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 Skills Workshop | Genetics Testing in Epilepsy Patients  Skills Workshop | Genetics Testing in Epilepsy Patients

Skills Workshop | Genetics Testing in Epilepsy Patients - PowerPoint Presentation

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Skills Workshop | Genetics Testing in Epilepsy Patients - PPT Presentation

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

epilepsy diagnostic autism epileptic epilepsy diagnostic autism epileptic neonatal work spasms genetic diagnosis considerations kcnq2 eiee modality choice encephalopathy

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Slide1

Skills Workshop | Genetics Testing in Epilepsy Patients

Ingo Helbig, MD

Children’s Hospital of Philadelphia

Slide2

Disclosure

I have nothing to disclose.

Slide3

Learning 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

Slide4

Resources – freely available

ILAE Genetic literacy seriesPrimer Part 1: The building blocks of epilepsy geneticsPrimer Part 2: Paradigm shifts in epilepsy geneticsThe Epilepsiomewww.epilepsygenetics.net

Slide5

Slide6

ClinGen

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

Slide7

Case 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

Slide8

Diagnostic considerations

Slide9

Diagnostic considerations

Slide10

Diagnostic considerations

Neonatal epileptic encephalopathies:

EIEE, EOEE

Slide11

Slide12

Diagnosis: KCNQ2 (Serino et al., 2013)

KCNQ2 encephalopathyDe novo NM_172107.3(KCNQ2):c.740C>G (p.Ser247Trp)

Slide13

Neonatal 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)

Slide14

Case 2

6 month-old admitted for abnormal movements

Unremarkable early development

Unremarkable pregnancy, delivery, neonatal period

EEG

Hypsarrythmia

, bilateral flexor spasms

Diagnosis: West Syndrome

Slide15

Diagnostic considerations EIEE vs. West Syndrome

How well can we apply the neonatal work-up?

Slide16

Diagnostic 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

Slide17

Diagnosis: DNM1 (Dynamin 1)

DNM1 encephalopathyDe novo NM_004408.3(DNM1):c.709C>T (p.Arg237Trp)

Pre-synaptic

Post-synaptic

Synaptic cleft

Dynamin

1

Slide18

Infantile 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

Slide19

Slide20

Case 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

Slide21

Slide22

Diagnosis 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

Slide23

Diagnosis: 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

Slide24

Learning 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

Slide25