Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease

J Neurol Neurosurg Psychiatry. 2022 Dec;93(12):1289-1298. doi: 10.1136/jnnp-2022-329772. Epub 2022 Sep 23.


Background: Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China.

Methods: Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.

Results: In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.

Conclusions: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Keywords: clinical neurology; neurogenetics.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cross-Sectional Studies
  • Dementia* / pathology
  • Humans
  • Intranuclear Inclusion Bodies / genetics
  • Intranuclear Inclusion Bodies / pathology
  • Movement Disorders*
  • Muscle Weakness / pathology
  • Peripheral Nervous System Diseases* / pathology

Supplementary concepts

  • Neuronal intranuclear inclusion disease