Encephalopathy, Acute, Infection-Induced (Herpes-Specific), Susceptibility To, 7

A number sign (#) is used with this entry because of evidence that susceptibility to acute infection-induced (herpes-specific) encephalopathy-7 (IIAE7) is caused by heterozygous mutation in the IRF3 gene (603734) on chromosome 19q13.

For a phenotypic description of herpes simplex encephalitis (HSE) and a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.

Clinical Features

Andersen et al. (2015) reported a 15-year-old girl of Danish descent with herpes simplex virus (HSV) encephalitis. After a week of headache, fever, and confusion, she developed nuchal rigidity, impaired consciousness, and seizures. Cerebrospinal fluid showed mononuclear pleocytosis and was positive for HSV-1. The patient had no previous history of increased susceptibility to infections; she had had routine childhood immunizations with no adverse events.

Mork et al. (2015) reported a 34-year-old Danish man who developed adult-onset HSE. He had continued mild neurologic deficits, but no history of other severe infections. Clinical details were limited.

Inheritance

The transmission pattern of herpes simplex encephalitis in the family reported by Andersen et al. (2015) was consistent with autosomal dominant inheritance with incomplete penetrance.

Molecular Genetics

In a 15-year-old girl of Danish descent with herpes simplex encephalitis, Andersen et al. (2015) identified a heterozygous missense mutation in the IRF3 gene (R285Q; 603734.0001). The mutation, which was found by whole-exome sequencing, was also present in the unaffected father, consistent with incomplete penetrance. Patient peripheral blood cells showed normal expression of the mutant protein, but significantly impaired interferon (see, e.g., IFNB1, 147640) response upon stimulation with synthetic pathogen-associated molecular patterns as well as variably decreased responses to HSV-1, HSV-2, and HSV-8 compared to controls. In vitro functional expression assays in HEK293 cells showed that the mutant protein was not properly phosphorylated at S386 and did not form homodimers upon infection or pathway-specific stimulation. The TLR3 (603029)/TRIF (607601) pathway was most affected. There was no evidence of a dominant-negative effect, and Andersen et al. (2015) postulated that haploinsufficiency was responsible for the phenotype. Expression of wildtype IRF3 in patient cells restored the ability to express IFNB1 in response to infection.

In a 34-year-old Danish man (P2) with adult-onset herpes simplex encephalitis, Mork et al. (2015) identified a heterozygous missense mutation in the IRF3 gene (A277T; 603734.0002). The mutation was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE (including the patient reported by Andersen et al., 2015) and confirmed by Sanger sequencing. Patient peripheral blood mononuclear cells showed significantly lower IFNB1, CXCL10 (147310), and TNFA (191160) responses to poly(I;C) stimulation and/or HSV-1 infection compared to controls, suggesting defective antiviral response and a loss of function. The findings suggested that IRF3 variants may also contribute to HSE susceptibility in adults.

Animal Model

Menachery et al. (2010) found that Irf3-null mice had impaired ability to control HSV-1 replication in brain tissue following corneal or intracranial infection compared to wildtype mice. Irf3-null mice had an increased inflammatory cytokine response and decreased interferon production in the brain, resulting in increased lethality. These findings demonstrated a critical role for IRF3 in the control of central nervous system infection following HSV-1 challenge.