Elsevier

Pediatric Neurology

Volume 46, Issue 4, April 2012, Pages 235-239
Pediatric Neurology

Original Article
Inheritance of Febrile Seizures in Sudden Unexplained Death in Toddlers

https://doi.org/10.1016/j.pediatrneurol.2012.02.007Get rights and content

Abstract

Sudden unexplained death in toddlers has been associated with febrile seizures, family history of febrile seizures, and hippocampal anomalies. We investigated the mode of inheritance for febrile seizures in these families. A three-generation pedigree was obtained from families enrolled in the San Diego Sudden Unexplained Death in Childhood Research Project, involving toddlers with sudden unexplained death, febrile seizures, and family history of febrile seizures. In our six cases, death was unwitnessed and related to sleep. The interval from last witnessed febrile seizure to death ranged from 3 weeks to 6 months. Hippocampal abnormalities were identified in one of three cases with available autopsy sections. Autosomal dominant inheritance of febrile seizures was observed in three families. A fourth demonstrated autosomal dominant inheritance with incomplete penetrance or variable expressivity. In two families, the maternal and paternal sides manifested febrile seizures. In this series, the major pattern of inheritance in toddlers with sudden unexplained death and febrile seizures was autosomal dominant. Future studies should develop markers (including genetic) to identify which patients with febrile seizures are at risk for sudden unexplained death in childhood, and to provide guidance for families and physicians.

Introduction

Sudden unexplained death in childhood is defined as the sudden death of a child older than 1 year of age that remains unexplained after a thorough investigation, including reviews of the clinical history and circumstances of death, and the performance of a complete autopsy with appropriate ancillary testing [1]. Sudden unexplained death in childhood is most common in toddlers aged 1-5 years, with approximately 1.3/100,000 deaths per year [2]. In a retrospective study of 49 toddlers with sudden unexplained death in childhood [3], 24% (12/49) had a history of febrile seizures, approximately fivefold higher than the general pediatric population incidence of 2-5% [4], [5], [6]. In addition, 67% (8/12) of these children also had a family history of febrile seizures, at 2.8-fold higher than the general population incidence of 24% [5]. These observations led to the hypothesis that a pathophysiologic connection exists between febrile seizures and sudden unexplained death in childhood, suggesting that a genetic susceptibility to febrile seizures may be important in defining this subset of patients with sudden unexplained death in childhood.

Among cases of sudden unexplained death in childhood with an individual or family history or both of febrile seizures, 82% (9/11) demonstrated gross asymmetry and microscopic anomalies of the hippocampus [3]. These microscopic anomalies were similar to those observed in chronic temporal lobe epilepsy [7], [8], [9], [10], [11], [12] or sudden unexpected death in epilepsy [13], [14], [15], and the mechanism may be similar, or identical, to sudden unexpected death in epilepsy [15].

Given the striking association of sudden unexplained death in childhood and febrile seizures in toddlers and their families, we sought to delineate the mode of inheritance of febrile seizures in these families. We selected cases of sudden unexplained death in childhood with an individual and family history of febrile seizures. Although this strategy limits our sample size, we think it holds the greatest potential to provide information on inheritance patterns. We report on the pedigrees of six such patients.

Section snippets

Classification of sudden unexplained death in childhood

Families were identified from the registry of the San Diego Sudden Unexplained Death in Childhood Research Project, which is under the direction of H.F.K. and was approved by the Institutional Review Board at Rady Children’s Hospital. Final classifications of cases as sudden unexplained death in childhood were based on reviews by H.F.K. of: (1) a Family Survey completed by the parents; (2) hospital and clinic records; (3) forensic reports of the death scene investigation, autopsy, and ancillary

Study population

We obtained family histories from a parent of each deceased child. Interviews were performed 1-10 years (median, 4.6 years) after the event of sudden unexplained death in childhood.

Clinical summary

All deaths were related to a sleep period (Table 1). Two cases (patients 2 and 3) underwent an evaluation for febrile seizures by a neurologist, with unremarkable results. None of the deaths were witnessed, and thus the occurrence of seizure at time of death is unknown.

Autopsy summary

Metabolic screening produced negative results in

Discussion

This series of pedigrees involving six toddlers with sudden unexplained death associated with an individual and family history of febrile seizures constitutes a first step in the search for the genetic basis of sudden unexplained death in childhood, to identify those at risk for sudden death in the setting of familial febrile seizures. In this series, the major pattern of inheritance for febrile seizures was autosomal dominant. The finding of two families with febrile seizures on the maternal

Conclusion

Febrile seizures may be the marker of an underlying process that leads to sudden unexplained death in childhood, and seizures may or may not be directly involved in the final lethal event. The potential pathophysiologic connection between sudden unexplained death in childhood and febrile seizures warrants urgent attention to develop means, potentially including the use of genetic markers, to determine who among the vast number of young children with febrile seizures may be at risk of sudden

References (20)

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    Two deaths occurred in children with a history of febrile seizures. Although febrile seizures have historically been classified as benign, research has identified an association between sudden unexpected deaths and febrile seizures under some circumstances [17,18]. This information has implications for the education of health professionals and parents regarding the ongoing investigation and management of children who have a febrile seizure and highlights the necessity of identifying such cases for research.

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