nuronal Intranuclear Inclusion Disease Parkinsonism-Dominant ALS Amyotrophic Lateral Sclerosis UMN Upper motor neuron LMN Lower motor neuron FAS Flail arm syndrome MMSE Min-mental state examination MRI Magnetic resonance imaging DWI Diffuse weighted imaging Flair Fluid attenuated inversion recovery MCV Motor conduction velocity CMAP Compound muscle action potential EMG Electromyogram MUP Motor unit potential CT Computed tomography FVC Forced Vital Capacity Declarations Ethics approval and consent to participate: The patient signed the written informed content for the publication of this report. We also obtained approval (No.IIT20250772B) from the ethics committee of First Affiliated Hospital, School of Medicine, Zhejiang University. Consent for publication: All authors agreeed to publish this article on the jouranl of BMC neurology and comfirmed the authors listing. Availability of data and materials: The datasets generated or analysed during this study are presented in this article. Requests to access any other datasets should be directed to the corresponding authors. Competing interests: The study was conducted in the absence of any commercial or financial relationships that could be may potentially influence the manuscript . The authors have no conflicts of interest to declare. Funding: Our study was not supported by any funder or sponsor. Authors' contributions: Siyuan Liu wrote the original draft and revised the draft. Meiping Wang and Kang Wang collected the clinical data, interpreted data , revised the draft. Xiaoqun Ba confirmed pathology. Fang Ji confirmed the data of nerve conduction and EMG . 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Yuan Y, Liu Z, Hou X, Li W, Ni J, Huang L, Hu Y, Liu P, Hou X, Xue J, Sun Q, Tian Y, Jiao B, Duan R, Jiang H, Shen L, Tang B, Wang J. Identification of GGC Repeat Expansion in the NOTCH2NLC Gene in Amyotrophic Lateral Sclerosis. Neurology. 2020;95(24):e3394–405. https://doi.org/10.1212/WNL.0000000000010945 . Xu K, Li Y, Allen EG, Jin P. Therapeutic Development for CGG Repeat Expansion-Associated Neurodegeneration. Front Cell Neurosci. 2021;15:655568. https://doi.org/10.3389/fncel.2021.655568 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7790975","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":546474515,"identity":"ad3f1470-35e4-4d0a-8db6-9c3912ffd4cb","order_by":0,"name":"Siyuan Liu","email":"","orcid":"","institution":"First Affiliated Hospital Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Siyuan","middleName":"","lastName":"Liu","suffix":""},{"id":546474516,"identity":"14ac3ad5-31d7-40bb-aeb8-8dccdfc8026a","order_by":1,"name":"Kang Wang","email":"","orcid":"","institution":"First Affiliated Hospital Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Kang","middleName":"","lastName":"Wang","suffix":""},{"id":546474517,"identity":"51994bbe-5ff5-4fd6-947b-46185504a252","order_by":2,"name":"Xiaoqun Ba","email":"","orcid":"","institution":"First Affiliated Hospital Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoqun","middleName":"","lastName":"Ba","suffix":""},{"id":546474518,"identity":"b5b5d677-9b30-4654-8d57-2767386b760d","order_by":3,"name":"Fang Ji","email":"","orcid":"","institution":"First Affiliated Hospital Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Ji","suffix":""},{"id":546474519,"identity":"6f1f33dd-3fd4-4fe7-82a7-f3f1f3958e77","order_by":4,"name":"Jianfang Zhang","email":"","orcid":"","institution":"First Affiliated Hospital Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Jianfang","middleName":"","lastName":"Zhang","suffix":""},{"id":546474520,"identity":"33fc9b6a-0791-40c9-b942-9436a58edab0","order_by":5,"name":"Jiajia Zhou","email":"","orcid":"","institution":"First Affiliated Hospital Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Jiajia","middleName":"","lastName":"Zhou","suffix":""},{"id":546474521,"identity":"d274866c-f123-4d9d-babb-0475252f47d6","order_by":6,"name":"Meiping Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYPACCQY2BgbGxz8qGJghXCK1MBsznCFeCxiwSTO2wUzAAwyOnz386kaFRR6fdPtl48J5dewGB5gP3uZhsMvDqeVMXpp1zhmJYjaZM4WPZ25jYzY4wJZszcOQXIxLi9mBHDPj3DaJxDaJnGQD3m08QC08ZtI8DAcSG3BpOf8GqOUfWEuaBO8cCaAW/m/4tdzIMX6c2wDSkn5MmrfBAGQLG14t9jfemDHnHAP6RSKH2XDGsQRmycNsxpZzDJJxapHszzH+nFNTlyc/I/3hgw81dcl8x5sf3nhTYYdTCxCwgWIhgYGBxwDES4ZEpgFu9UDA/AGihf0BiGeHV+0oGAWjYBSMSAAAHf1TGITDF9gAAAAASUVORK5CYII=","orcid":"","institution":"First Affiliated Hospital Zhejiang University","correspondingAuthor":true,"prefix":"","firstName":"Meiping","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-10-06 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12:35:59","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":103900,"visible":true,"origin":"","legend":"","description":"","filename":"4ddc18216cef42ab9f11047969e255e91structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7790975/v1/2ee73dc991f06c4693ca5810.xml"},{"id":96181174,"identity":"5db72ba6-e31b-4570-834a-1618e63a27e1","added_by":"auto","created_at":"2025-11-18 12:35:59","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":110449,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7790975/v1/eca7f0c2bdc404fdbe5e8bd5.html"},{"id":96181170,"identity":"eb9511d3-7d3a-432c-bf54-859522f58abf","added_by":"auto","created_at":"2025-11-18 12:35:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1008214,"visible":true,"origin":"","legend":"\u003cp\u003eBrain and cervical spine cord MR Imaging of the patient. T1-weighted (A, B), T2-weighted scans (C, D) and DWI (G, H) indicated no abnormality. FLAIR sequence (E, F) existed scattered high-intensity signal in sub-cortical location (shown by arrowhead on E). T2-weighted scans (I, k) of cervical spinal cord showed short line-like high-intensity signal (shown by arrow in I) situated at the level of C1 and C2 vertebrae. T1-weighted scan (J) were normal.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7790975/v1/32e9e6ae037b6ac24e1eaf22.jpeg"},{"id":96181167,"identity":"ed681ce1-5dfe-448a-b1ad-aad2125c0e38","added_by":"auto","created_at":"2025-11-18 12:35:59","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":125851,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological findings of patients’ skin biopsy. Hematoxylin-eosin staining of the skin portraying sweat gland (shown as arrow in A and B) under low-power magnification (A) and high-power magnification (B). Immuno-stained anti-p62 antibody, with a dark brown appearance (shown as arrow in C), can be identified in the epithelial cells of sweat glands.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7790975/v1/417b6f9562cbd3ef6c9e4302.jpeg"},{"id":99315932,"identity":"a745257a-4916-42fc-a9a1-825c2de6a7b4","added_by":"auto","created_at":"2025-12-31 16:27:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1684315,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7790975/v1/654e48a8-c378-4d06-ac29-9f3ac735b354.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Case Review: An unusual presentation of amyotrophic lateral sclerosis-like symptoms in confirmed adult-onset neuronal intranuclear inclusion disease","fulltext":[{"header":"Background","content":"\u003cp\u003eNeuronal Intranuclear Inclusion Disease (NIID), is a rare chronic progressive neurodegenerative disease that can be defined by the presence of histopathologic eosinophilic hyaline intranuclear inclusions within not only both central and peripheral nervous system, but also the autonomic nervous system, visceral organs, and dermal cells\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The etiology of NIID may be either sporadic or familial, where the first reported NIID case can be dated back to 1968 and until 2011, only 40 NIID-affected individuals have been identified via post-mortem brain biopsy\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Whilst the pathogenesis of NIID still remains indefinite, the identification of an extended GGC repeat can be located at the 5\u0026rsquo; end of the Notch 2 N-terminal like C (\u003cem\u003eNOTCH2NLC\u003c/em\u003e) via long-read genome sequencing (LRS) of the dermal tissue obtained during biopsy\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. This enabled the clarification of the hereditary basis of NIID\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Although both sporadic and familial NIID have been reported in previous studies, the onset of NIID can vary greatly and is commonly categorized into three subgroups depending primarily on the age of onset: infant, juvenile, and adult forms\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The clinical manifestations of adult-onset familial NIID are highly heterogenous where the diagnosis of NIID can also be classified into dementia-dominant (NIID-D), muscle weakness-dominant (NIID-W), with or without parkinsonism-dominant (NIID-P) type\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. By inferring to these types of manifestations, there are a plethora of symptoms of NIID that may be exhibited, including dementia, peripheral neuropathy, autonomic dysfunction, cerebellar ataxia, parkinsonism, stroke like episodes, disturbance of consciousness, and encephalitic episodes\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e ,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, when the patient is presented with limb atrophy and bilaterally positive Babinski sign, without dementia and Diffuse Weighted Imaging (DWI) abnormalities in the corticomedullary junction, it is hard to differentiate from amyotrophic lateral sclerosis (ALS), as autonomic dysfunction in ALS patients is increasingly recognized (e.g., urinary urgency and incontinence)\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eALS, is a fatal neurodegenerative disease which involves the damage of both upper motor neuron (UMN) and lower motor neuron (LMN) functions, thereby affecting the bulbar, cervical, thoracic, or lumbar segments\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. While the clinical manifestations of ALS may vary to a certain degree, the most prevalent is weakness and atrophy of the proximal limb muscles\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, 25%-30% of cases may be presented as dysarthria, dysphagia, dysphonia, and less frequently, displayed as dyspnea\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. According to the dissimilar onset and spread, ALS can be divided into 16 phenotypes, with the phenotype of bulbar and spinal cord-onset being the most common presentations. The less frequent presentations are flail arm and leg syndrome, primary lateral sclerosis, progressive muscular atrophy, respiratory onset, hand hemiplegia\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eWith the low life expectancy of ALS, the phenotypes of flail arm and leg contributes to the best prognosis. However, when ALS patients exhibit flail arm syndrome (FAS) in the absence of autonomic dysfunction, it is difficult to differentiate from NIID. The identification of GGC repeat within the \u003cem\u003eNOTCH2NLC\u003c/em\u003e gene is also interestingly observed in specific patients with a clinical diagnosis of ALS.Thus, we can infer that ALS-like manifestation may be the special phenotype of NIID and has the potential to coexist with NIID due to specific part(s) of the pathophysiology ALS shares with NIID\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThus far, there are only a handful of cases of NIID with clinical manifestation of ALS\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. In our case review, a patient was reported to have confirmed NIID, coexisting with symptoms and signs of ALS in conjunction with observable characteristics of FAS, a variant phenotype of ALS. However, as the disease course established for over 5 years, the patient had gradually developed autonomic and respiratory dysfunctions.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 53-year-old female patient was admitted to our hospital on October 7, 2022, due to weakness of limbs for more than 10 years and had difficulty in urination for more than 3 years. The patient experienced difficulty in lifting heavy objects 10 years ago and developed weakness of both upper limbs which had gradually aggravated. 6 years ago, the patient was unable to lift both upper limbs, accompanied by proximal muscle atrophy, with no abnormalities whilst walking on flat surfaces. When she went to a local hospital for diagnosis, she was suspected of possible FAS. Gradually, she was experiencing lower limb weakness. At the time of admission, the patient was completely inadequate to lift the proximal ends of upper limbs and would fall upon climbing up stairs and stated that she could only walk on flat surfaces. Additionally, the patient began to experience urination difficulty with an increase in frequency and urgency 3 years ago, which has been progressively deteriorating. Half a year ago, upon walking for a prolonged duration, she felt chest tightness with no chest pain and is often alleviated by rest. She had denied family history of neuromuscular disorders.\u003c/p\u003e\u003cp\u003ePhysical examination of the patient indicated muscle weakness in all limbs with grade I for proximal muscle strength, grade III for distal muscle strength of both upper limbs and grade IV for both proximal and distal muscles of both lower limbs. Bilateral deltoid, biceps, and triceps had significantly atrophied with slight atrophy in the first dorsal interosseus muscle. Fasciculations were not observed in the tongue and in all extremity muscles. All limbs\u0026rsquo; deep tendon reflexes were brisk. Babinski\u0026rsquo;s signs were positive bilaterally with bilateral Hoffman\u0026rsquo;s sign being negative. The patient had normal cognitive function with a score of 29 in min-mental state examination (MMSE), with normal cranial nerve function and normal sensory nerve test.\u003c/p\u003e\u003cp\u003eMagnetic resonance imaging (MRI) of the brain portrayed no significant abnormalities in the corticomedullary junction in T1-weighted, T2-weighted, diffuse weighted imaging (DWI) and Fluid attenuated inversion recovery (FLAIR) sequence (seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). MRI of the cervical spinal cord indicated two short line-like high-intensity signals in the T2-weighted imaging at the level of C1 and C2 vertebrae, suggesting potential spinal cord degeneration (seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe Nerve conduction examination has shown a slightly reduced motor conduction velocity (MCV) in almost all tested motor nerves (seen in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), while compound muscle action potential (CMAP) partly decreased and distal latencies prolonged only in the right median and right peroneal nerve. The ratio and latency of F-waves were normal in all tested motor nerves. The damage to sensory nerves was less severe than that to motor nerves, with a slight reduction of conduction velocity in both bilateral median and ulnar nerves coupled with decreased sensory nerve action potentials in both the left sural and superficial peroneal nerves (seen Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, the needle electromyogram (EMG) study indicated that there were no abnormal insertional activity and spontaneous discharge unit in the tested muscles. However, with normal interference patterns, partial muscle latencies of motor unit potential (MUP) were extended to varying degrees, and all muscle amplitudes were enhanced. (seen in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eNerve Conduction study results of the patient\u0026rsquo;s Extremities.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eMotor nerve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u003cp\u003eSensory never\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLatency (ms)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMVC\u003c/p\u003e\u003cp\u003e(m/s)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCMAP\u003c/p\u003e\u003cp\u003e(mV)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF-wave latency\u003c/p\u003e\u003cp\u003e(ms)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNever\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSCV\u003c/p\u003e\u003cp\u003e(m/s)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSNAP (\u0026micro;V)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR Median\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.5\u0026uarr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40.3 \u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.1\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eR Median\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e44.6 \u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e10.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL median\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.4\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eL median\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47.9\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR Ulnar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.2 \u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.5 (\u0026gt;\u0026thinsp;4.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e32.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eR Ulnar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e44.7\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e12.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL Ulnar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.3\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.0\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eL Ulnar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e48.6\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e9.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR Peroneal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.4\u0026uarr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38.2\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.3 (\u0026gt;\u0026thinsp;0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eR Sural\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e15.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL Tibial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34.7\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e58.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eL Sural\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e7.5\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR Tibial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35.5\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e61.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eR Superficial peroneal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e40.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e25.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL Perineal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36.4\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.3\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eL Superficial peroneal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e10.1\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eR: right, L: left, MCV: motor conduction velocity, CMAP: compound muscle action potential, SCV: sensory conduction velocity ,SNAP: sensory nerve action potential.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eNeedle Electromyogram results of the patient.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eMUP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMuscle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLatency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAmplitude\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInterference\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR 1st dorsal interosseous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR abductor policis brevis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR deltoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProlonged\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR sternocleidomastoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProlonged\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR Trapezius\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR T9 parasternal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProlonged\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL Tibialis anterior\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProlonged\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eL Vastus medialis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eincreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFurthermore, the urodynamic test revealed that the residual urine volume was more than 100 milliliters (ml), and the bladder detrusor muscles were overactive with obstruction in the lower urinary tract. Computed tomography (CT) scans of the chest were shown to be normal. The Pulmonary function test revealed that there was a decrease in the forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1), with a diminished rate of FEV1. Furthermore, all values of the forced expiratory volume curve had similarly decreased. The patient exhibited weak and unsustainable exhalation with a diminished maximum ventilation volume. It is also important to note that there was a decrease in both carbon monoxide diffusion capacity and specific diffusion capacity, which was made prevalent via lung diffusion testing.\u003c/p\u003e\u003cp\u003eAs the patient exhibited both UMN and LMN impairment with the autonomic nerves, as well as subclinical sensory and respiratory function abnormalities, it is evident that this is not a typical motor neuron disease or peripheral neuropathy. Considering the significant abnormal autonomic functions, a genetic test was conducted in which it revealed two abnormal repeated sequence of \u003cem\u003eNOTCH2NLC\u003c/em\u003e gene, 21 and 97 times, respectively. The site of 97 repeated units were identified as the pathogenic genes. The patient\u0026rsquo;s parents expired due to natural causes and her daughter had rejected for genetic test. Further skin biopsy was thus proceeded and indicated endodermal interstitial collagen fiber hyperplasia with eosinophilic and p62-positive intranuclear inclusions in dermal cells (seen in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In essence, the patient was diagnosed with NIID, and no special treatments were provided.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSkin biopsy was conducted and indicated endodermal interstitial collagen fiber hyperplasia with eosinophilic and p62-positive intranuclear inclusions in dermal cells, ultimately confirming the diagnosis of NIID.\u003c/p\u003e"},{"header":"Discussion and conclusion","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003cp\u003eThe patient in our case review displayed an onset of progressive muscle weakness, originating from the bilateral proximal upper limbs to distal upper limbs and lower limbs. The weakness and atrophy present in the bilateral proximal upper limb were more severe than other muscles, giving the impression of \u0026ldquo;person-in-the-barrel\u0026rdquo;, also known as FAS. FAS is known as the atypical ALS with significantly better prognosis than typical ALS. The neurological examination also indicated UMN and LMN abnormality without sensory dysfunctions. Thus, ALS should be considered as a differential diagnosis. The patient was clinically diagnosed with bladder dysfunction more than 5 years after the clinical onset, casting doubt on the ALS diagnosis. However, the clinical presentation of respiratory dysfunction, supported the possibility of ALS as the diagnosis. Nerve conduction study indicated a reduction in both MCV and SCV, suggesting clinical dysfunction of motor nerves and subclinical dysfunction of sensory nerves. Needle EMG showed chronic denervation in the absence of active denervation, together, with subclinical dysfunction of sensory nerves and significant autonomic nerves impairment, ALS may be excluded as the diagnosis. Hence, the patient was arranged for both a gene test and skin biopsy, ultimately confirming the diagnosis of NIID.\u003c/p\u003e\u003cp\u003eAdult-onset NIID exhibits a plethora of clinical presentations which can fall under three distinctive categories depending on the manifestations, including NIID-D, NIID-M, and NIID-P\u003csup\u003e6\u003c/sup\u003e. Less common symptoms of NIID were leukoencephalopathy, paroxysmal symptoms, movement disorders, autonomic dysfunction, essential tremors, or cognitive impairment. These symptoms can overlap and occur simultaneously. Due to the variable clinical manifestations and multiple systematic involvements, occasionally it can be difficult to diagnose, let alone to be differentiated from other diseases such as ALS and peripheral neuropathy.\u003c/p\u003e\u003cp\u003eIn our patient, there was a coexistence of NIID-M and autonomic dysfunction. The patient displayed profound muscle atrophy and weakness, particularly in the proximal upper limbs with slight deterioration of the lower limbs. This is demonstrated to be distinct from earlier researches, which indicated that NIID-M frequently initiated from lower limb weakness and is more severe when compared to upper limbs\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Reports have also shown that patients with NIID-M not only predominantly portrayed signs of distal lower limb weakness coupled with deterioration, but also had mild dementia coupled with distally prevailing sensory impairments\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. It is important to note that it is rare to observe muscle weakness in the proximal upper limbs. As previously reported, clinical and subclinical peripheral neuropathies were common in more than 40% \u003cem\u003eNOTCH2NLC\u003c/em\u003e-related NIID cases in patients from China\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This study coincided with our case where the patient had normal cognition in conjunction with subclinical sensory impairment. Autonomic dysfunction was also frequently observed (ranging from 20% to 40%) in NIID patients and the incidence rate can be positively correlated with the duration of the disease\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Our patient exhibited bladder dysfunction 7 years after the onset of the disease, which may be due to the pathology of intranuclear inclusions as well as diffuse inflammatory cell infiltration as indicated via the bladder biopsy report. Further urodynamic test demonstrated bladder dysfunction, including both detrusor overactivity and decreased bladder sensation, as well as a large post-void residual urine.\u003c/p\u003e\u003cp\u003eHowever, the manifestation of UMN dysfunction and pulmonary function impairment displayed in our case made the diagnosis of NIID more perplex. It has been reported that NIID patients typically exhibits muscle atrophy, negative pathologic reflex as well as a reduction in tendon reflex response\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. However, our patient displayed not only hyperreflexia in all extremities, but also portrayed bilaterally positive Babinski\u0026rsquo;s sign. Although the patient was presented with a mild spinal cord degeneration in the cervical spinal cord, it is not adequate enough to explain the damage of both LMN and UMN. With this being mentioned, a differential diagnosis between NIID and ALS should be made clear for which they attain similar characteristics upon clinical examinations. Through the conduction of Nerve Conduction Test, Needle EMG and Neuroimaging, it has played an essential role in our differential diagnosis of NIID. The decrease and reduction in MCV, SCV, CAMP, and SNAP reported via nerve conduction test were commonly observed in NIID-M patient. In ALS, however, these values should generally be normal or near normal and can be excluded when MCV is observed to be lower than 70% with distal motor latencies over 30% of the lower and upper limit of normal values. Abnormalities within the sensory nerve conduction test without entrapment syndromes and coexisting peripheral nerve disease can also exclude ALS as the diagnosis\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. It should also be noted that needle EMG portraying chronic denervation was not frequently observed in the patients with NIID whilst respiratory dysfunction was always seen in ALS, and only reported in four NIID patients\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003c/sup\u003e However, recent studies discovered that NIID may coexist with ALS or ALS-like symptoms and has been observed in two patients, both of which had respiratory dysfunction and expired due to respiratory failure or pneumonia \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Interestingly, neuronal intranuclear protein inclusions\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, 11\u003c/sup\u003eand NOTCH2NCL gene mutation\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e may be detected in ALS patients. As reported, the time required for respiratory support therapy in NIID patients with ALS ranged from 5 to 22 months and passed away 1.5 to 4.5 years after onset\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In contrast, NIID patients with ALS-like presentation required 48 months of respiratory support and expired 15 years after onset\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Thus, NIID patients with ALS-like symptoms may contribute to a special phenotype where respiratory dysfunction is prevalent whilst the prognosis may be related to the degree of similarity to ALS. Thus, our patient whom had been diagnosed with NIID with clinical similarity to ALS, though not laboratory supported, displayed respiratory dysfunction 10 years after onset and did not require respiratory support.\u003c/p\u003e\u003cp\u003eSimilar to NIID, ALS may also arise from an extended GGC repeat in the \u003cem\u003eNOTCH2NCL\u003c/em\u003e gene, suggesting the comparable clinical manifestations\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Yuan et al\u003csup\u003e20\u003c/sup\u003e identified four (0.73%) of the 545 ALS patients harboring the GGC repeat expansions, and the sizes of the expanded repeats in these four ALS patients were 44, 54, 96, and 143, respectively. Another study revealed the distribution of the GGC repeat sizes in the ALS patients did not differ from healthy people. The sizes of the GGC repeats ranged from 7 to 36 in the ALS patients and 4 to 46 in the controls\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Therefore, the role of NOTCH2NLC GGC repeat expansion in ALS remains uncertain, although having a profound effect on NIID development. The number of GGC repeats in \u003cem\u003eNOTCH2NLC\u003c/em\u003e-related NIID ranged from 66 to 517. The \u003cem\u003eNOTCH2NLC\u003c/em\u003e GGC repeat size in NIID-W patients were longer (median 155.00) compared to other types. GGC repeat number is also negatively correlated with the age of the patient at disease onset, i.e., the larger the repeat size, the younger the onset age \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Our patient had a repeat size of 97 times which correlated with the age of disease onset at 43. The presence of GGC abnormal repeat expansions in the 5\u0026prime; region of \u003cem\u003eNOTCH2NLC\u003c/em\u003e gene, results in a polyglycine-containing protein, uN2CpolyG expression. This protein in a mice model produced locomotor alterations, neuronal cell loss, and premature death of the animal\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eBy delving into this case, few limitations were present. Firstly, the sphincter EMG was not examined and was unable to make sure the autonomic nervous function was impaired. Secondly, though NIID can be diagnosed, there is no effective treatment, where the only option is to control the symptoms, namely muscle weakness and atrophy, impaired consciousness, and sensory impairments via medications prescribed\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Lastly, our patient required a prolonged duration of follow-up observation. By controlling such aspects, it aims to improve one\u0026rsquo;s quality of life and can be accomplished via levodopa and phenytoin followed by carbamazepine for patients with NIID-P and NIID with seizures, respectively\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Recently, however, different therapeutic strategies have been put forth for NIID such as CRISPR-based therapy, anti-sense oligonucleotide therapy, small molecule RNA drugs, and RNA interference\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Although promising, it attains high possibility leading to out-of-target therapy as well as low specificity\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Thus, it is possible to target the \u003cem\u003eNOTCH2NLC\u003c/em\u003e genes or the protein uN2CpolyG for a promising treatment in the future.\u003c/p\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv id=\"AGS1\" class=\"AbbreviationGroupSection\"\u003e\u003cdiv class=\"Heading\"\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNIID\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNuronal Intranuclear Inclusion Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLRS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLong-read Genome Sequencing\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNIID-D\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNuronal Intranuclear Inclusion Disease Dementia-Dominant\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNIID-W\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNuronal Intranuclear Inclusion Disease Muscle Weakness-Dominant\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNIID-P\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNuronal Intranuclear Inclusion Disease Parkinsonism-Dominant\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmyotrophic Lateral Sclerosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUMN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUpper motor neuron\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLMN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLower motor neuron\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFAS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFlail arm syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMMSE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMin-mental state examination\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic resonance imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDWI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDiffuse weighted imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFlair\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFluid attenuated inversion recovery\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMCV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMotor conduction velocity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCMAP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCompound muscle action potential\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEMG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectromyogram\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMUP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMotor unit potential\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eComputed tomography\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFVC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eForced Vital Capacity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThe patient signed the\u0026nbsp;written\u0026nbsp;informed content\u0026nbsp;for\u0026nbsp;the publication of this report. We also\u0026nbsp;obtained\u0026nbsp;approval\u0026nbsp;(No.IIT20250772B)\u0026nbsp;from the ethics committee of First Affiliated Hospital, School of Medicine, Zhejiang University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eAll authors agreeed to publish this article on the jouranl of \u0026nbsp;BMC neurology and comfirmed the authors listing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets generated or analysed during this study are presented in this article. Requests to access any other datasets should be directed to the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003eThe study was conducted in the absence of any commercial or financial relationships that could be may potentially \u0026nbsp;influence the manuscript . The authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003eOur study was not supported by any funder or sponsor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003eSiyuan Liu wrote the original draft and revised the draft. Meiping Wang and Kang Wang collected the clinical data, interpreted data , revised the draft. Xiaoqun Ba confirmed pathology. Fang Ji confirmed the data of nerve conduction and EMG . Jiajia Zhou and Jianfang Zhang discuss the case together and give advise.All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNone of the authors has any conflict of interest to disclose.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFu J, Zhao C, Hou G, Liu X, Zheng M, Zhang Y, Zhang S, Zheng D, Zhang Y, Huang X, Ye S, Fan D. A Case Report of Neuronal Intranuclear Inclusion Disease with Paroxysmal Peripheral Neuropathy-like Onset Lacking Typical Signs on Diffusion-Weighted Imaging. 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Front Cell Neurosci. 2021;15:655568. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fncel.2021.655568\u003c/span\u003e\u003cspan address=\"10.3389/fncel.2021.655568\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neuronal intranuclear inclusion disease, Amyotrophic lateral sclerosis, NOTCH2NCL gene, Autonomic nerve, Amyotrophy","lastPublishedDoi":"10.21203/rs.3.rs-7790975/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7790975/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eNeuronal intranuclear inclusion disease (NIID) is defined via the presence of histopathologic eosinophilic hyaline intranuclear inclusion within not only the central and peripheral nervous system, but also the autonomic system as well as several visceral organs and dermal cells. The presence of these intranuclear inclusions produces a gradually progressive neurodegenerative disease characterized by a GGC repeat in the 5\u0026rsquo; end of the Notch 2 N-terminal like C (\u003cem\u003eNOTCH2NCL\u003c/em\u003e) gene. The primary types of clinical manifestation of NIID are exhibited by muscle weakness, dementia, and parkinsonism type. With NIID attaining a high heterogeneity in terms of clinical presentation, it is often easily misdiagnosed with other diseases including amyotrophic lateral sclerosis (ALS). Similar to NIID, ALS may also arise through the mutation of the \u003cem\u003eNOTCH2NCL\u003c/em\u003e gene, leading to an extended GGC repeat and can coexist with NIID as reported by two cases. With this being mentioned, it can be hypothesized that ALS may contribute to a special phenotype of NIID and may attain comparable clinical attributes upon clinical diagnosis.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e\u003cp\u003eIn this case review, although the clinical presentation was highly indicative towards ALS, the patient was confirmed NIID via genetic analysis and skin biopsy. This can be further attributed to the absence of sensory and autonomic nerve impairment during the preliminary manifestation, and physical examination with upper motor neuron signs as well as the lack of hyper-intensive signals in the corticomedullary junctions in DWI.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003eThis review aims to provide insights towards the differential diagnosis of NIID with diseases exhibiting similar manifestation such as ALS.\u003c/p\u003e","manuscriptTitle":"Case Review: An unusual presentation of amyotrophic lateral sclerosis-like symptoms in confirmed adult-onset neuronal intranuclear inclusion disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 12:35:54","doi":"10.21203/rs.3.rs-7790975/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"79c8ac8a-f3a2-48ea-ae21-ba5e4f08bc17","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T05:09:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-18 12:35:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7790975","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7790975","identity":"rs-7790975","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}