Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare, progressive multisystem disorder most commonly associated with GGC repeat expansion in the NOTCH2NLC gene. Parkinsonism can be an initial presentation and may be misdiagnosed as idiopathic Parkinson’s disease, particularly when prominent non-motor features are present. While many cases are levodopa-responsive, diagnosis is challenging when prominent non-motor features and drug intolerance are present. Case presentation We report a case of a 70-year-old woman of Han Chinese who developed atypical parkinsonism, severe cognitive decline, and severe gastrointestinal dysfunction. A therapeutic trial of levodopa/benserazide produced only minimal and transient motor benefit but resulted in marked worsening of nausea and vomiting, precluding dose escalation. Brain MRI demonstrated a characteristic corticomedullary junction (CMJ) hyperintensity on diffusion-weighted imaging. Skin biopsy revealed intranuclear inclusions on electron microscopy, and genetic testing confirmed pathogenic GGC repeat expansion in NOTCH2NLC , establishing the diagnosis of NIID. Conclusions This case highlights that profound levodopa intolerance in patients with atypical parkinsonism, especially when accompanied by severe gastrointestinal dysfunction and early cognitive decline, should prompt consideration of NIID. Early recognition of this clinical pattern, together with characteristic MRI findings and confirmatory pathology/genetics, may help reduce diagnostic delay and facilitate timely multidisciplinary supportive care.
Zang et al. (2026) studied this question.