Encephalopathy, Acute, Infection-Induced (Herpes-Specific), Susceptibility To, 8

A number sign (#) is used with this entry because of evidence that susceptibility to acute infection-induced (herpes-specific) encephalopathy-8 (IIAE8) is caused by heterozygous mutation in the TBK1 gene (604834) on chromosome 12q14.

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

Herman et al. (2012) reported 2 unrelated girls, of Polish and French descent, with onset of HSE at ages 7 years and 11 months, respectively. The diagnosis in the first girl was confirmed by positivity for HSV-1 antibodies, detection of HSV-1 DNA in the cerebrospinal fluid (CSF), and abnormal brain imaging patterns. There was no family history of encephalitis or herpes labialis. She was successfully treated for the acute episode, but subsequently showed cognitive impairment and drug-resistant epilepsy. The second girl presented in infancy with otitis, fever, seizures, hemiparesis, and encephalitis-like lesions on the left side of the brain. She subsequently had cognitive and motor disabilities, seizures, and obesity. Her mother and sister had bouts of herpes labialis once or twice a year, but no other significant infectious phenotype. Neither patient had additional susceptibility to infections, and serologic studies indicated that both patients had been exposed to multiple viruses, including VSV, CMV, EBV, B19, and influenza A. Both were also immunized against multiple diseases with no adverse effects.

Mork et al. (2015) reported a Danish woman (P10) who presented with HSE due to HSV-2 at age 50 years. Brain imaging showed diffuse cerebral edema. She had no other severe infections associated with immunodeficiency. Clinical details were limited.

Inheritance

The transmission pattern of herpes simplex encephalitis in the families reported by Herman et al. (2012) was consistent with autosomal dominant inheritance with incomplete penetrance.

Molecular Genetics

In 2 unrelated patients with herpes simplex encephalitis, Herman et al. (2012) identified heterozygous missense mutations in the TBK1 gene (G159A, 604834.0008 and D50A, 604834.0009). Transfection of the mutations into TBK1-null cells failed to restore poly(I:C)-induced interferon production via the TLR3 (603029) pathway, consistent with a loss of function. In vitro functional expression assays showed that the G159A mutation had a dominant-negative effect, whereas the D50A mutation resulted in haploinsufficiency. Studies of patient fibroblasts, which were heterozygous for the mutation, showed variable responses to extracellular poly(I:C), although both showed enhanced viral replication and cell death caused by TLR3-dependent viruses, HSV-1 and VSV. Interferon production in response to TLR3-independent agonists and viruses tested were maintained in patient fibroblasts and peripheral blood mononuclear cells, which explained the clinical phenotype in these patients being limited to HSE.

In a Danish woman (P10) with herpes simplex encephalitis, Mork et al. (2015) identified a heterozygous missense mutation in the TBK1 gene (I207V; 604834.0010). The mutation was found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing. Peripheral blood mononuclear cells showed impaired induction of CXCL10 (147310) and TNF-alpha (TNFA; 191160) after HSV-1 infection compared to controls. However, interferon-beta (IFNB1; 147640) production was significantly increased in response to poly(I:C). The findings suggested abnormal and impaired responses to viral infection in this patient. The findings also suggested that TBK1 variants may contribute to HSE susceptibility in adults.