NIID is a progressive neurodegenerative disease characterized pathologically by the presence of eosinophilic intranuclear inclusion bodies within neurons of the central, peripheral, and autonomic nervous system, as well as in visceral organs. Clinically, NIID typically has a subacute or chronic onset, with disease duration ranging widely from less than 1 year to 49 years. Patients have been reported ranging in age from 2 to

78 years, with a male-to-female ratio of approximately 1:2 [1]. The clinical manifestations of NIID are notably heterogeneous. Based on the age of onset, it is categorized into infantile, juvenile, and adult forms. The infantile form often presents with initial symptoms such as limb ataxia, dysarthria, and notable involuntary movements. Juvenile-onset NIID commonly manifests as personality changes and learning difficulties. Adult-onset cases exhibit substantial variability, including cognitive impairments, episodic encephalopathy, psychiatric symptoms, seizures, movement disorders, autonomic dysfunction, peripheral neuropathy, myopathy, and various visceral system diseases, such as intestinal pseudo-obstruction; however, tremor, cognitive impairment, and muscle weakness are the most frequently reported initial symptoms. As the number of reported cases has increased, the clinical spectrum of NIID has broadened to include initial symptoms such as recurrent vomiting, dysphagia [2, 3]. Despite this broadening spectrum, erectile dysfunction (ED) as an initial symptom remains exceptionally rare. A comprehensive PubMed review (1969–2025) found rare cases [4]. We present three cases of NIID in which ED was the initial presenting symptom, with a final diagnosis established many years later. These cases prompt an exploration of the potential pathophysiological mechanisms linking ED to this neurodegenerative disorder.

Data for this study were retrospectively collected from three patients with NIID at our hospital between 2018 and 2022. Clinicopathological, radiographic, and genetic features were extracted from the patients’ medical records and follow-up data. Additionally, a comprehensive literature review was performed on PubMed to investigate reports of sexual dysfunction associated with NIID.

A 61-year-old male was admitted to our hospital with a three-year history of ED, accompanied by a two-and-a-half-year history of progressive memory loss and personality changes, and a two-year history of urinary incontinence. Approximately three years before admission, he developed ED of unknown cause, which gradually worsened until he was unable to achieve an erection. Due to embarrassment, he did not seek medical attention for this condition. Approximately 2.5 years ago, he developed cognitive decline, primarily manifesting as recent memory impairment, along with personality alterations including irritability, agitation, and aggressiveness. Two years ago, he was diagnosed with a neurogenic bladder and subsequently underwent a cystostomy. His past medical history was significant for a three-year history of chronic obstructive pulmonary disease (COPD). His family history was significant for similar complaints of ED and urinary incontinence in his two brothers, and a reported head tremor in his younger sister. On physical examination, both pupils were round (approximately 2.0 mm) and reacted briskly to light. Bilateral hearing impairment was noted. His MMSE score was 26/30 and MoCA score was 22/30. Laboratory investigations revealed mild anemia, with the Hb level of 118 g/L and the RBC count of 3.51×10¹²/L. Urinalysis demonstrated the presence of leukocytes, erythrocytes, and protein. Brain MRI revealed diffuse cortical atrophy accompanied by multifocal hyperintensities in the white matter of the bilateral cerebral hemispheres. Furthermore, small patchy high signals were observed in the cerebellar vermis on FLAIR sequences. However, no abnormal hyperintensities were observed on DWI (Fig. 1). Muscle and skip biopsy of the right biceps were performed and no EIIs were found. Subsequent genetic testing revealed an abnormal GGC repeat expansion in the NOTCH2NLC gene, with 94 repeats (normal range: <40).

A 61-year-old male was admitted to our institution with a seven-year history of recurrent syncope and progressive limb weakness. Nine days prior to admission, he experienced an episode of transient loss of consciousness, typically precipitated by postural changes. His symptoms began 14 years prior with the onset of ED without an identifiable cause. One year after, he developed additional autonomic dysfunction, including constipation, incomplete bladder emptying, and limb numbness. Urinary incontinence developed gradually thereafter. Two years prior to admission, cognitive decline became apparent, notably manifesting as forgetfulness (e.g., forgetting items to purchase) and personality changes marked by irritability. Concurrently, he reported frequent choking episodes while drinking. One year ago, he noted reduced sweating and increased cold sensitivity. Also, bilateral vision impairment emerged, characterized by blurred vision following prolonged visual effort. Six months prior to admission, hearing loss was noted. His past medical history included hypertension for 20 years, diabetes for 30 years, and long-standing proteinuria for 30 years. On neurological examination, bilateral miosis, bilateral hearing loss, and absent deep tendon reflexes in all limbs were noted. Vibratory sensation was reduced in both lower limbs. Bilateral Babinski signs were positive. During his initial hospitalization, MMSE and MoCA scores were 30/30 and 24/30, respectively, suggesting mild cognitive impairment. Laboratory findings revealed mild anemia (Hb 123 g/L, RBC 4.25 × 10¹²/L) and mild renal impairment (urea 6.9 mmol/L, creatinine 100.4 µmol/L, estimated glomerular filtration rate 76.27 mL/min). The serum vitamin B12 level was 1091 pg/mL. Urinalysis showed leukocytes, red blood cells, protein, and glucose.Urinary ultrasound demonstrated a significant post-void residual volume of 325 mL. Brain MRI revealed diffuse white matter hyperintensities on T2WI and FLAIR sequences, as well as subcortical hyperintensities in the frontal lobes on DWI (Fig. 1). Muscle biopsy of the right biceps revealed fatty infiltration with extensive perimysial and endomysial fibrosis, as well as variation in muscle fiber size and the presence of central nuclei (Fig). ATPase staining revealed atrophy of type I fibers. EIIs were found in the muscle specimens. Furthermore, skin biopsy revealed EIIs within sweat glands and fibroblasts, which were positive for anti-ubiquitin and anti-p62 antibodies. Genetic testing identified an abnormal GGC repeat expansion (129 repeats) in the 5'untranslated region (5' UTR) of the NOTCH2NLC gene.

This case series describes three patients in whom NIID manifested initially as ED,

with disease durations ranging from 3 to 14 years. Over time, these patients developed

central nervous system symptoms and other autonomic dysfunction (Aut D).

The diagnosis of NIID was prompted by characteristic brain MRI findings, although these were faint and atypical. To our knowledge, ED has been identified as the initial symptom of NIID in only a few reported cases [4]. The clinical features of these patients were summarized in Table 1. Our patients showed unique clinical presentations and uncommon MRI findings, complicating early diagnosis of NIID.

NIID is a genetically confirmed neurodegenerative disorder characterized by significant clinical heterogeneity, affecting multiple systems, and pathologically defined by the presence of EIIs [1]. Its clinical presentation is remarkably diverse, encompassing symptoms such as dementia, peripheral neuropathy, movement disorders, episodic symptoms, and autonomic dysfunction.

Autonomic dysfunction (AutD) — including urinary incontinence, miosis, vomiting, gastrointestinal dysfunction, orthostatic hypotension, arrhythmia, and sexual dysfunction [5]— is frequently observed in patients with NIID, particularly in older individuals. However, AutD is not typically recognized as the initial manifestation. Notably, in some cases, AutD has persisted as the sole clinical symptom for many years, suggesting that it may serve as a potential diagnostic biomarker for NIID [6].

Sexual dysfunction in NIID is considered an autonomic presentation, with reported prevalence ranging from 3.1% to 57.63% across NIID cases [7]. However, detailed reports of NIID cases where sexual dysfunction serves as an initial and main symptom remain scarce. Our study presents patients in whom ED emerged 3 to 14 years prior to the onset of central nervous system symptoms. As the disease progressed, these patients developed a range of neurological deficits, including dementia, impaired consciousness, personality changes, bradykinesia, and psychiatric disturbances. Furthermore, all patients exhibited other AutDs, particularly urinary incontinence and miosis. Notably, we also documented visual and hearing impairment, which have been infrequently mentioned in previous NIID studies. Initially, the atypical presentation complicated diagnosis, partly due to limited awareness of NIID and potential patient reluctance to disclose sexual issues. Consequently, these patients experienced prolonged diagnostic delay, unnecessary procedures, and treatments until subtle, atypical clues on brain MRI suggested NIID. Clinicians should maintain a high index of suspicion for NIID in patients presenting with ED as an initial symptom, even in the absence of classic neurological features.

The process of penile erection is orchestrated through an integrated pathway involving the CNS, the ANS, and the peripheral genital organs. Neurological regulation of this function relies on a complex network comprising primary afferents, spinal cord interneurons, sympathetic, and parasympathetic nerves. The sequence of events is as follows: initially, the CNS receives sexual stimulation via sensory modalities (e.g., visual, auditory, olfactory, and tactile). This information is then transmitted through activated neural pathways to the spinal cord and ANS. Finally, signals are relayed to the genital organs, culminating in penile erection [8].The underlying mechanism for sexual dysfunction in NIID is hypothesized to be linked to the formation of neuronal intranuclear inclusions or the loss of neurons in the CNS and ANS.

The hypothalamus plays a key role in the CNS in governing penile erection and can trigger the erectile response evoked by erotic clips [9]. Research has indicated numerous EIIs are present within the hypothalamus and ANS [10, 11]. As an extension of the brain, the spinal cord serves as a critical bridge linking the brain to the genital organs, relying on an entire neural pathway like ANS. Crucially, any lesion along the neural pathway that interrupts the transmission of signals may induce ED [8]. Sone et al [12] reported that EIIs were widespread, especially in sympathetic and myenteric ganglion neurons, dorsal root ganglion neurons, and spinal motor neurons, which were observed in the autopsy of two patients with NIID. These patients also had peripheral neuropathy and AutD. Furthermore, in an autopsy study by Sung et al [13] involving a 21 year-old female patient, significant loss of neurons in the Onuf's nucleus and the intermediolateral nucleus of sacral autonomic neurons was observed.

Brain MRI is a critical tool for diagnosing suspected NIID. On DWI, CMJ hyperintensity is a strong imaging marker for NIID [14], while subcortical high signals correlate with the spongiotic changes in those lesions. In our study, two patients presented subtle subcortical hyperintensities in the frontal lobes on DWI. Despite their faint appearance, these findings proved to be a crucial diagnostic clue, consistent with the patients’ clinical presentation of mild cognitive impairment. Conversely, no DWI hyperintensities were observed in Case 2. Previous studies indicate that DWI high-signal pathologies are not always exhibited in NIID patients, and the susceptibility is 88.0% [8]. Notably, in Case 1 and Case 2, high signals adjacent to the bilateral cerebellar vermis (paravermal sign) were observed, and Case 3 exhibited hyperintense signals in the bilateral middle cerebellar peduncles (MCP sign). Furthermore, pontine high signals on FLAIR were noted in three patients, a finding we have also documented in prior studies [15]. Han et al. [4] also reported hyperintense signals in the bilateral external capsules (kite sign) on DWI and FLAIR sequences. Collectively, these atypical imaging patterns, even in the absence of classic presentations, are valuable for guiding clinical diagnosis and patient assessment.

Interestingly, in our study cohort, we found another 58-year-old male who also initially presented with ED for three years, personality changes for eight months, and bradykinesia for six months. Physical examination showed miosis, rigidity, ataxia. Cognitive function was mildly impaired (MMSE 27/30 and MoCA 21/30). Brain MRI demonstrated MCP sign on T2/FLAIR, but no DWI restriction. Muscle biopsy showed fibrosis, fatty infiltration, and intranuclear inclusion bodies (IIBs). Skin biopsy confirmed ubiquitin/p62-positive IIBs. However, NOTCH2NLC GGC repeats were normal. NIID was excluded, leading us to suspect Fragile X Tremor/Ataxia Syndrome (FXTAS) in this patient. FMR1 gene tests were scheduled. FXTAS is an important differential diagnosis for late-onset NIID, as both share similar clinical, radiological, and pathological features. For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis is essential.

In summary, we report three cases of NIID where ED was the initial presenting symptom. We propose that the underlying pathophysiology involves neuronal IIBs formation and neuronal loss within the central and autonomic nervous systems, disrupting neural circuits critical for ED. Given NIID's rarity and its propensity for non-specific early symptoms and atypical imaging, a high index of suspicion and broad differential diagnosis are essential for clinicians and radiologists to prevent diagnostic delays.