Erectile dysfunction as initial presentation of NOTCH2NLC-related Neuronal intranuclear inclusion disease: a retrospective case series

Background Erectile dysfunction (ED) is a prevalent clinical condition. It is well-established that ED can be an early or concurrent manifestation of several neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the potential etiological link between ED and neuronal intranuclear inclusion disease (NIID) has not been elucidated. Case Presentation We report a series of four patients with NIID (three from our institution and one from the literature) whose initial and primary presenting symptom was ED. The diagnosis of NIID was subsequently confirmed in all cases by skin biopsy and genetic testing for NOTCH2NLC gene repeats. The mean interval from the onset of sexual dysfunction to the definitive diagnosis was 7.6 years (range, 3–14 years). Following the initial presentation, all patients progressively developed neurological symptoms, which included altered consciousness, cognitive decline, psychiatric manifestations, and limb weakness. Notably, initial cognitive assessments revealed only mild impairment (MMSE/MoCA scores: 26/30, 19/30; 26/30, 22/30; and 30/30, 24/30, respectively). Brain MRI findings were also subtle: one patient had a negative diffusion-weighted imaging (DWI) sequence, while the other two exhibited only subtle linear hyperintensities on DWI, confined to the bilateral frontal lobes. Autonomic dysfunction was a prominent feature, with anemia in three patients and abnormal urinalysis in all four. In addition to ED, other autonomic and neurological features included urinary disorders (n = 4), constipation (n = 3), miosis (n = 3), and hearing impairment (n = 2). Conclusions Our findings suggest that ED can rarely serve as the sole initial manifestation of NIID, often preceding a definitive diagnosis by several years (mean, 7.6 years). This report expands the differential diagnosis of ED and underscores the importance of considering NIID in patients presenting with unexplained ED, especially when accompanied by subtle neurological or autonomic symptoms. ED may represent a crucial early diagnostic clue for NIID, enabling earlier intervention and genetic counseling.