Recurrent migraine with visual aura as the primary phenotype of familial neuronal intranuclear inclusion disease

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized by highly heterogeneous clinical manifestations and multi-system involvement. The most common initial symptoms include tremor, cognitive impairment, and muscle weakness. Characteristic neuroimaging features comprise symmetrical diffusion-weighted imaging (DWI) high signal intensity in the corticomedullary junction and extensive leukoencephalopathy. NIID manifesting as migraine with visual aura as the predominant symptom has rarely been reported. In this study, we describe a Chinese NIID pedigree comprising eight affected members, all of whom consistently exhibited migraine with visual aura as the primary clinical feature. Notably, none of the followed-up patients showed abnormalities on neuroimaging. In one case, serial follow-up over 7 years revealed no abnormal DWI high signal intensity at the corticomedullary junction or leukoencephalopathy. Skin biopsies confirmed the presence of neuronal intranuclear inclusions in two affected patients within this pedigree. Genetic testing for the NIID-causing mutation identified the GGC repeat expansion in the NOTCH2NLC gene in three patients in this family. This study provides new insights into the phenotypic complexity of NIID.