No relevant disclosures

Transcription

1

2 No relevant disclosures

3 - Epileptic Encephalopathy (EE): Epileptic activity itself contributes to cognitive and behavioural impairments - Developmental and Epileptic Encephalopathy (DEE): Impairments occur in part due to both epileptic activity and underlying pathology ** Can have a developmental encephalopathy with seizures (1) Scheffer et al (2017) (** ILAE Commission on Classification and Terminology)

4

5

6 - Genotype-phenotype correlation weak (2) - Developmental impairment range from near-normal to severe ID - Likely to need multiple medications to control seizures (if controlled at all) - 15% mortality by age 20 (3,4) - SUDEP rate of 9.32/1000 patient-years (5) (2) Zuberi et al (2011); (3) Akiyama et al (2010), (4) Genton et al (2011), (5) Cooper et al (2016)

7 - 6 yo boy with epilepsy - Rare afebrile GTC from 2 y - On VPA - 6 mths ago had developmental regression, coinciding with appearance of a new event type

8

9

10 - Genetic testing revealed a novel truncation in variant in ASXL3 - ASXL3 encodes a sex comb-like protein - Mutations associated with Bainbridge-Ropers Syndrome - 28 published patients: dysmorphic features, hypotonia, severe ID, feeding difficulties (6) - 9/28 patients had seizures (7) (6) Balasubramanian et al (2017); (7) Myers et al (2018)

11 - Counseling limited due to few reported cases overall - Severity may be exaggerated due to ascertainment bias - Epilepsy phenotyping not thorough in any of the reported cases

12

13 - There are double blind RCTs demonstrating benefit of stiripentol (as add-on therapy to VPA and clobazam) over placebo (8,9) - More recent data demonstrating long-term safety and efficacy, even when used in unrestricted polypharmacy (10) - Cannabidiol also shown effective compared to placebo (11) - Generally avoid sodium channel inhibitors (8) Chiron et al (2000), (9) Guerrini et al (2002), (10) Myers et al (2018), (11) Devinsky et al (2017)

14 - Term newborn baby - Seizures started on 3rd day of life, having ~11/day - Refractory to phenobarbital, levetiracetam and topiramate - EEG showed intermittent burst suppression

15

16

17

18 - Onset of refractory focal seizures in first year of life - Severe encephalopathy - Seizures arise in either hemisphere and migrate from one region to another during one seizure - Mutations in KCNT1, SCN1A, SCN2A, PLCB1, TBC1D24, CHD2 associated

19 - CGH microarray: de novo microdeletion affecting KCNQ2 KCNQ2 associated with both (1) Self-limited (benign) familial neonatal epilepsy (2) Neonatal epileptic encephalopathy

20 - Next day, loaded with carbamazepine. - Seizure-free since.

21

22 - De novo SCN1A mutations in 90% of cases - ~10% of these are actually parental mosaics

23 - 8-month-old girl begins to have clusters of spasms - Sat at 6 months and was babbling, but has become less physically active, quieter, and less socially interactive - EEG: chaotic, high amplitude, chaotic slow activity with multifocal and bisynchronous sharply contoured discharges * Based on amalgam of different cases seen

24 (12) Conti et al (2015) (* imaging only)

25 - Surgical resection of FCD - Spasms controlled and developmental trajectory improves (12) Conti et al (2015) (* imaging only)

26 - Can cause EE, with developmental trajectory often improving with successful surgery - Mutations in DEPDC5 can cause familial FCD, as well as FFEVF (13,14) - In FCD cases, genetic basis may be double-hit or one or more somatic mutations alone (12) (12) Conti et al (2015), (13) Dibbens et al (2013), (14) Baulac et al (2015)

27 (1) Genetic diagnosis of an EE can help with prognosis but more phenotyping studies are needed (2) Genetic diagnosis can help guide treatment, sometimes with dramatic results (3) Somatic mutations should always be considered

28 (1) Scheffer et al (2017) ILAE classification of the epilepsies: Position paper of the ILAE commission for Classification and Terminology Epilepsia 58: (2) Zuberi et al (2011) Genotype-phenotype correlation in SCN1A epilepsies Neurology 76: (3) Akiyama et al (2010) A long-term follow-up study of Dravet syndrome up to adulthood Epilepsia 51: (4) Genton et al (2011) Dravet syndrome: the longterm outcome Epilepsia 52(supp 2): (5) Cooper et al (2016) Mortality in Dravet syndrome Epilepsy Research 128: (6) Balasubramanian et al (2017) Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of the published literature J Med Genet 54: (7) Myers et al (2018) Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome Epilepsy Research 140: (8) Chiron et al (2000) Stiripentol in severe myoclonic epilepsy of infancy: a randomised placebo-controlled syndrome-dedicated trial 356: (9) Guerrini et al (2002) Stiripentol in severe myoclonic epilepsy of infancy (SMEI): a Epplacebo-controlled Italian trial Epilepsia 43:155. (10)Myers et al (2018) Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study Dev Med Child Neurol 60: (11) Devinsky et al (2017) Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome NEJM 376:

29 (12) Conti et al (2015) Focal cortical dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene Clinical Genetics 88: (13) Dibbens et al (2013) Mutations in DEPDC5 cause familial focal epilepsy with variable foci Nature Genetics 45: (14) Baulac et al (2015) Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations Ann Neurol 77: