EEF1A2 mutations in epileptic encephalopathy/intellectual disability: Understanding the potential mechanism of phenotypic variation.

EEF1A2 encodes protein elongation factor 1-alpha 2, which is involved in Guanosine triphosphate (GTP)-dependent binding of aminoacyl-transfer RNA (tRNA) to the A-site of ribosomes during protein biosynthesis and is highly expressed in the central nervous system. De novo mutations in EEF1A2 have been identified in patients with extensive neurological deficits, including intractable epilepsy, globe developmental delay, and severe intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel and a recurrent de novo mutation, c.294C>A; p.(Phe98Leu) and c.208G>A; p.(Gly70Ser), in patients with Lennox-Gastaut syndrome. The further systematic analysis revealed that all EEF1A2 mutations were associated with epilepsy and intellectual disability, suggesting its critical role in neurodevelopment. Missense mutations with severe molecular alteration in the t-RNA binding sites or GTP hydrolysis domain were associated with early-onset severe epilepsy, indicating that the clinical expression was potentially determined by the location of mutations and alteration of molecular effects. This study highlights the potential genotype-phenotype relationship in EEF1A2 and facilitates the evaluation of the pathogenicity of EEF1A2 mutations in clinical practice.

Dengue virus and Japanese encephalitis virus infection of the central nervous system share similar profiles of cytokine accumulation in cerebrospinal fluid.

Dengue virus (DENV) and Japanese encephalitis virus (JEV) are two important pathogenic viruses that can cause severe encephalitis, which is accompanied by inflammatory cytokines. However, the inflammatory cytokine content of cerebrospinal fluid (CSF) in DENV and JEV infection of central nervous system are not sufficiently studied. To investigate cytokine levels in serum and CSF of hospitalised children with DENV and JEV infection of the central nervous system, a total of 183 hospitalised children with viral encephalitis-like syndrome were enrolled between May 2014 and April 2015 at the Children's Hospital of Chenzhou, Hunan, China. DENV and JEV infection was diagnosed by ELISA. Cytokine levels in the serum and CSF were measured by commercial ELISA kits. Twenty-nine (15.85%) and 26 (14.21%) DENV and JEV infections were detected in 183 patients with viral encephalitis-like syndrome, respectively. Higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were detected in the serum of JEV infected patients than in DNEV patients (p < 0.05) or in healthy controls (p < 0.001), and levels of GM-CSF, interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) were higher in the CSF than serum in both DENV and JEV infection. Both DENV and JEV infection induced similar cytokine accumulation profiles in the CSF, which probably contributed to DENV- and JEV-induced immunopathogenesis.

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children.

BACKGROUND/AIMS: Coronavirus (CoV) infections induce respiratory tract illnesses and central nervous system (CNS) diseases. We aimed to explore the cytokine expression profiles in hospitalized children with CoV-CNS and CoV-respiratory tract infections. METHODS: A total of 183 and 236 hospitalized children with acute encephalitis-like syndrome and respiratory tract infection, respectively, were screened for anti-CoV IgM antibodies. The expression profiles of multiple cytokines were determined in CoV-positive patients. RESULTS: Anti-CoV IgM antibodies were detected in 22/183 (12.02%) and 26/236 (11.02%) patients with acute encephalitis-like syndrome and respiratory tract infection, respectively. Cytokine analysis revealed that the level of serum granulocyte colony-stimulating factor (G-CSF) was significantly higher in both CoV-CNS and CoV-respiratory tract infection compared with healthy controls. Additionally, the serum level of granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly higher in CoV-CNS infection than in CoV-respiratory tract infection. In patients with CoV-CNS infection, the levels of IL-6, IL-8, MCP-1, and GM-CSF were significantly higher in their cerebrospinal fluid samples than in matched serum samples. CONCLUSION: To the best of our knowledge, this is the first report showing a high incidence of CoV infection in hospitalized children, especially with CNS illness. The characteristic cytokine expression profiles in CoV infection indicate the importance of host immune response in disease progression.