References were identified by searching PubMed for articles published from Jan 1, 1969, to Sept 15, 2015, and for references from relevant articles. The search terms “epileptic encephalopathy”, “early infantile epileptic encephalopathy”, “early onset epileptic encephalopathy”, “Ohtahara syndrome”, “early myoclonic epileptic encephalopathy”, “migrating partial seizures of infancy”, “epilepsy of infancy with migrating focal seizures”, “Dravet syndrome”, “severe myoclonic epilepsy of infancy”,
ReviewThe genetic landscape of the epileptic encephalopathies of infancy and childhood
Introduction
Severe epilepsies of infancy and childhood are a group of devastating disorders characterised by frequent epileptic seizures associated with developmental delay or regression. These conditions encompass a large group of disorders known as epileptic encephalopathies, in which the infant or child typically has several types of seizures and abundant epileptiform activity on EEG, associated with developmental slowing or regression that might follow seizure onset or exacerbation. The onset of epileptic encephalopathies might occur against a background of normal or delayed development. Comorbidities are common, including autism spectrum disorder, and behavioural and movement disorders; the outcome is often poor.
Epileptic encephalopathies comprise many age-related epilepsy syndromes characterised by specific seizure types, and EEG and neurological features (table). Evolution from one age-related epilepsy syndrome to another might occur. For example, Ohtahara syndrome begins in the first 2 months of life, often evolving to West syndrome, and later, to Lennox-Gastaut syndrome.1, 2 Not all patients can be classified as having a known epilepsy syndrome, but with rapidly evolving scientific discoveries, new disorders are emerging. As more genes causing epileptic encephalopathies are identified, specific genetic encephalopathies are being delineated with distinctive electroclinical features and comorbidities, enabling classification of disorders in patients for whom this was not previously possible.3, 4
Epilepsy is most common in childhood,5 with an incidence of 70·1 per 100 000 children aged younger than 2 years.6 A prospective population-based study identified an epileptic encephalopathy in 22 (39%) of 57 infants, but the overall incidence of epileptic encephalopathies was probably underestimated because many disorders in children were not classifiable despite severe neurodevelopmental sequelae.6 The most common epileptic encephalopathies of infancy are West syndrome with an incidence of 25–42 per 100 000 per year,7 and Dravet syndrome, with an incidence of one per 22 000.8, 9
In this Review, we explore the genetic landscape of the epileptic encephalopathies by focusing on how growth in gene discovery has radically changed our understanding of this severe group of diseases. Major insights have been made into mechanisms of inheritance and biological pathways involved. We aim to untangle the relation between genotype and phenotype, and describe present and emerging genetic technologies responsible for this new era of gene discovery. We show how, for the first time in epileptic encephalopathies, the new genetic era is informing understanding of pathogenesis, which is being translated to tailored precision management to improve patient outcomes. Finally, we address remaining research questions and future directions.
Section snippets
The concept of an epileptic encephalopathy
The concept underpinning an epileptic encephalopathy is that the epileptic activity itself contributes to the severe cognitive and behavioural impairment, above that expected from the underlying pathology alone.10 West syndrome, in which infantile spasms are associated with hypsarrhythmia and developmental regression, is an archetypal epileptic encephalopathy related to continuous epileptiform activity. In epilepsy with myoclonic–atonic seizures, periods of cognitive regression might be
Aetiology
Until 2001, the cause of epileptic encephalopathies was unknown, and they were thought to probably be due to a so-called symptomatic cause such as an acquired insult. A minority of cases undoubtedly have symptomatic causes in which a child has a structural aetiology such as a stroke or hypoxic-ischaemic encephalopathy underlying their epileptic encephalopathy. An exception is West syndrome, in which almost 30% of patients have an acquired aetiology.19 The structural abnormality is associated
Gene discovery and mechanisms of inheritance
A genetic cause for an epileptic encephalopathy was first recognised in 2001, with the finding that all seven children in a study of Dravet syndrome had a de-novo SCN1A mutation.30 With the advent of molecular techniques, such as chromosomal microarray and next-generation parallel sequencing of multiple genes, a rapid growth in gene discovery for epileptic encephalopathies has occurred.23, 24, 27, 28, 29
Copy number variation is an important molecular cause of epileptic encephalopathy, with up
Phenotypic heterogeneity
A crucial issue underpinning gene discovery in epileptic encephalopathies is that each gene shows phenotypic pleiotropy, and that each epilepsy syndrome shows genetic heterogeneity (figure 1). This heterogeneity or pleiotropy means that clinical phenotyping is central to interpretation of the relevance of a genetic finding in a patient to understand pathogenesis, guide therapy, and improve outcomes.
Phenotypic heterogeneity or pleiotropy, in which mutations in a single gene cause different
Genetic heterogeneity
Genetic heterogeneity occurs in every epilepsy syndrome. Even in the prototypical genetic epileptic encephalopathy, Dravet syndrome, in which more than 80% of patients have a SCN1A mutation, other genes (eg, STXBP1 and GABRA1) account for a small proportion of cases.71 Often a few cases of a novel genetic encephalopathy are initially recognised, and further studies are needed to confirm the role of the newly identified gene as causative. Analysis of larger numbers of genetically homogeneous
Challenges and pitfalls
Although valid biological explanations exist for much of the genetic heterogeneity and phenotypic pleiotropy, there is a risk that a variant claimed to be pathogenic is benign and not causative. As 22 000 single-nucleotide variants are identified on WES, and 5 million variants on whole-genome sequencing (WGS) of an individual, whether a variant is causative and of major effect should always be questioned. The gold standard would be for all newly identified variants, even in known genes, to
Insights into the neurobiology of severe epilepsies
Gene identification has implicated a broad range of disease mechanisms in severe epilepsies, including channelopathies, synaptic dysfunction, transporter defects, transcriptional dysregulation, impaired DNA repair and chromatin remodelling, and metabolic defects (figure 2). In many cases, the mechanisms by which gene mutations produce severe epilepsies are poorly understood. However, bioinformatic approaches (eg, computer-generated network maps of interacting genes) and in-vitro or in-vivo
Effect of a diagnosis
The importance of making a definitive diagnosis in a patient cannot be overemphasised. Diagnosis changes people's lives. Once a cause is established, the fraught and often lengthy, painful, and time-consuming diagnostic journey ends. Most patients will have had many investigations, including brain imaging and neurophysiological, blood, CSF, and urine testing, and sometimes more invasive tests such as liver and muscle biopsies. Some might even have faced epilepsy surgery with variable benefits
Conclusions
The complex genetic landscape of epileptic encephalopathies is emerging with the exciting revelations of the genomic revolution. Several aspects are clear. De-novo mutations are frequently found, especially in genes that encode proteins involved in synaptic function and ion channels. Mosaicism, both somatic and germline, is of increasing importance in understanding pathogenesis, especially in patients for whom exome and panel sequencing is negative. Development of functional pipelines to
Search strategy and selection criteria
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Authors contributed equally