No evidence supports the genetic heterogeneity of Neuronal intranuclear inclusion disease.

Dear Editor,

We read with great interest the recently published article by Chen et al. titled neuronal intranuclear inclusion disease is genetically heterogeneous. In this study, the authors examined the GGC repeat expansion of the NOTCH2NLC gene in the patients with the clinical diagnosis of neuronal intranuclear inclusion disease (NIID). They found that only one patient had abnormal GGC repeat expansion of NOTCH2NLC in 12 patients diagnosed with NIID, and concluded that NIID is genetically heterogeneous. Although we believe that there is a possibility for this conclusion, we do not agree with the authors’ inference without evidence.

First, the authors did not propose a new genetic mutation as the pathogenic genes of NIID. At present, the published literature shows that NOTCH2NLC is the only causative gene reported for the genetic diagnosis of NIID. , Although the authors did not find expanded GGC repeats in the NOTCH2NLC gene in 11 patients clinically diagnosed with NIID in the European population, we think it is inappropriate to infer the genetic heterogeneity without evidence of new causative genes for NIID.

Second, the clinical manifestations and pathological results caused by FMR1 mutation are very similar to those of NOTCH2NLC mutation, and it is a possible heterogeneous gene that causes NIID. However, FMR1 repeated CGG expansion results in a disease called fragile X‐associated tremor/ataxia syndrome (FXTAS) in clinical diagnosis, it is not NIID. At the same time, the authors also considered them to be two different diseases in their own diagnostic criteria, denying the possibility that FMR1 is a heterogeneous gene. Therefore, even if other genes cause similar pathophysiological processes and clinical manifestations, they may be two completely different diseases. In the authors' own diagnostic criteria, only NOTCH2NLC repeat expansion causes NIID, as does not reflect the view that NIID has genetic heterogeneity.

Finally, the author's diagnosis of NIID mainly relies on pathological results, but intranuclear eosinophilic ubiquitinated inclusions also have been reported in a variety of neurodegenerative diseases besides NIID. , Although the authors had demonstrated this point, the conclusion is that NOTCH2NLC expansion is not the only driver for diseases with neuronal intranuclear inclusions (NIIs), and it is not a supplement to the conclusion that NIID is genetically heterogeneous. In addition, the authors should also provide more evidence to prove the correctness of the diagnosis in their patients, such as imaging results.

In conclusion, we believe that there was no evidence to support the genetic heterogeneity of NIID so far.

Conflict of Interest

All authors report no disclosures.