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Abstract
Objective To determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS).
Methods In this study, 545 patients with ALS and 1,305 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 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 electrophysiologic studies, were conducted in the genetically affected patients.
Results GGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, 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.
Glossary
- ALS=
- amyotrophic lateral sclerosis;
- ALS-FTD=
- ALS with frontotemporal dementia;
- DWI=
- diffusion-weighted imaging;
- ECAS=
- Edinburgh Cognitive and Behavioral ALS Screen;
- ET=
- essential tremor;
- 18F-FDG=
- 18F-fluorodeoxyglucose;
- FAB=
- Frontal Assessment Battery;
- fALS=
- familial ALS;
- FXTAS=
- fragile X tremor/ataxia syndrome;
- MCV=
- motor nerve conduction velocity;
- MMSE=
- Mini-Mental State Examination;
- MoCA=
- Montreal Cognitive Assessment;
- NIID=
- neuronal intranuclear inclusion disease;
- NIID-M=
- NIID muscle weakness–dominant subtype;
- RP-PCR=
- repeat-primer PCR;
- sALS=
- sporadic ALS
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Editorial, page 1080
- Received February 20, 2020.
- Accepted in final form August 3, 2020.
- © 2020 American Academy of Neurology
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