NOTCH2NLC Repeat Expansions in Parkinsonian Disorders: Clinical and Neuroimaging Characteristics

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by NOTCH2NLC GGC repeat expansions, with heterogeneous clinical manifestations, including parkinsonism. Recent studies have identified NOTCH2NLC repeat expansions in patients with Parkinson's disease (PD) and atypical parkinsonism (aPM), suggesting a potential genetic contribution. However, it remains unclear whether such cases represent NIID-related parkinsonism or typical PD. To address this, we screened NOTCH2NLC repeat expansions in a parkinsonian cohort and analyzed associated clinical and neuroimaging features.

We examined 1017 unrelated patients with PD, 115 with aPM, 11 with multiple system atrophy, six with progressive supranuclear palsy, three with dementia with Lewy bodies, and 321 healthy controls. NOTCH2NLC GGC repeat expansions were detected using repeat-primed PCR and amplicon length analysis. Clinical data and neuroimaging findings were comprehensively reviewed.

Pathological NOTCH2NLC repeat expansions were identified in four patients with aPM and none with PD or in controls, with significantly higher frequency in aPM than in PD. An additional affected family member was also identified. All five patients showed clinical or neuroimaging features suggestive of NIID, including white matter hyperintensities in the paravermis and/or corticomedullary junction, curvilinear hyperintensities on diffusion-weighted imaging. Skin biopsies in two patients revealed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and fibroblasts. No patient responded well to levodopa. TRODAT scans revealed normal findings in three patients, symmetric dopaminergic deficits in one, and asymmetric deficits in another.

NOTCH2NLC repeat expansions appear to be more frequently associated with aPM with NIID-like features than with typical PD.