Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5’-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum, and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsy from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patents presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%, 4/34), and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesion on diffusion weighted imaging (DWI) was the best biomarker to diagnose NIID with high specificity (98.4%) and sensitivity (88.2%). However, such DWI abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, presence of white matter hyperintensity lesions (WMH) either in paravermis or middle cerebellar peduncles also favored the diagnosis of NIID with a specificity of 85.3% and a sensitivity of 76.5%. Among the ten patients’ MRI performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical DWI hyperintense lesions and two revealed focal brain edema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients ever developed encephalitis-like episodes with restricted diffusion in the cortical regions at the acute stage DWI. Corticomedullary junction hyperintense lesions, WMH in paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnose NIID.

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