# Levodopa intolerance as a potential clinical red flag for neuronal intranuclear inclusion disease (NIID) in atypical parkinsonism: a case report

## TL;DR

A case report shows that severe intolerance to levodopa in atypical parkinsonism may signal neuronal intranuclear inclusion disease (NIID), a rare disorder linked to genetic mutations.

## Contribution

This case report identifies levodopa intolerance as a potential red flag for NIID in atypical parkinsonism, aiding earlier diagnosis.

## Key findings

- Levodopa treatment caused severe gastrointestinal side effects in a patient with atypical parkinsonism.
- MRI and genetic testing confirmed NIID diagnosis in the patient.
- Early recognition of NIID can improve multidisciplinary care and reduce diagnostic delays.

## Abstract

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.

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.

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.

The online version contains supplementary material available at 10.1186/s12883-026-04696-w.