Ingo Helbig MD Childrens Hospital of Philadelphia Disclosure I have nothing to disclose Learning Objectives Diagnostic workup in suspected genetic epilepsies Neonatal epileptic encephalopathy ID: 774894
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Skills Workshop | Genetics Testing in Epilepsy Patients
Ingo Helbig, MD
Children’s Hospital of Philadelphia
Slide2Disclosure
I have nothing to disclose.
Slide3Learning Objectives
Diagnostic work-up in suspected genetic epilepsies
Neonatal epileptic encephalopathy
Infantile/Epileptic Spasms
Patient with autism and epilepsy
Choice of the most appropriate testing modality
Slide4Resources – freely available
ILAE Genetic literacy seriesPrimer Part 1: The building blocks of epilepsy geneticsPrimer Part 2: Paradigm shifts in epilepsy geneticsThe Epilepsiomewww.epilepsygenetics.net
Slide5Slide6ClinGen
ILAE
MONDO
HPO
ACMG criteria
GCI
SVI
Three-star variant
ILAE classification
Genotype-phenotype correlations
Historical classifications
Lumping
versus splitting
Deep phenotyping
Lab diagnostics versus epilepsy diagnostics
Slide7Case 1
3 day-old boy
Multifocal seizures, focal motor seizures of left or right arms and legs with head deviation
EEG with discontinuous pattern evolving to burst-suppression during sleep
No response to pyridoxine, various AEDs
Available information
Normal pregnancy, birth, delivery, 40+1,
Apgars
6/8
No family history, no consanguinity
Slide8Diagnostic considerations
Slide9Diagnostic considerations
Slide10Diagnostic considerations
Neonatal epileptic encephalopathies:
EIEE, EOEE
Slide11Slide12Diagnosis: KCNQ2 (Serino et al., 2013)
KCNQ2 encephalopathyDe novo NM_172107.3(KCNQ2):c.740C>G (p.Ser247Trp)
Slide13Neonatal epileptic encephalopathy
Limited genetic architecture
50% of individuals have disease-causing variants
Genes:
SCN2A
,
KCNQ2
,
CDKL5
,
STXBP1
,
SCN8A
First-line modality of choice
Epilepsy panel – all available panels cover the major genes
Rapid/non-rapid
Testing possible through clinical studies (e.g. ERGENT)
Slide14Case 2
6 month-old admitted for abnormal movements
Unremarkable early development
Unremarkable pregnancy, delivery, neonatal period
EEG
Hypsarrythmia
, bilateral flexor spasms
Diagnosis: West Syndrome
Slide15Diagnostic considerations EIEE vs. West Syndrome
How well can we apply the neonatal work-up?
Slide16Diagnostic considerations EIEE vs. West Syndrome
How well can we apply the neonatal work-up?
Metabolic work-up should be performed, but in parallel to genetics
Slide17Diagnosis: DNM1 (Dynamin 1)
DNM1 encephalopathyDe novo NM_004408.3(DNM1):c.709C>T (p.Arg237Trp)
Pre-synaptic
Post-synaptic
Synaptic cleft
Dynamin
1
Slide18Infantile Spasms (without prior EIEE)
Wide genetic architecture
Large number of 1% genes, ~30% yield
New-onset spasms unlikely metabolic
No diagnostic yield in self-resolving spasms
First-line modality of choice
Epilepsy panel, then exome
Identify common genes first
Slide19Slide20Case 3
15 male with autism and new-onset focal epilepsy
1x GTCS, 2x FIAS, EEG with left temporal spikes
Prior history
Unremarkable prenatal course, birth, postnatal period
Diagnosed with autism at age 2
Largely non-verbal, unremarkable MRI x2
Slide21Slide22Diagnosis 16p11.2 microdeletion
Common microdeletion in autism/intellectual disability
Diagnostic yield for microarray 15-20%
Deletions not identified through gene panel/exome
Deletion calling from panel/exome
In development, not ready for prime time yet
Slide23Diagnosis: Autism plus focal epilepsy
Question: is this an epileptic encephalopathy?
Not really
Does the presence of seizures change the work-up?
Patients with autism have a relatively high risk of seizures
EE is possible, but rare with onset at 15 years
Consider same work-up as with autism/intellectual disability
Slide24Learning Objectives
Diagnostic work-up in suspected genetic epilepsies
Neonatal epileptic encephalopathy
Infantile/Epileptic Spasms
Patient with autism and epilepsy
Choice of the most appropriate testing modality
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