Background/Objective: Neuronal intranuclear inclusion disease (NIID) is characterized by widespread deposition of eosinophilic intranuclear inclusions in multiple systems throughout the body. The aim of this study was to investigate the clinical and phenotypic features of NIID, with a focus on the potential association between the morphological features of fibrils formed by polyG (polyglycine) proteins and cognitive dysfunction in patients with NIID. Methods: This study involved a retrospective collection of clinical data from 15 patients with NIID harboring GGC repeat expansions in the NOTCH2NLC (Notch 2 N-Terminal Like C) gene (including symptoms, signs, biochemical markers, cranial MRI, MMSE, and MoCA cognitive scores). All patients underwent skin biopsy, with one additional autopsy of brain tissue. Some skin samples were stained with hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining with anti-p62 antibody. The remaining skin samples and brain tissue samples obtained from autopsies were analyzed using anti-p62 antibody immunofluorescence (IF) staining and transmission electron microscopy (TEM). The number of GGC repeats was quantified using repeat primer PCR (RP-PCR). Based on ultrastructural characteristics (morphology and diameter), inclusion fibers were classified into two subtypes, and differences in the severity of cognitive impairment between subtypes were compared. Results: The majority of patients in this cohort with NIID were female (73.3%), with an average age of onset of 61.06 ± 7.67 years. The core clinical manifestations were cognitive decline (93.3%) and autonomic dysfunction (93.3%). Cranial MRI revealed characteristic DWI “ribbon sign” in 93.3% of patients, accompanied by lateral ventricle enlargement (93.3%), cerebellar atrophy (86.6%), and high T2-FLAIR signal in the corpus callosum (93.3%). All patients were found to have pathogenic GGC amplification in the NOTCH2NLC gene (median 115, range 88–210). Skin/brain tissue pathology confirmed p62-positive nuclear inclusions, and transmission electron microscopy revealed two fiber subtypes for the first time: type A (Long, thin filamentous, 202.38 ± 42.35 nm) and type B (short rod-shaped, 73.08 ± 11.56 nm). Group analysis indicated that the diameter of fibers was significantly larger in the cognitive impairment group (p < 0.05), and the type B fiber group had lower cognitive levels (p < 0.05) and larger diameters (p < 0.05), suggesting a strong association between type B fibers and severe cognitive impairment and poor prognosis. Conclusions: The presence of two different forms of fibrils, type A and type B, in the inclusion bodies of NIID patients, and the poorer cognitive level of NIID patients in the type B group than that of type A suggest that type B fibrils can be used as a novel pathological marker of severe cognitive impairment and poor prognosis in NIID.
Zhou et al. (2025) studied this question.