Clinical and imaging characteristics of NOTCH3-negative CADASIL-suspected patients with NOTCH2NLC GGC repeat...

Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant inherited neurodegenerative disease caused by NOTCH2NLC GGC repeat expansions. A high-intensity signal in the corticomedullary junction (CMJ) on magnetic resonance (MR) diffusion-weighted imaging (DWI) is a well-known characteristic of NIID. However, because of its diverse clinical symptoms and frequent presence of cerebral white matter hyperintensity (WMH) lesions on MRI, patients with NIID may be suspected of having other leukoencephalopathies. The aim of the present study was to identify patients with NOTCH2NLC GGC repeat expansions among those with undiagnosed leukoencephalopathies, recruited from NOTCH3-negative cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-suspected and GFAP-negative Alexander disease (AxD)-suspected patients. Among 459 NOTCH3-negative CADASIL-suspected patients, 18 (3.9%) showed NOTCH2NLC GGC repeat expansions; however, among 40 GFAP-negative AxD-suspected patients, none exhibited such repeat expansions. On comparing 17 patients with GGC repeat expansions, whose clinical information was available, with 179 CADASIL probands previously reported by us, the former showed significantly higher frequencies of seizure (23.5 vs. 6.9%, respectively), WMH in the corpus callosum (92.9 vs. 9.2%, respectively), paravermis (21.4 vs. 2.7%, respectively), and middle cerebellar peduncle (21.4 vs. 3.4%, respectively), and DWI high-intensity signals in CMJ (61.5 vs. 1.4%, respectively). In conclusion, not only DWI high-intensity signals in CMJ, but also the WMH distribution, particularly a high frequency in the corpus callosum, and presence of seizures are useful for detecting NIID in patients with undiagnosed leukoencephalopathies.