Encephalopathy, Acute, Infection-Induced (Herpes-Specific), Susceptibility To, 6

A number sign (#) is used with this entry because of evidence that susceptibility to acute infection-induced (herpes-specific) encephalopathy (IIAE6) is caused by heterozygous or homozygous mutation in the TICAM1 gene (607601), also called TRIF, on chromosome 19p13.

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

Sancho-Shimizu et al. (2011) reported 2 unrelated patients from Saudi Arabia and Europe with childhood-onset HSE resulting from autosomal recessive or autosomal dominant TRIF deficiency. Both patients presented at around 2 years of age with persistent high fever, and their cerebrospinal fluid contained herpes simplex virus (HSV)-1. Both patients responded well to different antiviral treatments. Overall, the clinical phenotypes of these 2 patients were remarkably similar to those observed in patients with HSE resulting from UNC93B1 deficiency (610551), TLR3 deficiency (613002), or TRAF3 deficiency (614849).

Mork et al. (2015) reported 2 unrelated men (P5 and P6) who developed HSE after age 60 years. Neither patient had suffered from any other severe viral infections, although P6 experienced a severe genital herpes eruption a few days prior to the HSE episode, which was caused by HSV-2. The infection in P5 was due to HSV-1. Additional clinical details were not provided.

Inheritance

Sancho-Shimizu et al. (2011) reported 2 unrelated patients who had inherited susceptibility to HSE due to TRIF deficiency in an autosomal dominant or autosomal recessive manner. The autosomal dominant form showed incomplete penetrance, similar to HSE susceptibility resulting from UNC93B or TLR3 deficiency.

Molecular Genetics

Sancho-Shimizu et al. (2011) identified causative mutations in the TRIF gene in 2 unrelated patients with HSE. The first patient, a Saudi Arabian boy with autosomal recessive HSE susceptibility, had a homozygous nonsense mutation (R141X; 607601.0001) that resulted in premature termination and no detectable TRIF protein. No other family members were homozygous for this mutation. The second patient, a European girl of mixed European descent with autosomal dominant HSE susceptibility, was heterozygous for a ser186-to-leu (S186L; 607601.0002) substitution in the N terminus of the protein. This patient was the only family member to develop HSE, although her mother and maternal grandfather also carried the S186L mutation and had HSV-1-specific serum antibodies. Sancho-Shimizu et al. (2011) also reported a third patient, an Iranian boy who presented with HSE at age 4.5 years, who was heterozygous for a pro625-to-leu (P625L) missense mutation in the C terminus of TRIF. However, unlike the other TRIF mutations, P625L showed no deleterious effects in cellular assays and was considered nonpathogenic.

In 2 unrelated Danish men (P5 and P6) with onset of herpes simplex encephalitis after age 60 years, Mork et al. (2015) identified heterozygous missense mutations in the TICAM1 gene (A568T, 607601.0003 and S160F, 607601.0004). The mutations were found by whole-exome sequencing of a cohort of 16 patients with adult-onset HSE and confirmed by Sanger sequencing. One patient was infected with HSV-1 and the other with HSV-2. Peripheral blood mononuclear cells from both patients showed variable but significantly impaired beta-interferon (INFB1; 147640), CXCL10 (147310), and/or TNFA (191160) responses to poly(I;C) stimulation and/or HSV-1 infection compared to controls. The findings suggested that TICAM1 variants may also contribute to HSE susceptibility in adults.