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The Genetic Landscape of the Epileptic Encephalopathies of Infancy and Childhood

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The Genetic Landscape of the Epileptic Encephalopathies of Infancy and Childhood Review The genetic landscape of the epileptic encephalopathies of infancy and childhood Amy McTague*, Katherine B Howell*, J Helen Cross, Manju A Kurian, Ingrid E Scheff er Lancet Neurol 2016; 15: 304–16 Epileptic encephalopathies of infancy and childhood comprise a large, heterogeneous group of severe epilepsies Published Online characterised by several seizure types, frequent epileptiform activity on EEG, and developmental slowing or November 16, 2015 regression. The encephalopathies include many age-related electroclinical syndromes with specifi c seizure types and http://dx.doi.org/10.1016/ EEG features. With the molecular revolution, the number of known monogenic determinants underlying the epileptic S1474-4422(15)00250-1 encephalopathies has grown rapidly. De-novo dominant mutations are frequently identifi ed; somatic mosaicism and *Authors contributed equally recessive disorders are also seen. Several genes can cause one electroclinical syndrome, and, conversely, one gene Molecular Neurosciences (A McTague MBChB, might be associated with phenotypic pleiotropy. Diverse genetic causes and molecular pathways have been implicated, M A Kurian PhD) and Clinical involving ion channels, and proteins needed for synaptic, regulatory, and developmental functions. Gene discovery Neurosciences provides the basis for neurobiological insights, often showing convergence of mechanistic pathways. These fi ndings (Prof J H Cross PhD), underpin the development of targeted therapies, which are essential to improve the outcome of these devastating Developmental Neurosciences Programme, UCL Institute of disorders. Child Health, London, UK; Department of Neurology, Introduction with an incidence of 25–42 per 100 000 per year,7 and Great Ormond Street Hospital Severe epilepsies of infancy and childhood are a group of Dravet syndrome, with an incidence of one per 22 000.8,9 for Children NHS Foundation Trust, London, UK (A McTague, devastating disorders characterised by frequent epileptic In this Review, we explore the genetic landscape of the Prof J H Cross, M A Kurian); seizures associated with developmental delay or epileptic encephalopathies by focusing on how growth in Department of Neurology, regression. These conditions encompass a large group of gene discovery has radically changed our understanding Royal Children’s Hospital, disorders known as epileptic encephalopathies, in which of this severe group of diseases. Major insights have been Melbourne, VIC, Australia (K B Howell MBBS, Prof the infant or child typically has several types of seizures made into mechanisms of inheritance and biological I E Scheffer PhD); Department and abundant epileptiform activity on EEG, associated pathways involved. We aim to untangle the relation of Paediatrics, University of with developmental slowing or regression that might between genotype and phenotype, and describe present Melbourne, Melbourne, VIC, follow seizure onset or exacerbation. The onset of and emerging genetic technologies responsible for this Australia (K B Howell, Prof I E Scheffer); Neurosciences epileptic encephalopathies might occur against a new era of gene discovery. We show how, for the fi rst Group, Murdoch Childrens background of normal or delayed development. time in epileptic encephalopathies, the new genetic era is Research Institute, Melbourne, Comorbidities are common, including autism spectrum informing understanding of pathogenesis, which is VIC, Australia (K B Howell); disorder, and behavioural and movement disorders; the being translated to tailored precision management to Department of Medicine, Epilepsy Research Centre, outcome is often poor. improve patient outcomes. Finally, we address remaining University of Melbourne, Epileptic encephalopathies comprise many age-related research questions and future directions. Austin Health, Melbourne, VIC, epilepsy syndromes characterised by specifi c seizure Australia (Prof I E Scheffer); and types, and EEG and neurological features (table). The concept of an epileptic encephalopathy Florey Institute of Neurosciences and Mental Evolution from one age-related epilepsy syndrome to The concept underpinning an epileptic encephalopathy Health, Melbourne, VIC, another might occur. For example, Ohtahara syndrome is that the epileptic activity itself contributes to the severe Australia (Prof I E Scheffer) begins in the fi rst 2 months of life, often evolving to West cognitive and behavioural impairment, above that Correspondence to: syndrome, and later, to Lennox-Gastaut syndrome.1,2 Not expected from the underlying pathology alone.10 West Prof Ingrid E Scheffer, University all patients can be classifi ed as having a known epilepsy syndrome, in which infantile spasms are associated with of Melbourne, Austin Health, Melbourne, VIC, Australia syndrome, but with rapidly evolving scientifi c discoveries, hypsarrhythmia and developmental regression, is an [email protected] new disorders are emerging. As more genes causing archetypal epileptic encephalopathy related to continuous epileptic encephalopathies are identifi ed, specifi c genetic epileptiform activity. In epilepsy with myoclonic–atonic encephalopathies are being delineated with distinctive seizures, periods of cognitive regression might be electroclinical features and comorbidities, enabling associated with potentially treatable episodes of classifi cation of disorders in patients for whom this was myoclonic status epilepticus, or in Lennox-Gastaut not previously possible.3,4 syndrome, with non-convulsive status epilepticus.11,12 Epilepsy is most common in childhood,5 with an In other cases, whether the epileptiform activity per se incidence of 70·1 per 100 000 children aged younger than accounts for developmental slowing is unclear. A good 2 years.6 A prospective population-based study identifi ed example is Dravet syndrome, in which seizures begin at an epileptic encephalopathy in 22 (39%) of 57 infants, but 6 months classically with recurrent febrile status the overall incidence of epileptic encephalopathies was epilepticus. Development is normal until aged 1–2 years, probably underestimated because many disorders in despite frequent, prolonged seizures. To add to this children were not classifi able despite severe complexity, the EEG is often normal until age 2 years, neurodevelopmental sequelae.6 The most common despite development plateauing before frequent epileptic encephalopathies of infancy are West syndrome epileptiform activity begins. More than 80% of patients 304 www.thelancet.com/neurology Vol 15 March 2016 www.thelancet.com/neurology www.thelancet.com/neurology Genes (and approximate Sex aff ected and Age at onset Seizures at onset EEG Treatment Epilepsy evolution Syndrome Development proportion of syndromic incidence and outcome diff erential cases where known) diagnosis Early infantile STXBP1 in ~30%; KCNQ2 in Equal; exception: 0–3 months Tonic seizures; might Interictal: burst- Limited response to 75% evolve to West Early myoclonic Severe-to-profound epileptic ~20% (emerging syndrome ARX is X-linked and have seizure types suppression pattern; treatments; ketogenic syndrome ; ongoing encephalopathy delay encephalopathy with discrete features); mainly aff ects boys; including focal ictal: diff use diet seizures in most (Ohtahara SCN2A in ~10%; AARS, ARX, rare seizures and infantile attenuation or low- syndrome) BRAT1, CACNA2D2, GNAO1, spasms; myoclonus voltage fast activity; KCNT1, NECAP1, PIGA, PIGQ, rare focal rhythmic spiking Vol 15March 2016 Vol SCN8A, SIK1, SLC25A22 seen with focal seizures; often evolves to hypsarrhythmia Early myoclonic ERBB4, PIGA, SETBP1, SIK1, Equal; rare 0–3 months Fragmentary Interictal: burst Resistant to several No evolution in Early infantile Severe-to-profound encephalopathy SLC25A22 myoclonus; might suppression, which is antiepileptic drugs most, but persistent epileptic delay have seizure types worse in sleep and myoclonic and focal encephalopathy including tonic and persists beyond infancy; seizures focal seizures ictal: myoclonias do not show EEG correlation Epilepsy of KCNT1 in ~50%; SCN2A in Equal; 0–6 months Focal seizures that Interictal: can be normal Resistant to several Infantile spasms Early-onset Pre-seizures, some have infancy with ~25%; PLCB1, QARS, SCN1A, 1:200 000–400 000 (median 7 weeks) migrate from one initially, becomes slow antiepileptic drugs develop later in ~7%; epileptic a period of normal migrating focal SCN8A, SLC25A22, hemisphere to the with multifocal (most patients); ongoing seizures in encephalopathy development; seizures TBC1D24, SLC12A5 other epileptiform benefi cial (some some, others have (starting before regression or plateau abnormalities; ictal: patients): phenytoin, infrequent seizures 3 months) occurs in many after migrating ictal focus ketogenic diet, after fi rst year of life seizure onset; outcome: between hemispheres levetiracetam, severe-to-profound rufi namide, delay in most corticosteroids, bromides West syndrome CDKL5 in ~10% (emerging Equal; exceptions: 2–12 months Infantile spasms Interictal: First-line treatment: Might evolve to Pre-seizure syndrome with discrete ARX aff ects boys, (peak 6 months) hypsarrhythmia; ictal: corticosteroids Lennox-Gastaut development can be features); STXBP1 in ~2%; CDKL5 aff ects girls electrodecremental (vigabatrin fi rst line syndrome or develop normal or abnormal; ARX, ALG13, DOCK7, DNM1, more than boys; response or high- for tuberous sclerosis); other seizure types most plateau or FOXG1 (duplications), 1:2 000–6000 amplitude midline slow other benefi cial regression
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