Repeat expansion scanning of the NOTCH2NLC gene in patients with multiple system atrophy

Objective Trinucleotide GGC repeat expansion in the 5'UTR of the NOTCH2NLC gene has been recognized as the pathogenesis of neuronal intranuclear inclusion disease (NIID). Previous studies have described that some NIID patients showed clinical and pathological similarities with multiple system atrophy (MSA). This study aimed to address the possibility that GGC repeat expansion in NOTCH2NLC might be associated with some cases diagnosed as MSA. Methods A total of 189 patients with probable or possible MSA were recruited to screen for GGC repeat expansion in NOTCH2NLC by repeat-primed PCR (RP-PCR). In addition, long-read sequencing (LRS) was performed for all patients with RP-PCR-positive expansion, five patients with RP-PCR-negative expansion, and five controls on the Nanopore platform. Skin biopsies were performed on two patients with GGC expansion. Results Five of 189 patients (2.6%) were found to have GGC expansion in NOTCH2NLC. LRS results identified that the five patients had GGC expansion between 101 and 266, but five patients with RP-PCR-negative expansion and five controls had GGC expansion between 8 and 29. Besides the typical symptoms and signs of MSA, patients with GGC expansion might have longer disease duration, severe urinary retention, and prominent cognitive impairment. In the skin samples from the patients with GGC expansion, typical p62-postive but alpha-synuclein-negative intranuclear inclusions were found in fibroblasts, adipocyte and ductal epithelial cells of sweat glands. Conclusion Trinucleotide GGC repeat expansion in NOTCH2NLC could be observed in patients with clinically diagnosed MSA. Adult-onset NIID should be considered as a differential diagnosis of MSA.