Age-Dependent Mendelian Predisposition to Herpes Simplex Virus Type 1 Encephalitis in Childhood

Abel, Laurent; Plancoulaine, Sabine; Jouanguy, Emmanuelle; Zhang, Shen-Ying; Mahfoufi, Nora; Nicolas, Nathalie; Sancho‐Shimizu, Vanessa; Alcaïs, Alexandre; Guo, Yiqi; Cardon, Annabelle; Boucherit, Soraya; Obach, Dorothée; Clozel, Thomas; Lorenzo, Lazaro; Amsallem, D.; Berquin, Patrick; Blanc, Thierry; Bost-Bru, C.; Chabrier, Stéphane; Chabrol, B.; Cheuret, Emmanuel; Dulac, Olivier; Evrard, Philippe; Héron, Bénédicte; Lazaro, Leïla; Mancini, J.; Pédespan, Jean-Michel; Rivier, François; Vallée, Louis; Lebon, Pierre; Rozenberg, Flore; Casanova, Jean‐Laurent; Tardieu, Marc

doi:10.1016/j.jpeds.2010.04.020

Cited by 88 publications

(85 citation statements)

References 35 publications

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“…We felt that there could be no better infection on which to test our non-Mendelian monogenic model. One observation guided the entire project in the right direction: We found that 12% of French children with HSE were born to consanguineous parents (112). This finding was surprising, because all cases in this 20-y nationwide epidemiological study were considered to be sporadic.…”

Section: Hse: a Model Diseasementioning

confidence: 92%

“…This life-threatening disease strikes otherwise healthy children once (recurrence is rare) in the course of primary infection with the herpes simplex virus, which is ubiquitous and typically innocuous (111). The arguments against a genetic hypothesis and against a monogenic hypothesis in particular included the sporadic nature of the disease, with only four multiplex families having been reported since its first description in 1941 (112). Moreover, none of the known primary immunodeficiencies, including severe combined immunodeficiency, and none of the known acquired immunodeficiencies of childhood, including AIDS, had been identified as risk factors.…”

Section: Hse: a Model Diseasementioning

confidence: 99%

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Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

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This paper reviews the developments that have occurred in the field of human genetics of infectious diseases from the second half of the 20th century onward. In particular, it stresses and explains the importance of the recently described monogenic inborn errors of immunity underlying resistance or susceptibility to specific infections. The monogenic component of the genetic theory provides a plausible explanation for the occurrence of severe infectious diseases during primary infection. Over the last 20 y, increasing numbers of life-threatening infectious diseases striking otherwise healthy children, adolescents, and even young adults have been attributed to single-gene inborn errors of immunity. These studies were inspired by seminal but neglected findings in plant and animal infections. Infectious diseases typically manifest as sporadic traits because human genotypes often display incomplete penetrance (most genetically predisposed individuals remain healthy) and variable expressivity (different infections can be allelic at the same locus). Infectious diseases of childhood, once thought to be archetypal environmental diseases, actually may be among the most genetically determined conditions of mankind. This nascent and testable notion has interesting medical and biological implications.

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Section: Hse: a Model Diseasementioning

confidence: 92%

Section: Hse: a Model Diseasementioning

confidence: 99%

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Casanova

2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

202

163

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“…4,5 The pathogenesis of HSE had long remained unclear. Our recent studies have demonstrated that HSE may result from singlegene inborn errors of TLR3-mediated immunity in some children, 6 with homozygous or…”

Section: Methodsmentioning

confidence: 99%

“…3 HSE is the most common form of sporadic viral encephalitis in Western countries. 4,5 The pathogenesis of HSE had long remained unclear. Our recent studies have demonstrated that HSE may result from singlegene inborn errors of TLR3-mediated immunity in some children, 6 with homozygous or heterozygous mutations of a TLR3 pathway gene (TLR3, UNC93B1, TRIF, TRAF3, and TBK1).…”

mentioning

confidence: 99%

TLR3 deficiency in herpes simplex encephalitis

Lim¹,

Seppänen²,

Hautala³

et al. 2014

Neurology

137

120

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Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. Methods:We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype.Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency ,0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D1R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients.Conclusions: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully. TLR3 is one of the most highly conserved TLRs in humans that have evolved under the strongest purifying selection.1 TLR3 recognizes double-stranded RNA (dsRNA), a by-product produced during the viral replication of most viruses, including herpes simplex virus 1 (HSV-1).2 The most common known clinical consequence of human TLR3 deficiency is childhood herpes simplex encephalitis (HSE). Childhood HSE is a rare life-threatening complication of primary infection with HSV-1, a common neurotropic dsDNA virus that is innocuous in most children.3 HSE is the most common form of sporadic viral encephalitis in Western countries. 4,5 The pathogenesis of HSE had long remained unclear. Our recent studies have demonstrated that HSE may result from singlegene inborn errors of TLR3-mediated immunity in some children, 6 with homozygous or

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“…The incidence of HSVE worldwide is estimated to be between 2 and 4 cases/1,000,000 [44], and the incidence in the USA is similar [53]. There is a bimodal distribution with peak incidence in the very young (up to 3 years of age), and again in adults aged > 50 years, but the majority of cases occur in those over 50, with both sexes equally affected [44,[54][55][56].…”

Section: Epidemiologymentioning

confidence: 99%

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

2016

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Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be lifesaving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.

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Age-Dependent Mendelian Predisposition to Herpes Simplex Virus Type 1 Encephalitis in Childhood

Cited by 88 publications

References 35 publications

Severe infectious diseases of childhood as monogenic inborn errors of immunity

Severe infectious diseases of childhood as monogenic inborn errors of immunity

TLR3 deficiency in herpes simplex encephalitis

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

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