The clinical and neuropathological picture of adult neuronal intranuclear inclusion disease with no radiological abnormality

Neuropathology. 2022 Jun;42(3):204-211. doi: 10.1111/neup.12792. Epub 2022 Mar 10.


In typical adult neuronal intranuclear inclusion disease (NIID) with predilection for the basal ganglia or cerebral cortex, not only neurons but also glial cells harbor intranuclear inclusions. In addition, these inclusions are present in the peripheral autonomic nervous system, visceral organs and skin. In NIID cases with an expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of the Notch 2 N-terminal like C (NOTCH2NLC) gene, these repeats are located in an upstream open reading frame (uN2C) and result in the production of a polyglycine-containing protein called uN2CpolyG. Typically, patients with adult NIID show high-intensity signals at the corticomedullary junction on diffusion-weighted brain magnetic resonance imaging. We report a case of adult NIID in a 78-year-old Japanese male, who suffered from mild, non-progressive tremor during life but showed no radiographic abnormalities suggestive of adult NIID. Pathologically, ubiquitin-, p62- and uN2CpolyG-positive neuronal intranuclear inclusions were particularly frequent in the hippocampal formation, but were also seen in the enteric plexuses, kidney and cardiac muscles. By contrast, glial intranuclear inclusions were barely evident in the affected regions. The present case also had an immunohistochemical profile differing from that of typical adult NIID. The findings in this case suggest that adult NIID can show clinical, radiographic and pathological heterogeneity.

Keywords: NOTCH2NLC; heterogeneity; immunoprofile; intranuclear inclusions; neuronal intranuclear inclusion disease.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Aged
  • Brain / pathology
  • Humans
  • Intranuclear Inclusion Bodies* / metabolism
  • Male
  • Neurodegenerative Diseases* / metabolism
  • Neuropathology

Supplementary concepts

  • Neuronal intranuclear inclusion disease