Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy
(CADASIL)
https://www.nature.com/articles/s10038-026-01470-1
Neuronal Intranuclear Inclusion Disease (NIID) is a neurodegenerative disorder caused by GGC repeat expansions in the NOTCH2NLC gene, often presenting with heterogeneous neurological symptoms and white matter changes on MRI. As these features overlap with other leukoencephalopathies, including CADASIL, some NIID cases may be misdiagnosed, particularly when standard genetic testing is negative. This study investigated whether a proportion of patients with a CADASIL-like phenotype but negative for NOTCH3 mutations may instead have NOTCH2NLC GGC repeat expansions. A secondary group of patients suspected of Alexander disease but negative for GFAP mutations was also analysed for comparison. A total of 459 NOTCH3-negative CADASIL-suspected patients and 40 GFAP-negative Alexander disease–suspected patients were screened. NOTCH2NLC repeat expansions were identified in 18/459 (3.9%) of the CADASIL-suspected group and in none of the Alexander disease group, indicating a distinct subset within undiagnosed leukoencephalopathies. Clinical data from 17 patients showed that seizures were more frequent than in typical CADASIL, while stroke and other cerebral small vessel disease features were less common. MRI findings demonstrated both overlap and key differences, including a high frequency of white matter hyperintensities in the corpus callosum, paravermis, and middle cerebellar peduncle, as well as diffusion-weighted imaging hyperintensity at the corticomedullary junction, which is characteristic of NIID. Overall, NOTCH2NLC GGC repeat expansions represent an alternative genetic cause in a small proportion of CADASIL-like cases. Recognition of specific clinical and imaging features, particularly seizures and corticomedullary junction involvement, may improve diagnostic accuracy and guide appropriate genetic testing.