Clinical, radiological, and molecular analyses of neuronal intranuclear inclusion disease with polyglycine inclusions

Neuronal intranuclear inclusion disease (NIID) is a clinically complex neurological disorder that appears sporadically or autosomally. Expansions of intronic GGC trinucleotide repeats in the NOTCH2 N-terminal-like C (NOTCH2NLC) gene cause NIID. In this study, to clarify the clinical characteristics useful for the differential diagnosis of NIID, clinical data of neurological examination, neuroimaging, and nerve conduction studies of six NIID patients diagnosed by pathological or genetic investigations were analyzed. Clinically useful characteristics for diagnosing NIID include general hyporeflexia, episodic disturbance of consciousness, sensory disturbance, miosis, and dementia. Furthermore, neuroimaging findings, such as leukoencephalopathy in T2-weighted magnetic resonance imaging and a linear high intensity of subcortical U-fibers in diffusion-weighted imaging (DWI), as well as decreased motor nerve conduction velocity, are especially important biomarkers for NIID. However, it is necessary to remember that these features may not always be present, as shown in one of the cases who did not have a DWI abnormality in this study. This study also investigated whether expanded GGC repeats were translated into polyglycine. Immunohistochemical analysis using a custom antibody raised against putative C-terminal polypeptides followed by polyglycine of uN2CpolyG revealed that polyglycines were localized in the intranuclear inclusions in skin biopsy specimens from all six patients, suggesting its involvement in the pathogenesis of NIID.