Chapter 6 - Genetic Background of Encephalopathy

Abstract

The molecular pathomechanisms of acute encephalopathy and/or encephalitis (AE) remain largely unknown. The high incidence of AE among individuals of East Asian ethnicity suggests an underlying genetic background. In particular, the identification of RANBP2 mutations as a cause of monogenic AE provides evidence that genetic factors contribute to AE. This chapter covers the genetic background of AE in relation to three aspects: immunologic, neuronal network, and metabolic. An immunologic genetic background is suggested through several factors such as the association of specific HLA class II types with AE susceptibility and mutations of the Toll-like receptor 3 and UNC-93B genes in influenza-associated AE. Furthermore, mutations in the genes encoding the Na+ channels SCN1A and SCN2A have been identified in AE, and this disorder has also been associated with adenosine A2a receptor (ADORA2A) gene polymorphisms. Specifically, SCN1A and SCN2A mutations are known to cause fever-sensitive epilepsy including Dravet syndrome, and ADORA2A is suspected to underlie theophylline-associated AE. These findings suggest a close link between the neuronal transmission and AE. Metabolism, especially for energy production, also seems to crucially impact AE. For example, the RANBP2 protein is considered to represent a modulator of glucose catabolism. Additionally, genetic polymorphisms confer thermolability to carnitine palmitoyltransferase II (CPTII) and hence can be predisposing factors for AE. Such genetic identifiers and future massive genetic analyses of larger AE cohorts should provide new insights regarding the genetic background of AE and facilitate the development of therapeutic and preventive measures for AE.