Adult-Type Neuronal Intranuclear Inclusion Disease with Limb Tremor Onset: Case Report and Literature Review

doi:10.21203/rs.3.rs-3252597/v1

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Case Report

Adult-Type Neuronal Intranuclear Inclusion Disease with Limb Tremor Onset: Case Report and Literature Review

https://doi.org/10.21203/rs.3.rs-3252597/v1

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Background: Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disorder characterized by pathological features and eosinophilic intranuclear inclusions found in the central and peripheral nervous systems as well as in visceral organs. Herein, we report the case of a 62-year-old woman who presented with limb tremors and gradually developed cognitive impairment and unresponsiveness.

Case presentation: A 62-year-old woman was admitted to our hospital because of limb tremors for 7 years, along with mental disorders,slow reactions, and gait instability for 5 years. Brain magnetic resonance imaging revealed high-intensity signals in the corpus callosum and corticomedullary junction on diffusion-weighted imaging. Additionally, fluid-attenuated inversion recovery sequences showed high-intensity signals in the bilateral cerebellar vermis and middle cerebellar peduncle. Next, cerebrospinal fluid examination indicated a pressure of 95 mmH2O, positive Pandy’s test, glucose level of 4.0 mmol/L, protein level of 1100 mg/L, and chloride level of 122 mmol/L. Other laboratory tests showed no significant abnormalities. We considered a diagnosis of NIID. Subsequently, a skin biopsy was performed 10 cm above the left lateral malleolus. P62-immunoreactive abnormal material was confirmed in individual fibroblasts. Ultrathin sectioning and imaging revealed spherical, lightly stained, short filamentous inclusion structures in fibroblast nuclei. Genetic testing found pathogenic repetitions of GGC in NOTCH2NLC.

Conclusion: NIID is a rare clinically heterogeneous disease. In clinical work, a diagnosis of NIID should be considered when patients present predominantly with limb tremors and persistent abnormal high-intensity signals in the corpus callosum on diffusion-weighted imaging; NIID should especially be considered when patients do not demonstrate tendon reflexes. Long-term follow-up should be conducted to confirm the diagnosis, treatment, and prognosis of the disease.

neuronal intranuclear inclusion disease

limb tremor

corpus callosum

neurodegenerative disorder

tendon reflexes

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disorder characterized by pathological features and eosinophilic intranuclear inclusions found in the central and peripheral nervous systems, as well as in visceral organs(1–3). Inclusion bodies are aggregations of abnormal proteins(3–6), which can be seen as dense filamentous material without a membrane structure under electron microscopy, with a diameter of 1.5–10.0 µm(2, 4). Inclusions in cellular nuclei are easily detectable using immunohistochemistry for p62 and ubiquitin(2, 7). NIID can affect multiple systems and is considered a heterogeneous disease that can manifest as dementia, abnormal cognition, limb weakness, and urinary incontinence(4). Its antemortem diagnosis is challenging due to the diverse nature of its clinical manifestations. Before the discovery of skin biopsy as a diagnostic method in 2011, fewer than 40 patients had been diagnosed with NIID(1, 2, 8). To date, a few cases of adolescent- or infant-onset NIID have been reported in China, with adult-onset NIID accounting for the majority of cases in East Asian populations(1, 9). Recent studies have shown a paternal bias in NIID transmission(10). NIID can be categorized into dementia-dominant, myasthenic-dominant, and parkinsonism-dominant subtypes based on initial and main symptoms(11). As the number of reported NIID cases increases, additional clinical subtypes, including tremor-dominant, amyotrophic lateral sclerosis, and peripheral neuropathy subtypes, have been defined(8, 11–13). Herein, we report a case of NIID with limb tremor onset and provide a review of recent studies on NIID to update our understanding of its clinical features, therapeutics, and pathogenesis. This information may be beneficial for clinicians seeking a better understanding of the disease.

A 62-year-old woman was admitted to our hospital in March 2023 with limb tremors for the prior 7 years, along with mental disorders, slow reactions, and gait instability for 5 years. The tremor initially started in the patient’s right upper extremity; it was particularly noticeable during movement or when holding objects. However, it did not significantly affect her daily life. The patient experienced a mental abnormality following a fever 5 years prior, characterized by aimless wandering and providing irrelevant responses. Concurrently, she began to exhibit unstable walking, occasional swaying, and falling. Her symptoms worsened 3 months prior to visiting our hospital after infection with the SARS-CoV-2 respiratory virus, making her unable to care for herself. After one day of fever, her symptoms worsened again. Throughout the course of her illness, she also experienced urinary incontinence, restlessness, and diminished vision.

On neurological examination, notable findings included a clear consciousness level, hazy consciousness content, confused speech expression, small bilateral pupils with a diameter of 2 mm. Radial and bicep reflexes were diminished. The remaining neurological examinations could not be performed.

Laboratory tests revealed the following results. The white blood cell count was 15.91 × 10⁹/L (neutrophils 89.8, leukocytes 5.4, monocytes 4.6%), glucose was 12.4 mmol/L, total cholesterol was 8.29 mmol/L, triglyceride was 2.37 mmol/L, low-density lipoprotein cholesterol was 5.63 mmol/L, fasting blood sugar was 13.8 mmol/L, thyroid-stimulating hormone was 0.037 µIU/mL, glycoantigen 19 − 9 was 37.90 U/mL, cytokeratin 19 fragment was 12.50 ng/mL, and pepsinogen I/II was 0.61. Next, a lumbar puncture was performed, and the examination revealed the following results for the cerebrospinal fluid: pressure of 95 mmH₂O, positive Pandy’s test, glucose of 4.0 mmol/L, protein of 1100 mg/L, and chloride of 122 mmol/L. Other laboratory tests showed no significant abnormalities.

Brain magnetic resonance imaging (MRI) showed progressive changes over time. In 2017, when the patient was first admitted to our hospital, high signals on diffusion-weighted imaging (DWI) were only observed in the corpus callosum (Fig. 1a). In 2020, during the patient’s readmission, the abnormal signal in the corpus callosum persisted on DWI (Fig. 1b). However, unlike before, diffusion restriction was also observed in the corticomedullary junction of the frontal lobe (Fig. 1c). In 2023, brain MRI continued to show the abnormal signal in the corpus callosum (Fig. 1d) and the corticomedullary high signal on DWI extended downward to the parietal lobe (Fig. 1e). Additionally, fluid attenuated inversion recovery imaging showed high-intensity signals in the bilateral cerebellar vermis and middle cerebellar peduncle (Fig. 1f).

Subsequently, a skin biopsy was performed 10 cm above the left lateral malleolus. P62 immunofluorescence staining of the skin tissue indicated the deposition of P62-reactive abnormal material in individual fibroblasts (Fig. 2a). Ultrathin section examination revealed spherical, lightly stained, short filamentous inclusion structures in the nuclei of fibroblasts (Fig. 2b). Genetic testing was performed with repeat-primed polymerase chain reaction to amplify the NOTCH2NLC gene, and capillary fluorescence electrophoresis sequencing was performed on products to find pathogenic repetitions of GGC in NOTCH2NLC.

The patient had a chronic disease onset, and her clinical manifestations involved the central nervous system and autonomic nervous system. Brain MRI showed a high signal on DWI at the corticomedullary junction, which progressed along the cortex as the disease progressed, but the lesion never reached the medulla. Her skin pathological examination revealed intranuclear inclusion bodies in skin fibroblasts, and immunofluorescence showed p62 antibody positivity. The number of GGC repeat sequences in the NOTCH2NLC gene was abnormal. Therefore, the patient was diagnosed with NIID. The timeline associated with the case can be seen in Fig. 3.

Hitherto, there is no specific treatment for NIID, and patients can only be treated symptomatically(6). Some studies have shown that hormone therapy was effective in some patients(2, 14). In the present case, in addition to symptomatic treatment, we administered a shock therapy of methylprednisolone (500 mg) and halved the dose every three days for nine consecutive days. On the third day of methylprednisolone therapy, the patient’s daughter expressed that the patient’s mental status and memory were better than before. Before the methylprednisolone, the patient’s Mini-Mental State Examination score was 11 and her Montreal Cognitive Assessment score was 3. After treatment, the Mini-Mental State Examination score increased to 14 and the Montreal Cognitive Assessment score to 10. The patient’s orientation and calculation ability were still poor, but her memory was improved. Then, methylprednisolone was orally administered after discharge from the hospital. We followed up with the patient, and she still had paroxysmal behavioural abnormalities and urinary incontinence, and her general status was acceptable, but she showed limb weakness and unstable walking.

This study involving a human participant was reviewed and approved by the Ethics Committee of the First Hospital of Jilin University. The patient provided written informed consent to participate in this study; written informed consent was also obtained for the publication of any potentially identifiable images or data included in this article.

In 1968, Lindenberg et al. discovered extensive eosinophilic intranuclear inclusions in the brain and internal organs of a 28-year-old man with intellectual disability by autopsy, marking the first recorded case of NIID(15). Until 2011, only approximately 40 cases of NIID diagnosed through postmortem brain biopsy had been described worldwide(1, 8). In recent years, the number of reported NIID cases has gradually increased due to the use of skin biopsies and genetic tests for diagnosis. The understanding of NIID is also constantly being updated.

3.1 Pathogenesis of NIID

NIID is associated with GGC repeat amplification in the 5'UTR of the human-specific NOTCH2NLC gene(16). NOTCH2NLC is one of three human-specific NOTCH2NL-associated genes that have been implicated in recurrent neurodevelopmental disorders(8). The exact pathogenesis of GGC amplification in NOTCH2NLC is currently unknown. Researchers have proposed several hypotheses regarding the pathogenesis of NIID, including the toxicity of polyamino acid proteins(17–19), toxic RNA gain-of-function(19, 20), and aberrant methylation of GGC repeat sequences(21). Recently, some studies have suggested that dysfunction of ribosome biogenesis and translation and mitochondrial dysfunction might be related to the pathogenesis of NIID(22, 23). However, the specific mechanisms driving the pathogenesis of NIID remain unclear, and extensive experiments in cellular and animal models are required for further studies.

3.2 Clinical manifestations of NIID

NIID is a clinically heterogeneous, multisystemic intranuclear inclusion body disease. The clinical symptoms of adult-onset NIID mainly involve the central, peripheral, and autonomic nervous systems. Here, we report the case of a patient with NIID who developed tremors. YouNi et al. demonstrated that tremors were the most common initial symptom, and the mean age at onset and diagnosis in patients who started with tremors was lower than in patients without tremors(24). Cao et al. also showed that tremor was not only common in adult-onset NIID but also an early disease manifestation(9). Compared with previous studies, there was a higher prevalence of tremors (64.71% vs. 15.8–47.5%)(11, 24). The subtype of NIID with tremor is easily misdiagnosed as essential tremor, and after long-term follow-up, some patients initially diagnosed with essential tremor are eventually diagnosed with NIID(11). Yang et al. suggested that the loss of tendon reflexes could be an important clinical clue(11). The case reported herein also showed an absence of tendon reflexes. Therefore, considering that the clinical course of NIID is usually slow and insidious, one should consider NIID in patients with tremor as the main presentation, especially in combination with absent tendon reflexes. Long-term follow-up should be conducted to confirm the diagnosis, treatment, and prognosis of the disease. During follow-up visits, it is particularly important to note any impairments of higher neurological functions, such as in the patient reported herein, who showed symptoms of mental abnormality and unresponsiveness as the disease progressed. It is essential to actively enhance skin biopsy and genetic testing to clarify the diagnosis. A recent study summarized the mean age of onset of different systemic involvements in patients with NIID and found that the neurological system was the last to be involved compared with other systems(4). This suggests that early clinical symptoms in patients with NIID may be atypical, and further clinicopathological studies are needed to identify the differences between the early clinical manifestations of NIID and other systemic diseases. This will facilitate early diagnosis, slow disease progression, and improve patient prognosis as much as possible.

3.3 Imaging features of NIID

High DWI signals along the corticomedullary junction is a typical neuroimaging manifestation of NIID(25). Pathology studies have revealed areas of focal spongiform vasculopathy in the subcortical white matter proximal to U-fibres, corresponding to a high DWI signal on MRI(3). High DWI signals at the corticomedullary junction usually show a progression from anterior to posterior, which typically starts from the frontal lobe and gradually involves the temporoparietal and occipital lobes. The newly identified imaging features include a high DWI signal in the corpus callosum and a high T2-weighted signal in the caudal cerebellar vermis and middle cerebellar peduncle, and abnormal signals in the corpus callosum may be an early imaging change of the disease. It has been shown that some patients can present with a separate lesion involving the corpus callosum prior to the corticomedullary junction area, suggesting a similar susceptibility of the callosal contact fibres and subcortical arcuate fibres(26). A high signal (corticomedullary junction) on DWI may not appear(27), and it may appear or disappear in the late stages(28). The present patient only showed a high-intensity signal in the corpus callosum on DWI in the early stages of the disease; as the disease progressed, the signal did not increase significantly and never disappeared. We also observed that the high-intensity signal at the corticomedullary junction gradually progressed from the frontal lobe. Simultaneously, a high-intensity signal in the bilateral cerebellar vermis and middle cerebellar peduncle was also observed on fluid attenuated inversion recovery images. The above imaging features demonstrate that the appearance of a persistent non-resolving high-intensity DWI signal in the corpus callosum should be taken seriously; it should be followed up, and the possibility of NIID should be considered.

3.4 Diagnosis of NIID

As research progresses on the pathogenesis of NIID, the diagnostic criteria for the disease are constantly evolving(2, 4, 29). In 2011, Sone et al. found that dermal intranuclear inclusions had similar pathological backgrounds to those seen in neuronal cells of patients with NIID. Therefore, skin biopsies are widely used as a convenient and concise diagnostic method for NIID. Ubiquitin- and p62-reactive eosinophil inclusions are highly sensitive and specific pathological markers of NIID(2, 7, 26). However, it has been shown that eosinophil intranuclear inclusions are also observed in other GGC repetitive expansion disorders, such as fragile X-associated tremor/ataxia syndrome and oculopharyngeal myopathy(30, 31). Therefore, the diagnosis of NIID should integrate clinical manifestations, imaging features, pathological features, and genetic testing to avoid misdiagnosis. In 2016, Sone et al. proposed that DWI hyperintensities at the corticomedullary junction were a strong diagnostic basis for NIID diagnosis. Thus, they proposed a diagnostic pipeline for NIID in adults and applied exclusion criteria since no causative gene had been identified. Subsequently, a significantly larger number of patients were diagnosed with NIID(25). However, given that no causative gene was found, only exclusion criteria can be applied. In 2019, four different teams successively reported that a GGC repeat expansion in the 5'UTR of the human-specific NOTCH2NLC gene was responsible for NIID(16, 32–34). Henceforth, genetic diagnosis has become the principal ascertainment criterion. However, Tian et al. found that GGC repeat expansions may also be seen in Alzheimer’s disease and parkinsonism phenotypes. Therefore, the term “NIID-related disorders” was proposed. It represents a spectrum of disorders that include NIID and other disorders caused by GGC repeat expansion in NOTCH2NLC(32). Recently, it has been shown that GGC repeat expansion in the NOTCH2NLC gene is associated with a broader disease spectrum, including NIID, Parkinson’s disease, essential tremor, and oculopharyngeal myopathy type 3. As a result, a new term, “NOTCH2NLC-related repeat expansion disorder”, was proposed. In fact, some patients who were diagnosed with dementia or parkinsonism early ended up clinically converting to the typical features of NIID during a long follow-up. However, whether all GGC repeat gene carriers in NOTCH2NLC will eventually be diagnosed with NIID requires further longitudinal studies in larger cohorts(35).

3.5 Treatment of NIID

No specific treatment can cure NIID, and only symptomatic treatment can be administered to patients(6). Advances in the study of disease mechanisms form the basis for the development of preventive and therapeutic interventions. It has been suggested that NIID may be associated with mitochondrial dysfunction; therefore, therapeutic measures for mitochondrial disease may be effective for patients with NIID(23). Yan et al. suggested that inflammation might also play an important role in the pathogenesis of NIID(29). Chen et al. found diffuse inflammatory cell infiltration and oedema in different tissues containing intranuclear inclusion bodies(36); therefore, dehydration and anti-inflammation may be therapeutic targets for NIID. Considering that fragile X-associated tremor/ataxia syndrome and NIID have similar pathogenesis and are both trinucleotide repeatable diseases, Xu et al. suggested that some therapeutic measures referring to CGG expansion disorder might be effective for the treatment of NIID. These therapeutic measures include antisense oligonucleotide therapy, ribonucleic acid interference, small molecules, and gene editing. However, there are some challenges, such as off-target effects, low delivery efficiency due to the blood-brain barrier, the risk of immunogenicity, and the potential problems associated with introducing a virus into patients(37).

The clinical presentation of NIID has been well described in the number of reported cases of NIID. We report a case of NIID with limb tremor onset. The patient’s clinical data were complete, but, unfortunately, she had not been tested for the number of GGC repeats, and during follow-up, the patient developed severe oral ulcers and had to stop hormone therapy; therefore, we have no way to observe the long-term prognosis of hormone therapy for NIID. Further analysis is needed to determine if there is a specific age interval associated with a particular range of GGC repeat expansions in the NOTCH2NLC gene or specific physical examinations that provide supporting evidence for the diagnosis of NIID in patients who start with limb tremors. This case report highlighted the importance of thorough whole-body evaluations, long-term MRI follow-up, extensive skin biopsy, and genetic testing for patients who start with limb tremors, particularly when accompanied by absent tendon reflexes, high-level nerve injury, and high-intensity callosal signal on DWI.

NIID, neuronal intranuclear inclusion disease

MRI, magnetic resonance imaging

DWI, diffusion-weighted imaging

CSF, cerebrospinal fluid

Ethics approval and consent to participate:

This study involving a human participant was reviewed and approved by the Ethics Committee of the First Hospital of Jilin University.

Consent for publication:

The patient provided written informed consent to participate in this study; written informed consent was also obtained for the publication of any potentially identifiable images or data included in this article.

Competing interests:

No.

Funding :

Authors' contributions:

SNW drafted the initial manuscript and selected the references, HZ and JYL revised the manuscript, HPL, RSZ, HYG, YSW and YL care for the patient.All authors approved the final version of the manuscript.

Acknowledgements:

Thank the patient who agreed to participate in the study.

Authors' information (optional): ¹Department of Neurology, Lequn Branch, The First Hospital of Jilin University, Jilin, China.

Availability of data and materials:

The date supporting the findings of this study

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No competing interests reported.

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Adult-Type Neuronal Intranuclear Inclusion Disease with Limb Tremor Onset: Case Report and Literature Review

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1 Background

2 Case presentation

3 Discussion and Conclusions

4 Conclusion

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