Neuronal intranuclear inclusion disease misdiagnosed as Parkinson’s disease: a case report

Abstract

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease that mainly manifests as dementia, muscle weakness, sensory disturbances, and autonomic nervous dysfunction. Herein, we report a 68-year-old Chinese woman who was hospitalized because of resting tremor and bradykinesia that had been present for 7 years. Five years prior, bradykinesia and hypermyotonia had become apparent. She had urinary incontinence and rapid eye movement sleep behavior disorder. She was diagnosed with Parkinson’s disease (PD) and received levodopa and pramipexole, which relieved her motor symptoms. During hospitalization, diffusion-weighted imaging revealed a high-intensity signal along the cortical medullary junction. Moreover, a skin biopsy revealed the presence of intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells. NIID was diagnosed by testing the Notch 2 N-terminal-like C (NOTCH2NLC) gene. We report this case to remind doctors to consider NIID when diagnosing patients with symptoms indicative of Parkinson’s disease. Moreover, we note that further research is needed on the mechanism by which levodopa is effective for NIID.

Background

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease that is characterized by eosinophilic intranuclear hyaline inclusions in the central, peripheral, and autonomic nervous systems, as well as in visceral organs. ¹ NIID manifests as pyramidal and extrapyramidal symptoms, dementia, tremor, and autonomic nervous dysfunction, among other symptoms. ² The classic imaging feature of NIID is a high-intensity signal along the cortical medullary junction on diffusion-weighted imaging (DWI). ³ Recently, the development of skin biopsies and genetic testing have facilitated its diagnosis. ⁴ Here, we report a patient who presented with static tremor and bradykinesia, which are common features of Parkinson’s disease (PD). Although her motor symptoms were ameliorated by levodopa treatment, a high-intensity signal at the corticomedullary junction in DWI drew our attention. The patient was finally diagnosed with NIID via a skin biopsy and gene analysis. The number of PD patients is predicted to increase to 14.2 million by 2040, meaning that PD is no longer considered a rare disease. ⁵ The possibility of misdiagnosing other neurological diseases, such as NIID, as PD thus exists. We therefore suggest that NIID should be included in the differential diagnosis of PD in clinical practice.

Case presentation

A 68-year-old woman was admitted to the hospital with limb weakness. She had begun to experience limb weakness approximately 2 weeks earlier, and gradually experienced difficulties walking and stayed in bed. There was nothing of note in her medical, family, or psycho-social history. On physical examination, her body temperature was 36.2°C, heart rate was 65 beats/minute, and blood pressure was 132/82 mmHg. The patient had few facial expressions. Cranial nerve function was normal, and muscle strength in the limbs was level four. She had an asymmetric resting tremor and rigidity in her limbs. The bilateral knee reflex was diminished, and the right Babinski sign was positive.

Obvious high signals around the bilateral lateral ventricles and corpus callosum on DWI caught our attention (Figure 1). The patient had visited our hospital for different reasons over the past 6 years (Figure 2). She presented with a testing tremor in her right hand at the age of 62 years. Her left hand developed a testing tremor at 63 years of age, and bradykinesia and hypermyotonia became apparent. She also had urinary incontinence as well as poor sleep quality and occasional shouting at night. She was diagnosed with PD (88 on the Movement Disorder Society Unified PD Rating Scale [MDS-UPDRS]) and received treatment with levodopa and pramipexole; her clinical symptoms improved (73 on the MDS-UPDRS) after several months. At the age of 65 years, she was administered selegiline because of the diminishing effects of levodopa and pramipexole; however, this treatment was not effective (85 on the MDS-UPDRS). In addition, she began to have memory loss and hallucinations. Her Mini-Mental State Examination score was 8/30 (primary school education).

Figure 1.

Brain magnetic resonance imaging. Diffusion-weighted imaging showed high signal changes in the cerebral cortex medullary junction, and T2-weighted and fluid-attenuated inversion recovery imaging showed cerebral atrophy.

Figure 2.

Summary of the symptoms, diagnosis, and treatments over the patient’s disease course. NIID, neuronal intranuclear inclusion disease; PD, Parkinson’s disease; RBD, rapid eye movement sleep behavior disorder.

On the basis of her past medical history, we considered that the patient had NIID rather than PD. To clarify this diagnosis, she underwent a skin biopsy and genetic testing at the age of 68 years. The skin biopsy showed intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells (Figure 3a). Furthermore, genetic testing revealed 103 GGC repeats in the Notch 2 N-terminal-like C (NOTCH2NLC) gene (Figure 3b). The patient was finally diagnosed with NIID. A telephone follow-up with her son 1 year after discharge revealed that she was unable to take care of herself in daily life and still had cognitive impairment, but that no significant worsening had occurred. The reporting of this study conforms to CARE guidelines (for CAse REports). ⁶

Figure 3.

Diagnosis methods included skin biopsy specimens (a) and genetic testing (b).

Discussion

The patient presented with static tremor, bradykinesia, urinary incontinence, sleep disorder, and mental disorder. Levodopa and pramipexole had positive therapeutic effects. All of the aforementioned features supported a diagnosis of PD. However, during the progress of the disease, she experienced cognitive impairment, which is rarely observed in PD. Furthermore, DWI showed a bilateral symmetrical high signal, which is the typical imaging feature of NIID. The results of a skin biopsy and genetic testing led to a final diagnosis of NIID for our patient.

In 1968, Lindenberg described the diagnosis of NIID for the first time. ⁷ NIID is a progressive neurodegenerative disease that is usually subacute or chronic in onset; it has a variety of clinical manifestations that mainly affect the central, peripheral, and autonomic nervous systems. ⁸ Cerebral cortex involvement leads to symptoms such as consciousness disorders, epilepsy, episodic encephalopathy, and abnormal mental behavior. The main manifestation of subcortical involvement is dementia, whereas the manifestations of extrapyramidal system involvement are tremors and rigidity. When the peripheral nervous system is involved, patients exhibit sensory disorders and decreased distal muscle strength. The main manifestations of autonomic nervous system involvement include miosis, bladder dysfunction, and syncope. Our patient presented with extrapyramidal symptoms, suggesting subcortical and autonomic nervous system involvement.

According to the age of onset, NIID can be divided into infantile, juvenile, and adult forms. ⁹ The majority of cases are sporadic, although several familial cases have been identified. The initial symptoms of the infantile form of NIID are limb ataxia and dysarthria; involuntary movements are another important symptom. ¹⁰ The most common clinical features of juvenile-onset NIID are personality changes and learning difficulties. ¹¹ Furthermore, parkinsonism often develops as the disease progresses. ¹² Researchers have therefore suggested that NIID should be added to the differential diagnosis of juvenile parkinsonism. ¹³ The main clinical manifestations of adult-onset NIID are dementia and muscle weakness. ¹⁴

It is rare for adult-onset NIID to start with parkinsonism. A sporadic Chinese case was reported in 2020; ¹³ this was the first report to describe a patient (a 68-year-old man) who was misdiagnosed with PD and eventually diagnosed with NIID using genetic testing. Although this patient received methyldopa therapy, his wife stated that he still occasionally experienced involuntary tremors. Similarly, in 2017, Yoshimoto et al. ¹⁵ reported a familial case whose initial symptom was resting tremor and bradykinesia. The elder sister had Parkinson's disease-like symptoms at the age of 66 years, and clinical manifestations did not improve with the administration of antiparkinson drugs. Six years later, dementia was noted, and at 76 years of age, she was diagnosed with NIID based on a skin biopsy. However, her younger sister mainly showed abnormal behavior and dementia. Unfortunately, the younger sister died in an accident in the bath and failed to complete a skin biopsy. At the disease onset, both sisters had high signals in the subcortical cortex and medullary boundary in DWI. Our patient was 62 years old at disease onset, and her family members had no relevant symptoms. This is the second reported case of adult sporadic NIID that started with parkinsonism, and differed from previous reports in that antiparkinsonian drugs were effective.^12–14,16

Given that the clinical characteristics of NIID vary greatly, accurate diagnosis was often difficult before 2011, when Sone et al.^17,18 reported that skin biopsy is a useful antemortem diagnostic tool for NIID. Recently, it has been demonstrated that the diagnostic performance of testing for a GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC is highly consistent with that of skin biopsy. ⁴ Additionally, GGC repeat expansion is responsible not only for adult-onset patients, but also for juvenile-onset patients. ¹⁹ With this improvement in diagnostic methods, the diagnostic rate of NIID has increased in recent years.

NOTCH2NLC is one of three functional Notch paralogs that have crucial roles in human neocortical development. ²⁰ It can expand human cortical progenitor cells and increase their neuronal output at the clone level by autonomously activating the Notch pathway, thereby participating in the evolution of the human cerebral cortex. ²¹ In 2019, researchers from China and Japan first discovered abnormal repeat expansions of GGC (>65 repeats) within the 5′ untranslated region of NOTCH2NLC in adult NIID patients; this expansion may be related to the pathogenesis of NIID.^18,22,23 A recent study has indicated that the genetic advances and possible underlying mechanisms of NIID are DNA damage, RNA toxicity, and polyglycine-NOTCH2NLC protein toxicity induced by GGC repeat expansion. ⁸ The normal adult NOTCH2NLC gene has no more than 40 GGC repeats, and more than 60 GGC repeats is considered pathogenic. NIID patients with tremors as the main clinical manifestation tend to have a GGC repeat frequency that is close to 60 repeats. The repeat frequency of GGC in patients with Parkinson's syndrome as the main manifestation is around 80; that of patients with cognitive impairment as the main manifestation is around 120, and that of patients with muscle weakness as the main manifestation can reach 200. ¹⁹ Moreover, large GGC repeat numbers—ranging from 66 to 517 units—were reported in patients affected by NIID, whereas control participants had fewer than 40 repeats. ²⁴ Notably, however, there is no apparent association between GGC repeat size and NIID severity or onset age. ²³ Notably, GGC repeat expansions not only lead to NIID, but may also participate in the pathogenesis of multiple progressive neurological disorders, including PD and Alzheimer’s disease. Furthermore, intermediate-length GGC repeat expansions in NOTCH2NLC are potentially associated with PD. ²⁵ However, the precise mechanisms by which GGC repeat expansions lead to disease development remain unclear. In addition, it has been reported that patients who carry GGC repeat expansions in NOTCH2NLC (>79 repeats) can present with typical parkinsonism requiring low levodopa dosages, and may have no other features of NIID, even after several years. ²⁴ Researchers have therefore suggested the term “NIID-related disorders,” which includes NIID and other related neurodegenerative diseases caused by expanded GGC repeats within the human-specific NOTCH2NLC gene. ²³

In conclusion, patients with NIID exhibit various clinical symptoms, and are often misdiagnosed as other diseases such as PD. In the future, more attention should therefore be paid to clarifying both the relationship between NOTCH2NLC and PD, and the relationship between PD and NIID. In clinical practice, NIID should be considered as a differential diagnosis of PD.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241233159 - Supplemental material for Neuronal intranuclear inclusion disease misdiagnosed as Parkinson’s disease: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605241233159 for Neuronal intranuclear inclusion disease misdiagnosed as Parkinson’s disease: a case report by Dandan Yu, Jing Li, Hongfei Tai, Jing Ma, Zaiqiang Zhang and Wei Tang in Journal of International Medical Research