Encephalopathy, Acute, Infection-Induced (Herpes-Specific), Susceptibility To, 1

A number sign (#) is used with this entry because of evidence that susceptibility to acute infection-induced (herpes-specific) encephalopathy-1 (IIAE1) is caused by homozygous mutation in the UNC93B1 gene (608204) on chromosome 11q13.

Description

Herpes simplex virus (HSV)-1 is most often associated with infection of the oral mucosa. Primary infection is most commonly asymptomatic, but it may lead to symptoms usually involving the mucosa and skin. Following replication at the infection site, HSV-1 enters the epithelial endings of sensory neurons and travels up the trigeminal cranial nerves to the trigeminal ganglia, where latent infection is established. Reactivation of HSV-1, usually in the form of herpes labialis (cold sores), may occur in 20 to 40% of the population. HSV-1 seroprevalence is high, with over 85% of adults between the ages of 20 and 40 years infected. HSV-1 rarely infects the central nervous system (CNS), resulting in herpes simplex encephalitis (HSE), with an incidence of 2 to 4 per 1,000,000 people per year. In HSE, HSV-1 invades and replicates in neurons and glial cells, where focal necrotizing infections occur, primarily affecting the temporal and subfrontal regions of the brain. Untreated, HSE is fatal in at least 70% of cases, although the mortality and morbidity have been drastically reduced with antiviral therapy. Approximately one-third of all HSE cases are due to primary infections, and 30% of all HSE cases occur in children under the age of 20 years. Among children, HSE peaks between 3 months and 3 years of age, coinciding with the time of primary infection. In a subset of children, HSE results from a series of monogenic primary immunodeficiencies that impair UNC93B1- and TLR3 (603029)-dependent production of IFNA (147660)/IFNB (147640) and IFNG (147570) in the CNS (summary by Sancho-Shimizu et al., 2007).

Genetic Heterogeneity of Susceptibility to Acute Infection-Induced Encephalopathy, including Herpes Simplex Encephalitis (HSE)

For other forms of susceptibility to acute infection-induced encephalopathy, see herpes-specific IIAE2 (613002), caused by mutation in the TLR3 gene (603029) on chromosome 4q35; IIAE3 (608033), caused by mutation in the RANBP2 gene (601181) on chromosome 2q12; IIAE4 (614212), caused by mutation in the CPT2 gene (600650) on chromosome 1p32; herpes-specific IIAE5 (614849), caused by mutation in the TRAF3 gene (601896) on chromosome 14q32; herpes-specific IIAE6 (614850), caused by mutation in the TICAM1 gene (607601) on chromosome 19p13; herpes-specific IIAE7 (616532), caused by mutation in the IRF3 gene (603734) on chromosome 19q13; herpes-specific IIAE8 (617900), caused by mutation in the TBK1 gene (604834) on chromosome 12q14; and IIAE9 (618426), caused by mutation in the NUP214 gene (114350) on chromosome 9q34.

Clinical Features

Casrouge et al. (2006) postulated that HSE susceptibility may be inherited as a monogenic trait resulting in the specific impairment of immunity to HSV-1. This notion of pathogen-specific mendelian immunodeficiency contrasts with the dominant paradigm, in which rare single-gene lesions confer vulnerability to multiple infections, whereas more common infections in otherwise healthy patients reflect polygenic predisposition. Lerner et al. (1983), Koskiniemi et al. (1995), Gazquez et al. (1996), and Jackson et al. (2002) reported 2 related patients with HSE in each of 4 unrelated families with intervals of years between episodes affecting relatives in 1 or 2 generations. Casrouge et al. (2006) cited a recent epidemiologic survey of pediatric HSE in France reporting a high frequency (13%) of affected consanguineous families. In a genetic epidemiologic survey of otherwise healthy French children with sporadic HSE, Casrouge et al. (2006) detected 2 unrelated patients, each born to first-cousin parents. Both presented with HSE but showed no other evidence of unusual infectious disease and had efficiently controlled infections with at least 9 viruses.

Pathogenesis

Casrouge et al. (2006) assessed interferon production by HSV-1 stimulated blood cells from a series of otherwise healthy French children with sporadic HSE. After 24 hours and 40 hours of HSV-1 stimulation, peripheral blood mononuclear cells (PBMCs) from patients with HSE produced markedly lower levels of IFN-alpha (see 147660) and IFN-beta (see 147640), and marginally lower levels of IFN-lambda (see 607403) than control cells from 50 healthy individuals. However, these PBMCs produced normal levels of IFN-gamma (147570), TNF-alpha (191160), IL1-beta (147720), and IL6 (147620). IFN-alpha, IFN-beta, and IFN-lambda production in response to 10 other viruses was also impaired. The cellular responses of the 2 patients resembled that described from mice lacking UNC93B (608204), an endoplasmic reticulum protein with 12 membrane-spanning domains involved in Toll-like receptor activation.

Lafaille et al. (2012) tested the hypothesis that the pathogenesis of Herpes simplex encephalitis involves nonhematopoietic CNS-resident cells. Lafaille et al. (2012) derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3 (603029)- and UNC93B (608204)-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes, and oligodendrocytes. The induction of interferon-beta and/or interferon-lambda-1 in response to stimulation by the double-stranded RNA analog polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC93B in all cells tested. However, the induction of IFN-beta and IFN-lambda-1 in response to HSV-1 infection was impaired selectively in UNC93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC93B- and TLR3-deficient cells with the corresponding wildtype allele showed that the genetic defect was the cause of the poly(I:C) and the HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-alpha or IFN-beta but not IFN-lambda-1. Thus, impaired TLR3- and UNC93B-dependent IFN-alpha/beta intrinsic immunity to HSV-1, in the CNS in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.

Molecular Genetics

Casrouge et al. (2006) found that 1 patient with HSE was homozygous for a 4-nucleotide deletion in exon 8 of the UNC93B1 gene (608204.0001). They found that an unrelated patient with HSE was homozygous for a single-nucleotide substitution at position 781 of UNC93B1 (608204.0002), a splice site mutation resulting in deletion of exon 6.