Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

We describe a peptide-based strategy for HCV vaccine design that addresses the problem of variability in hypervariable region 1 (HVR1). Peptides representing antibody epitopes of HVR1 from genotype 1a were synthesized and incorporated into multideterminant immunogens that also included lipid moieties and helper T (T h ) cell epitopes. Mice inoculated with these polyepitopes generated strong antibody responses. Antibody titers were highest in mice inoculated with polyepitope immunogens which contained the lipid moiety dipalmitoyl-S-glyceryl cysteine (Pam2Cys). Antisera were tested for their potential to neutralize HCV by 3 currently available assays. Antibodies elicited in mice by the polyepitope-based vaccine candidates were able to (1) bind to E2 expressed on the surface of E1/E2-transfected human embryonic kidney (HEK) 293T cells, (2) H epatitis C virus (HCV) is a human pathogen that has major global significance. It is estimated that 170 million people worldwide and more than 10% of the population in some countries are infected with HCV. 1 A range of illnesses have been associated with HCV including acute and chronic hepatitis, cirrhosis of the liver, and HCC. Hepatitis C infection is now the leading indication for liver transplantation in countries such as the United States. In the absence of a vaccine, treatment is confined to the use of the combination of interferon-␣ and pegylated interferon-␣ together with the antiviral drug ribavirin. [2][3][4][5] The development of a vaccine against HCV could prevent HCV-associated diseases. However, there are 2 major impediments to the development of a HCV vaccine: the vast diversity of viral genotypes and quasispecies and the complex nature of the immune response required to clear infection. Antibodies directed to epitopes in the viral glycoprotein E2 (including HVR1) are neutralizing. [6][7][8][9][10][11][12][13][14] Further evidence supporting the protective role of neutralizing antibody was recently highlighted by the demonstration of the presence of neutralizing antibodies in immune globulin prepared from anti-HCV serum. 13 This immune globulin protected chimpanzees from infection with HCV genotypes 1a and 2a, 13 strengthening the argument that neutralizing antibodies can be cross-protective. In addition, it has been shown that it is possible to prevent entry of retroviral particles pseudotyped with the

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