Objective

To determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS).

Methods

In this study, 545 ALS patients and 1305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including C9ORF72 and ATXN2) and polynucleotide repeat expansions in NOP56 and AR genes were excluded. Repeat-primed polymerase chain reaction PCR (RP-PCR) and GC-rich PCR were performed to determine the GGC repeat size in NOTCH2NLC. Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiological studies, were conducted in the genetically affected patients.

Results

GGC repeat expansion was observed in four patients (numbers of repeats: 44, 54, 96, and 143), accounting for approximately 0.73% (4/545) of all ALS patients. A comparison with 1305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher’s exact test, 4/545 vs 0/1305, p=0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle-weakness-dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration.

Conclusion

Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in NOTCH2NLC is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.