Recent incidence of type 1 diabetes mellitus in children 0-14 years in Newfoundland and Labrador, Canada climbs to over 45/100,000: a retrospective time trend study.

BACKGROUND: To study and update the provincial incidence of type 1 diabetes mellitus (T1DM) in Newfoundland and Labrador (NL), a province of Canada with a very high incidence previously reported in 2006, and one of the highest incidences reported worldwide. This is a retrospective time trend study of the incidence of T1DM, in children aged 0-14 years from 1987-2010 inclusive. FINDINGS: Over the study period 931 children aged 0-14 years were diagnosed with T1DM. The incidence of T1DM in this population over the period 1987 - 2010 inclusive was 37.7 per 100,000 per year (95% CI 35. 3, 40.2)The incidence from 2007-2010 was 49.9 per 100,000 per year (95% CI 42.2, 57.6). The incidence over this 24 year period increased by a factor of 1.03 per 100,000 per year. CONCLUSION: NL has one of the highest incidences of T1DM reported worldwide. Potential reasons for the very high incidence could be related to the unique genetic background of the population, northern latitude and vitamin D insufficiency, low breastfeeding rates, and high rates of cesarean section.

High incidence of pediatric idiopathic epilepsy is associated with familial and autosomal dominant disease in Eastern Newfoundland.

PURPOSE: To describe the incidence and epidemiology of pediatric idiopathic epilepsy (IE) in Newfoundland and Labrador. METHODS: All children in Newfoundland and Labrador aged 0-15 years with IE were ascertained through the provincial neurology clinic at the Janeway Child Health Centre. Family history, medical history and blood samples were obtained from probands and relatives. Two genes, SCN1A and KCNQ2, were screened for mutations by direct sequencing. RESULTS: The mean annual incidence of IE for the population of children living in the Avalon region of Newfoundland from 2000 to 2004 was 107 per 100,000. This rate is approximately three-fold greater than rates reported in other developed countries. Of 117 families with IE eligible for study, 86 (74%) provided detailed pedigree data. Multiple different epilepsy phenotypes were identified. Fifty-five families (64%) had a positive family history. Eight of these had family histories compatible with autosomal dominant (AD) inheritance and these families lived in five different geographic isolates. DNA was obtained from 21 families (79 individuals). The two previously identified mutations in Newfoundland families with epilepsy were sequenced and excluded as pathogenic sites in all but one family which had a mutation in SCN1A. CONCLUSION: The incidence of IE is high in the Avalon Peninsula of Newfoundland 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. It is likely that other novel mutations will be identified in this population.

Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A.

PURPOSE: To describe the spectrum of clinical disease in a mutliplex family with an autosomal dominant form of generalized epilepsy with febrile seizures plus (GEFS+) and determine its genetic etiology. METHODS: Medical and family history was obtained on 11 clinically affected individuals and their relatives across three generations through medical chart review and home visits. A candidate gene approach including haplotype analysis and direct sequencing was used. RESULTS: An epilepsy-associated haplotype was identified on 2q24. Direct sequencing of the entire SCN1A gene identified seven sequence variants. However, only one of these, c.1162 T>C, was not found in population controls. This transition in exon 8 of SCN1A predicts a substitution (Y388H) of a highly conserved tyrosine residue in the loop between transmembrane segments S5 and S6 of the sodium channel protein (Na(v)1.1). Clinical features in mutation carriers of this novel missense mutation were highly variable, ranging from febrile seizures to severe refractory epilepsy. CONCLUSION: A novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease.

First-drug treatment failures in children newly diagnosed with epilepsy.

In adults newly diagnosed with epilepsy, treatment with the first prescribed antiepileptic drug fails for approximately one half. In two studies that addressed this question in children, the failure rates were 20% and 40%. The present study used a detailed chart review of children newly diagnosed with epilepsy over a 4-year span in a major childhood epilepsy referral clinic to assess (1) the percentage of children for whom first-line antiepileptic drug treatment failed and (2) the reasons for the treatment failure. Charts were reviewed for 95 children who were diagnosed with epilepsy, started on their first antiepileptic drug, and then monitored for approximately 5 years. Of these 95 children, 48 were classified as having idiopathic epilepsy (50.5 %), 30 as having cryptogenic epilepsy (31.6%), and 17 as having symptomatic epilepsy (17.9%). The two main antiepileptic drugs used were valproic acid (43.2% of patients) and carbamazepine (38.9% of patients). Treatment with the first antiepileptic drug failed in 30/95 children (31.6%). Treatment failure was due to adverse effects in 12/30 children (40.0%), due to lack of efficacy in 11/30 (37.9%), and due to both adverse effects and lack of efficacy in 7/30 (24.1%). Also examined was the effect on treatment failure of patient age at diagnosis, antiepileptic drug choice, maximum drug dose, etiology of epilepsy, and particular epilepsy syndromes on treatment failures; there was no statistically significant effect of any of these variables on first-line treatment outcome. In this population, approximately one third of children newly diagnosed with epilepsy experienced treatment failure with the first antiepileptic drug used. Lack of efficacy and unacceptable adverse effects contributed equally to these treatment failures.

Long-term prognosis in children with neonatal seizures: a population-based study.

OBJECTIVE: To examine outcome and explore for prognostic markers in a cohort <10 years following neonatal seizures. METHODS: We prospectively diagnosed clinical neonatal seizures with high specificity for true epileptic seizures in a population-based setting of all live newborns in the province of Newfoundland, Canada, between 1990 and 1995. Children with neonatal seizures were followed by specialized provincial health services. Follow-up data were collected on epilepsy, physical and cognitive impairments, and other heath issues. RESULTS: Data were available on 82 out of 90 subjects. We added information on six others whose outcome was clearly predictable from earlier information. Prognosis was better for term than for preterm infants (p = 0.003): term: 28 (45%) normal, 10 (16%) deaths, and 24 (39%) with impairments; preterm: 3 (12%) normal, 11 (42%) deaths, and 12 (46%) with impairments. Of survivors, 17 (27%) developed epilepsy, 16 (25%) had cerebral palsy, 13 (20%) had mental retardation, and 17 (27%) had learning disorders. Variables associated with poor prognosis were Sarnat stage III or equivalent severe encephalopathy, cerebral dysgenesis, complicated intraventricular hemorrhage, infections in the preterm infants, abnormal neonatal EEGs, and the need for multiple drugs to treat the neonatal seizures. Pure clonic seizures without facial involvement in term infants suggested favorable outcome, whereas generalized myoclonic seizures in preterm infants were associated with mortality. CONCLUSIONS: Poor prognosis for premature infants with seizures is reflected in high rates of subsequent long-term disability and mortality. The severity and timing of the pathologic process continue to be the major determinants for outcome.