Incidence of Dravet Syndrome in a US Population

Abstract

OBJECTIVE: De novo mutations of the gene sodium channel 1α (SCN1A) are the major cause of Dravet syndrome, an infantile epileptic encephalopathy. US incidence of DS has been estimated at 1 in 40 000, but no US epidemiologic studies have been performed since the advent of genetic testing. METHODS: In a retrospective, population-based cohort of all infants born at Kaiser Permanente Northern California during 2007–2010, we electronically identified patients who received ≥2 seizure diagnoses before age 12 months and who were also prescribed anticonvulsants at 24 months. A child neurologist reviewed records to identify infants who met 4 of 5 criteria for clinical Dravet syndrome: normal development before seizure onset; ≥2 seizures before age 12 months; myoclonic, hemiclonic, or generalized tonic-clonic seizures; ≥2 seizures lasting >10 minutes; and refractory seizures after age 2 years. SCN1A gene sequencing was performed as part of routine clinical care. RESULTS: Eight infants met the study criteria for clinical Dravet syndrome, yielding an incidence of 1 per 15 700. Six of these infants (incidence of 1 per 20 900) had a de novo SCN1A missense mutation that is likely to be pathogenic. One infant had an inherited SCN1A variant that is unlikely to be pathogenic. All 8 experienced febrile seizures, and 6 had prolonged seizures lasting >10 minutes by age 1 year. CONCLUSIONS: Dravet syndrome due to an SCN1A mutation is twice as common in the United States as previously thought. Genetic testing should be considered in children with ≥2 prolonged febrile seizures by 1 year of age.

Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome

“…Our estimate of the minimum incidence of DS in Japan, 1:45,800, is similar to the estimate of Brunklaus et al 7 for a United Kingdom cohort (1:40,900), and lower than estimates based on much smaller cohorts from the United States (1:20,900) and Denmark (1:22,000). 4,6 The estimates from United Kingdom and Japan are likely to be lower bounds because they are based entirely on the incidence of DS in patients reporting to a single clinic in each country. The proportion of individuals with truncation variants in our DS cohort is 55% (158/285).…”

“…These multiple seizure types, which also tend to be refractory to treatment with antiepileptic drugs (AEDs), are associated with the onset of significant delays in cognitive, behavioral, and motor areas. DS is a rare disorder (OMIM: 607208) with an estimated incidence of 1:16,000–1:40,000 births . Approximately three fourths of patients with DS are found to have a variant in the voltage‐gated sodium channel gene, SCN1A .…”

The humanistic and economic burden of Dravet syndrome on caregivers and families: Implications for future research

“…Large numbers of the parents of the patients with DS also indicated significant difficulties, including scoring in the abnormal range of the Strength and Difficulties Questionnaire (SDQ) for "conduct problems" (35%), "hyperactivity/ inattention" (66%), and problems in "peer relationships" (76%). Epilepsy/seizure severity, presence of myoclonic seizures, and age at onset of seizures were among the strongest independent predictors of poor HRQOL, further underscoring the urgency and need for more effective antiepileptic treatment options for this patient population [3]. Other studies have found that DS is associated with significant financial costs to the family and to society [8,12], significant behavioral and medical comorbidities (such as autism spectrum characteristics, communication impairments, cardiovascular conditions, dysautonomia, cognitive dysfunction, disturbed sleep, and motor impairment, among many others) [4,8,10,13], and negative impact on the quality of life of caregivers [4,8].…”

“…DS is relatively rare, with early estimates of the incidence ranging from 1 in 20,000 to 1 in 40,000 [2]; however, more recent research suggests it may affect one out of every 15,700 live births in the US [3]. Although children with DS usually evidence normal early development in the first few months of life, they soon develop prolonged febrile and afebrile generalized clonic or hemiclonic seizures [4].…”

Motor development in children with Dravet syndrome

“…Dravet syndrome, previously known as severe myoclonic epilepsy in infancy, is a severe form of epilepsy that was first described by Charlotte Dravet in 1978 . Dravet syndrome has an incidence between 1 in 15 700 and 1 in 40 000 and is in 80 per cent of the patients associated with genetic abnormalities, mostly concerning a de novo mutation in the sodium voltage‐gated channel alpha subunit 1 gene ( SCN1A ) …”