SCN1A‐related phenotypes: Epilepsy and beyond Scheffer, Ingrid E.; Nabbout, Rima
Epilepsia (Copenhagen),
December 2019, 2019-12-00, 20191201, Letnik:
60, Številka:
S3
Journal Article
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SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a ...wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Dravet syndrome (DS) is the prototypic DEE with an early onset of febrile status epilepticus, hemiclonic or generalized tonic‐clonic seizures, and later onset of additional seizure types. Electroencephalography (EEG) and magnetic resonance imaging (MRI) are normal at onset. Development is normal in the first year of life but plateaus rapidly, with most patients ultimately having intellectual disability. Epilepsy is drug‐resistant and necessitates polytherapy. Most pathogenic variants occur de novo in the affected child, but they are inherited from mosaic affected or unaffected parents in rare cases. The molecular finding of haploinsufficiency is consistent with a loss‐of‐function defect in cells and animal models. Although seizures are the most commonly reported symptom in DS, many additional issues critically affect patients’ cognitive and behavioral functioning. Hemiplegic migraine (HM) is a rare form of migraine with aura, characterized by the emergence of hemiparesis as part of the aura phase. All SCN1A mutations reported in sporadic/familial HM3 are missense mutations. Most of the experimental results show that they cause a gain of function of NaV1.1 as opposed to the loss of function of the epileptogenic NaV1.1 mutations. SCN1A and SCN2A pathogenic variants have been identified in genetic studies of cohorts of patients with ASD. In addition, ASD features are often reported in patients with Dravet syndrome and other DEEs.
Summary Epileptic encephalopathies of infancy and childhood comprise a large, heterogeneous group of severe epilepsies characterised by several seizure types, frequent epileptiform activity on EEG, ...and developmental slowing or regression. The encephalopathies include many age-related electroclinical syndromes with specific seizure types and EEG features. With the molecular revolution, the number of known monogenic determinants underlying the epileptic encephalopathies has grown rapidly. De-novo dominant mutations are frequently identified; somatic mosaicism and recessive disorders are also seen. Several genes can cause one electroclinical syndrome, and, conversely, one gene might be associated with phenotypic pleiotropy. Diverse genetic causes and molecular pathways have been implicated, involving ion channels, and proteins needed for synaptic, regulatory, and developmental functions. Gene discovery provides the basis for neurobiological insights, often showing convergence of mechanistic pathways. These findings underpin the development of targeted therapies, which are essential to improve the outcome of these devastating disorders.
Summary
The International League Against Epilepsy has recently published a new classification of epileptic seizures and epilepsies to reflect the major scientific advances in our understanding of ...the epilepsies since the last formal classification 28 years ago. The classification emphasises the importance of aetiology, which allows the optimisation of management.
Antiepileptic drugs (AEDs) are the main approach to epilepsy treatment and achieve seizure freedom in about two‐thirds of patients.
More than 15 second generation AEDs have been introduced since the 1990s, expanding opportunities to tailor treatment for each patient. However, they have not substantially altered the overall seizure‐free outcomes.
Epilepsy surgery is the most effective treatment for drug‐resistant focal epilepsy and should be considered as soon as appropriate trials of two AEDs have failed. The success of epilepsy surgery is influenced by different factors, including epilepsy syndrome, presence and type of epileptogenic lesion, and duration of post‐operative follow‐up.
For patients who are not eligible for epilepsy surgery or for whom surgery has failed, trials of alternative AEDs or other non‐pharmacological therapies, such as the ketogenic diet and neurostimulation, may improve seizure control.
Ongoing research into novel antiepileptic agents, improved techniques to optimise epilepsy surgery, and other non‐pharmacological therapies fuel hope to reduce the proportion of individuals with uncontrolled seizures. With the plethora of gene discoveries in the epilepsies, “precision therapies” specifically targeting the molecular underpinnings are beginning to emerge and hold great promise for future therapeutic approaches.
The recent introduction of the term ‘developmental and epileptic encephalopathy’ by the International League Against Epilepsy has added another conceptual layer to understanding the most severe group ...of epilepsies. An epileptic encephalopathy is defined by the presence of frequent epileptiform activity that impacts adversely on development, typically causing slowing or regression of developmental skills, and usually associated with frequent seizures. Many of the epileptic encephalopathies are now known to have an identifiable molecular genetic basis. The term ‘developmental’ was introduced as there are multiple facets leading to developmental impairment in affected individuals. The underlying genetic cause often results in developmental delay in its own right, with the epileptic encephalopathy further adversely affecting development. Treatment of the epileptic encephalopathy may improve developmental progress, so early recognition and active management are essential to improve developmental outcomes. Equally, understanding that the genetic aetiology independently leads to developmental impairment means that precision therapies need to be holistic in addressing the devastating consequences of this group of diseases.
Since the launch of The Lancet Neurology in 2002, the subsequent two decades have seen a revolution in our understanding of the neurological diseases affecting children. ...the care of a patient ...requires two levels of diagnosis, an aetiological diagnosis and the diagnosis of the epilepsy syndrome, to ensure that comorbidities are recognised and management is optimal. New ways to access somatic variants include the analysis of cell-free DNA from CSF allowing, for the first time, mutation identification of brain-limited variants without the need of using brain tissue.12 A challenge for understanding neurobiology is the increasingly apparent overlap between the molecular determinants of paediatric neurological diseases, such as autism spectrum disorder, intellectual disability, movement disorders, cerebral palsy, and epilepsy, not to mention later onset diseases such as schizophrenia. Administration of an antisense oligonucleotide once every 3 months, designed to result in retention of exon 7 of SMN2 pre-mRNA to produce increased full length SMN2, has life-changing outcomes, compared with the natural history of this disease.19 An alternative form of gene therapy for this disease has also been successful using a safe, adeno-associated viral (AAV) vector.
Among children and young adults with the Dravet syndrome, a developmental disorder that is associated with treatment-resistant seizures, cannabidiol reduced the frequency of convulsive seizures but ...caused sleepiness and elevated liver enzymes in some patients.
Seizures are difficult to control in the Dravet syndrome, a rare genetic form of epileptic encephalopathy primarily due to loss-of-function mutations in the
SCN1A
gene. Interest in cannabidiol for the treatment of epilepsy was generated by media reports of efficacy in children with the Dravet syndrome.
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Four small trials of cannabidiol had yielded mixed results.
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–
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A series of in vitro and in vivo preclinical models of seizure showed that cannabidiol had activity against convulsive seizures.
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Subsequently, the safety and effectiveness of a standardized oral solution of cannabidiol was tested in an open-label trial involving 214 children and young adults . . .
Summary
The Commission on Classification and Terminology and the Commission on Epidemiology of the International League Against Epilepsy (ILAE) have charged a Task Force to revise concepts, ...definition, and classification of status epilepticus (SE). The proposed new definition of SE is as follows: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long‐term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures. This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t1) beyond which the seizure should be regarded as “continuous seizure activity.” The second time point (t2) is the time of ongoing seizure activity after which there is a risk of long‐term consequences. In the case of convulsive (tonic–clonic) SE, both time points (t1 at 5 min and t2 at 30 min) are based on animal experiments and clinical research. This evidence is incomplete, and there is furthermore considerable variation, so these time points should be considered as the best estimates currently available. Data are not yet available for other forms of SE, but as knowledge and understanding increase, time points can be defined for specific forms of SE based on scientific evidence and incorporated into the definition, without changing the underlying concepts. A new diagnostic classification system of SE is proposed, which will provide a framework for clinical diagnosis, investigation, and therapeutic approaches for each patient. There are four axes: (1) semiology; (2) etiology; (3) electroencephalography (EEG) correlates; and (4) age. Axis 1 (semiology) lists different forms of SE divided into those with prominent motor systems, those without prominent motor systems, and currently indeterminate conditions (such as acute confusional states with epileptiform EEG patterns). Axis 2 (etiology) is divided into subcategories of known and unknown causes. Axis 3 (EEG correlates) adopts the latest recommendations by consensus panels to use the following descriptors for the EEG: name of pattern, morphology, location, time‐related features, modulation, and effect of intervention. Finally, axis 4 divides age groups into neonatal, infancy, childhood, adolescent and adulthood, and elderly.
•The newly updated classifications of seizures and epilepsy are reviewed.•Important additions, changes, and reasons for why these changes have been made are discussed.•How these classification ...updates may impact patients, clinicians and researchers is explored.
This review discusses the updated classifications of seizures and the epilepsies, which were recently published by the International League Against Epilepsy (ILAE). While it is always a challenge to learn a new classification system, particularly one that has remained essentially unchanged for over three decades, these new classifications allow for the inclusion of some previously unclassifiable seizure types and utilize more intuitive terminology. In this review, we specifically discuss the use of these new classifications for patients, clinicians, and researchers.
Summary
The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms ...following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self‐limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
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