Mahoney, Krista (2014) The clinical and genetic epidemiology of pediatric idiopathic epilepsy in Newfoundland and Labrador. Doctoral (PhD) thesis, Memorial University of Newfoundland.
- Accepted Version
Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
Background: Epilepsy is a common and very heterogeneous neurologic disorder which shows a predilection towards the pediatric population. Idiopathic epilepsy (IE) refers to cases with no known underlying etiology other than a presumed genetic predisposition. IE accounts for approximately half of all cases of epilepsy. Newfoundland and Labrador has a tertiary referral center for pediatric neurology patients where virtually all children living on the Avalon Peninsula are treated. The current study aims to determine the clinical and genetic epidemiologic characteristics in this population. Purpose: To describe the incidence, genetic and clinical epidemiology of pediatric IE in the province of Newfoundland and Labrador. Methods: All children < 15 years of age with IE were ascertained through the provincial pediatric neurology clinic at the Janeway Child Health Centre. Family history, medical history and blood samples were obtained from affected children and their family members. All blood samples were screened for mutations in the seven candidate genes (SCN1A, SCN2A, SCN1B, KCNQ2, GABRA1, GABRG2 and KCNQ3) of highest priority, based on previously reported phenotype-genotype relationships, by direct bidirectional Sanger DNA sequencing. Results: The mean annual incidence of IE for the population of children living on the Avalon region of Newfoundland from 2000 to 2004 was 107 per 100 000. This rate is approximately three-fold greater than comparable populations in other developed countries. Incidence was similar in males and females. Multiple different epilepsy phenotypes were identified between and amongst families. Of 117 families with IE eligible for study, 86 (74%) provided detailed pedigree data. Fifty-five families (64%) had a positive family history. Eight (9%) of these had family histories compatible with autosomal dominant (AD) inheritance and these families lived in five different geographic isolates. DNA was obtained from 79 individuals in 21 families. Seven genes previously associated with childhood epilepsy were sequenced and excluded in all but one family which had a pathogenic mutation in SCN1A. This gene encodes a sodium channel subunit and a novel missense mutation (c.1162T>C, p.Tyr388His) was identified in a multiplex family segregating a severe, clinically novel form of autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+). The phenotype was consistent with GEFS+, with a variable phenotype that included mood and anxiety disorders, as well as ataxia – thereby expanding the phenotypic spectrum of GEFS+ to include neuropsychiatric disease. Conclusions: The incidence of IE in the Avalon Peninsula of Newfoundland is three times higher than comparison populations and the rate of familial disease is high throughout the province of Newfoundland and Labrador. The distribution of familial and AD IE in different geographic isolates, together with the clinical heterogeneity of disease, suggests substantial genetic heterogeneity. A novel SCN1A mutation and phenotype was identified.
|Item Type:||Thesis (Doctoral (PhD))|
|Additional Information:||Includes bibliographical references (pages 132-146).|
|Department(s):||Medicine, Faculty of|
|Geographic Location:||Newfoundland and Labrador|
|Library of Congress Subject Heading:||Epilepsy--Genetic aspects; Epileptic children--Newfoundland and Labrador; Epilepsy--Newfoundland and Labrador--Epidemiology; Familial diseases--Newfoundland and Labrador; Phenotype--Newfoundland and Labrador|
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