The four patients described by Yuan and colleagues, who harbored GGC repeat expansions in NOTCH2NLC, showed similar clinical findings, including limb muscle weakness and atrophy, widespread fasciculations, dysarthria, dysphagia, dyspnea, and upper motor neuron signs 4. The size of the abnormal repeat expansion was in the range of intermediate repeat numbers (between 43 and 59) in two cases, and in that of pathogenic expansions in the other two (96 and 143). Noteworthy, the two carriers of intermediate GCC repeat expansions died before reaching a definite diagnosis of ALS. High inter-individual clinical variability within families, nerve conduction abnormalities and intranuclear ubiquitin and p62-positive inclusions were identified in carriers of GGC repeat expansions in NOTCH2NLC and NIID-M patients. However, some significant differences argued against the presence of a unique clinical entity, including the significantly more severe phenotype and rapid deterioration of the four patients described by Yuan and colleagues, and the evidence of spontaneous activity on needle examination in more regions compared to NIID-M. Considering the different ranges of GCC repeat number detected in ALS (44–143) and NIID-M (118–517) patients, the authors suggested that the length of expansion might be related to the development of specific phenotypes, but further analysis are warranted to confirm this hypothesis. Alternatively, ALS with GGC repeat expansion in NOTCH2NLC might be a subtype of NIID previously undescribed.
To date, mutations in more than 30 genes have been associated with ALS. In Caucasian ALS patients the most recurring genetic defects are observed in C9orf72 (familial ALS (fALS) 33.7%, sporadic ALS (sALS) 5.1%), followed by SOD1 (fALS 14.8%, sALS 1.2%), TARDBP (fALS 4.2%, sALS 0.8%) and FUS (fALS 2.8%, sALS 0.3%) 10. The proportion of mutated individuals might differ remarkably in different ethnic backgrounds, as previously observed for the mutation spectrum of ALS genes in the Chinese population 11. However, a recent study failed to detect abnormal GGC repeats in NOTCH2NLC in a cohort of 304 unrelated Taiwan ALS patients, whereas an intermediate GCC repeat allele (46 repeats) was detected in 1 out of 637 control subjects 12.
This is the first assessment of the prevalence of GGC abnormal repeats in NOTCH2NLC in a European cohort of ALS patients. Although our study could be improved by the analysis of a control group and by the use of additional tests for a better detection of GGC repeat sizes or repeat interruptions, we think that these improvements are not expected to impact on the result.
Overall, we suggest that NOTCH2NLC expanded alleles might be absent or at least extremely rare in ALS Italian patients. Further investigations in larger cohorts with different ethnic backgrounds are required to support the involvement of NOTCH2NLC in ALS.