The inclusion of the ratios in diagnostic criteria increases sensitivity and NPV for the diagnosis of MCI due to AD.

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ObjectiveTo identify novel genetic mechanisms causing Charcot-Marie-Tooth (CMT) disease. MethodsWe performed a next-generation sequencing study of 34 genes associated with CMT in a patient with peripheral neuropathy. ResultsWe found a non-previously described mutation in EGR2 (p.P397H). P397H mutation is located within the loop that connects zinc fingers 2 and 3, a pivotal domain for the activity of this transcription factor. Using promoter activity luciferase assays, we found that this mutation promotes decreased transcriptional activity of EGR2. In this patient, we also found a previously described nonpathogenic polymorphism in lipopolysaccharide-induced TNF-α factor (LITAF) (p.T49M). We show that the p.T49M mutation decreases the steady-state levels of the LITAF protein in Schwann cells. Loss of function of LITAF has been shown to produce deregulation in the NRG1-erbB signaling, a pivotal pathway for EGR2 expression by Schwann cells. Surprisingly, our segregation study demonstrates that p.P397H mutation in EGR2 is not sufficient to produce CMT disease. Most notably, only those patients expressing simultaneously the LITAF T49M polymorphism develop peripheral neuropathy. ConclusionsOur data support that the LITAF loss-of-function interferes with the expression of the transcriptional-deficient EGR2 P397H mutant hampering Schwann cell differentiation and suggest that in vivo both genes act in tandem to allow the proper development of myelin. All Demyelinating disease (CNS)following collection(s):This article, along with others on similar topics, appears in the& Licensing http://ng.neurology.org/misc/about.xhtml#permissions its entirety can be found online at: Information about reproducing this article in parts (figures,tables) or in Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsus Information about ordering reprints can be found online: reserved. Online