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Potential Role of Febrile Seizures and Other Risk Factors Associated With Sudden Deaths in Children.

ABSTRACT: Importance:Sudden unexplained death in childhood (SUDC) is the fifth leading category of death among toddlers but remains underrecognized and inadequately studied. Objective:To assess the potential role of febrile seizures (FS) and other risk factors associated with SUDC and describe the epidemiology, mechanisms, and prevention of SUDC. Design, Setting, and Participants:This case series study reviewed 622 consecutive sudden child death cases aged 1 to 17 years from 2001 to 2017 from 18 countries. Data were collected from family members of children who died suddenly; these families voluntarily registered with the SUDC Foundation. Data analysis was conducted from November 2017 to February 2019. Main Outcome Measures:Certified manner of death characterized as accident, natural, or undetermined. Results:A total of 391 families with decedents aged 1 to 6 years completed a comprehensive interview on medical and social histories, and circumstances of death with forensic evaluations revealing a cause of death (sudden explained death in childhood [SEDC]) or no cause of death (SUDC). Of these children, 231 (59.1%) were male, the mean (SD) age at death was 24.9 (12.8) months, and 104 (26.6%) had a history of FS. Compared with the general population FS prevalence (2%-5%), FS prevalence among SUDC (28.8%; 95% CI, 23.3%-34.2%) and SEDC (22.1%; 95% CI, 14.8%-29.3%) were elevated. The odds of death during sleep was 4.6-fold higher in SUDC than in SEDC cases (odds ratio, 4.61; 95% CI, 1.92-11.09; adjusted P?=?.008). The siblings of SUDC cases were followed up for 3144 life-years, and none died prematurely from SUDC. Conclusions and Relevance:This analysis of the largest SUDC cohort confirmed an increased FS rate and found significantly increased rates of FS among SEDC. This study suggests that seizures may contribute to some SUDC and SEDC deaths. The risk of sudden death in a sibling was low. To develop and assess preventive strategies, population-based studies are needed to define the epidemiology and spectrum of risk factors and identify biomarkers of patients with FS at high risk of sudden death.

SUBMITTER: Crandall LG

PROVIDER: S-EPMC6487567 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Potential Role of Febrile Seizures and Other Risk Factors Associated With Sudden Deaths in Children.

Crandall Laura Gould LG Lee Joyce H JH Stainman Rebecca R Friedman Daniel D Devinsky Orrin O

JAMA network open 20190405 4

<h4>Importance</h4>Sudden unexplained death in childhood (SUDC) is the fifth leading category of death among toddlers but remains underrecognized and inadequately studied.<h4>Objective</h4>To assess the potential role of febrile seizures (FS) and other risk factors associated with SUDC and describe the epidemiology, mechanisms, and prevention of SUDC.<h4>Design, setting, and participants</h4>This case series study reviewed 622 consecutive sudden child death cases aged 1 to 17 years from 2001 to ...[more]

PMID: 31026025

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Project description:To explore the phenotype spectrum of DEPDC5 variants and the possible mechanisms underlying phenotypical variation, we performed targeted next-generation sequencing in 305 patients with focal epilepsies and 91 patients with generalized epilepsies. Protein modeling was performed to predict the effects of missense mutations. All previously reported epilepsy-related DEPDC5 variants were reviewed. The genotype-phenotype correlations with molecular sub-regional implications were analyzed. We identified a homozygous DEPDC5 mutation (p.Pro1031His) in a case with focal cortical dysplasia and eight heterozygous mutations in 11 families with mild focal epilepsies, including 13 patients in eight families with focal epilepsy with febrile seizures plus/febrile seizures (FEFS + /FS). The mutations included one termination codon mutation (p.Ser1601_Ter1604del_ext133), three truncating mutations (p.Val151Serfs?27, p.Arg239?, and p.Arg838?), and four missense mutations (p.Tyr7Cys, p.Tyr836Cys, p.Pro1031His, and p.Gly1545Ser) that were predicted to affect hydrogen bonds and protein stability. Analysis on epilepsy-related DEPDC5 variants revealed that malformations of cortical development (MCDs) had a tendency of higher frequency of null mutations than those without MCD. MCD-associated heterozygous missense mutations were clustered in structural axis for binding arrangement (SABA) domain and close to the binding sites to NPRL2/NPRL3 complex, whereas those associated with FEFS + /FS were a distance away from the binding sites. Evidence from four aspects and one possible evidence from sub-regional implication suggested MCD and FEFS + /FS as phenotypes of DEPDC5 variants. This study suggested that the phenotypes of DEPDC5 variants vary from mild FEFS + /FS to severe MCD. Heterozygous DEPDC5 mutations are generally less pathogenic and commonly associated with mild phenotypes. Bi-allelic mutations and second hit of somatic mutations, together with the genotype-phenotype correlation and sub-regional implication of DEPDC5 variants, explain severe phenotypes.

Dataset Information

Potential Role of Febrile Seizures and Other Risk Factors Associated With Sudden Deaths in Children.

Publications

Potential Role of Febrile Seizures and Other Risk Factors Associated With Sudden Deaths in Children.

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