NRSP 2019:Genetics & Epilepsy

Douglas M. Smith, MD

Minnesota Epilepsy Group

Minneapolis, MN

Learning Objectives

• At the end of this lecture, you will be able to:• Explore genetic testing involved in the diagnostic work-up

for infants with recurrent seizures

• Differentiate Dravet syndrome from other infantile-onset epileptic encephalopathies, including infantile spasms and Lennox-Gastaut syndrome (LGS).

Lecture Outline

• Historical perspective• From human genome project to 23 & Me• The evolving landscape of epilepsy genes

• High-yield epilepsy syndromes• Dravet syndrome (severe myoclonic epilepsy of infancy)• Cryptogenic West syndrome• Ohtahara / Early myoclonic encephalopathy• Benign familial infantile / neonatal convulsions• Genetic epilepsy with febrile seizures plus (GEFS+)• Early-onset absence epilepsy• Autosomal dominant nocturnal frontal lobe epilepsy• Familial lateral temporal lobe epilepsy• Familial focal epilepsy with variable foci

Lecture Outline

• Practical considerations• Who should we test?

• Variant analysis

• Utility of testing• Treatment implications

• Inheritance

• A glimpse into the future

Historical Perspective

• Human Genome Project (1990-2003)

• 13-year project to sequence the human genome

• Over 200 principal investigators and 20 institutions involved

• Total cost: $3.8 billion

https://web.ornl.gov/sci/techresources/Human_Genome/project/index.shtml

Historical Perspective

• Now, more than half the population of Iceland has had their genome sequenced

• Cost: ~$600 a person

https://www.bbc.com/news/business-49090754

Historical Perspective

Helbig I, et al. Epilepsia. 2016.

High-Yield Epilepsy Syndromes

Dravet Syndrome

• A.k.a. severe myoclonic epilepsy of infancy (SMEI)

• Onset before age 18 months

• Prolonged hemiconvulsive seizures, often with secondary generalization• Obtundation status, myoclonic seizures• Frequent status epilepticus• Often triggered by vaccinations, fever, elevated

temperatures

• Development slows after 1-2 years of age• Ataxia, “crouch gait” later

• Dravet-specific SUDEP rate = 9.32 per 1000 person years

Anwar A, et al. Cureus. 2019; Cooper MS, et al. Epilepsy Research. 2016.

Charlotte Dravet

Dravet Syndrome

Steel D, et al. Epilepsia. 2018.

PCDH19

Depienne C, et al. PLoS Genet. 2009.

Dravet Syndrome

• AVOID SODIUM CHANNEL BLOCKERS• Carbamazepine, oxcarbazepine, lamotrigine, lacosamide

• Avoid phenytoin as maintenance, but may be helpful in status epilepticus

• Reports of worsening of myoclonus with vigabatrin

• Duration of use of contraindicated medications corresponds with negative cognitive outcomes

de Lange IM, et al. Epilepsia. 2018.

Dravet Syndrome

• Preferred treatments:• First-line: valproic acid, clobazam

• Second-line: addition of stiripentol or topiramate or ketogenic diet

• Specific indication• Recent approvals (2018):

• Cannabidiol

• Stiripentol (approved in combination with clobazam)

• In the future: fenfluramine

Anwar A, et al. Cureus. 2019; FDA Prescribing Information.

To the editor of Lancet:

“Sir:- I beg, through your valuable and extensively circulating Journal, to call the attention of the medical profession to a very rare and singular species of convulsion peculiar to young children….”

Dr. William. J. West, in Lancet 1:724, 1841

West Syndrome

Eling P, et al. Neurology. 2002.

West Syndrome

• Combination of infantile spasms, hypsarrhythmia, and developmental regression

• Typical onset 3 to 7 months

• Numerous causes• Perinatal hypoxic-ischemic encephalopathy

• Tuberous sclerosis

• Aicardi syndrome

• Nearly one third of cases have no immediately identifiable cause - cryptogenic

Pellock JM, et al. Epilepsia. 2010.

West Syndrome

• Genetic testing is high-yield in cryptogenic spasms• Causal abnormality in 23.5% of cases

• VUS in 14.8% of cases

• Metabolic causes• ALDH7A1, PNPO (pyridoxine-responsive epilepsy)

• POLG1 (and other mitochondrial causes)

• Single-gene epilepsy disorders• STXBP1, CDKL5, KCNQ3

• Genetic-structural causes• TSC1/2, ARX

• Chromosomal microduplications & deletions

Wirrell EC, et al. Epilepsia. 2015; Pellock JM, et al. Epilepsia. 2010.

West Syndrome

Wirrell EC, et al. Epilepsia. 2015.

Early Infantile Encephalopathies

Ohtahara syndrome Myoclonic Encephalopathy

• Onset first month of life

• Myoclonic seizures predominate

• Burst suppression on EEG

• Onset first month of life

• Tonic seizures predominate

• Rare myoclonic seizures

• Burst suppression on EEG

Beal JC, et al. Pediatr Neurol. 2012.

Early Infantile Encephalopathies

• Overlapping genetic causes

• Rule out metabolic causes first• Pyridoxine-responsive epilepsy, mitochondrial

encephalopathies

• Positive genetic testing in 30-50% of cases• KCNQ2, SCN2A, SCN8A, STXBP1, ARX, PIGA, PRRT2

Olson HE, et al. Ann Neurol. 2017;Ostrander BEP, et al. NPJ Genom Med. 2018..

Infantile Epileptic Encephalopathies

• Ohtahara Syndrome / Early Myoclonic Encephalopathy• Onset around 1 month• Burst suppression on EEG• Tonic & myoclonic seizures

• West Syndrome• Onset around 5-6 months• Hypsarrhythmia on EEG• Infantile spasms

• Dravet syndrome• First seizures around 6 months, worst seizures 9-12 months• Focal or generalized epileptiform discharges on EEG• Myoclonic & hemiclonic seizures, febrile status epilepticus

Beal JC, et al. Pediatr Neurol. 2012; Pellock JM, et al. Epilepsia. 2010; Anwar A, et al. Cureus. 2019.

Benign Familial Convulsions

• Neonatal – First month of life• A.k.a. “fifth day fits”

• Diagnosis of exclusion

• KCNQ2, KCNQ3

• Infantile – First year of life (typically 4-6 months)• Associated with paroxysmal kinesiogenic dyskinesia

• PRRT2, SCN2A, KCNQ2, KCNQ3

Al Yazidi G, et al. Child Neurol Open. 2017; Ebrahimi-Fakhari D, et al. Brain. 2015.

Genetic Epilepsy with Febrile Seizures Plus (GEFS+)

• Familial inheritance pattern• Diagnosis is not for the individual

• Combination of family members with febrile seizures and epilepsy

• High yield – in this particular study, 23% with pathological genetic findings• SCN1A, SCN1B, GABRG2, PCDH19

• Note these are also Dravet genes!

• Also chromosome 7q21 deletions, CACNA1H?

Afawi Z, et al. Neurology. 2016.

Early-Onset Absence Epilepsy

• Absence seizures +/- GTCs before 3 years of age

• Often associated with a movement disorder

• Glut-1 deficiency due to SLC2A1 mutation

Pong AW, et al. Epilepsia. 2012.

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

• It’s all in the name

• Often normal interictal EEG

• Onset between infancy and adulthood• Usually during childhood

• DDx – parasomnias• Parasomnias usually first third of evening

• Genetics – CHRNA2, CHRNA4, CHRNB2 (nicotinic acetylcholine receptor)• Can treat with carbamazepine, zonisamide, nicotine,

fenofibrate?• Rare phenotype of KCNT1, DEPDC5

Willoughby JO, et al. Epilepsia. 2003;Kurahashi H, Hirose S. GeneReviews. 2018.

Familial Lateral Temporal Lobe Epilepsy

• A.k.a. autosomal dominant partial epilepsy with auditory features• But only about half have auditory features

• Autosomal dominant inheritance with 54% penetrance

• Highly variable age of presentation (~18 years)

• Genetics: LGI1• Rarely DEPDC5

Ottman R, et al. Neurology. 2004.

Familial Focal Epilepsy with Variable Foci

Scheffer IE, et al. Ann Neurol. 1998; epilepsygenetics.net.

• All in the name

• May have FCD

• mTOR pathway genes

• DEPDC5, NPRL2, NPRL3

Practical Considerations

Who Shouldn’t Get Tested

• A different cause has been proven

• Abnormal MRI• (With a few exceptions)

• Well controlled seizures• (With a few exceptions)

• Febrile seizures only• (With a few exceptions)

• Certain epilepsy syndromes• Juvenile myoclonic epilepsy (JME), typical childhood or

juvenile absence epilepsy (CAE or JAE), Jeavon syndrome

Who Should Be Tested

• Unexplained refractory epilepsy

• “Epilepsy plus”• Intellectual disability• Other unexplained rare problems

• Seizures under age 2

• Certain epilepsy syndromes• West syndrome, Dravet syndrome, Generalized Epilepsy

with Febrile Seizures Plus (GEFS+)

• Seizures “run in the family”

• Thinking about having kids/having more kids

Variant Analysis

• Step 1: Does the inheritance make sense?

• Step 2: Does the phenotype make sense?

• Step 3: Is it inherited or de novo?

• Step 4: Higher level analysis by genetic counselors• Grantham, SIFT, PANTHER, PolyPhen scores

• How much does this gene normally tolerate variation?

• In-silica, in-vitro, or in-vivo modeling of mutations

Benefits of Testing

• May help predict future challenges• Higher risk of SUDEP (SCN1A, SCN8A)

• Risk of movement disorder (SLC2A1, PRRT2)

• Additional testing – e.g. check overnight EEG (GRIN2A)

• Explains behavior challenges

• Anticipate future seizure types

• May help predict seizure pattern• Seizures worst when infant (KCNQ2, KCNQ3, PRRT2)

• Seizures worst in early childhood (SCN1A, PCDH19)

• Importance of management of seizure clusters (CACNA1A, PCDH19)

• Inheritance pattern & family planning

Benefits of Testing

• Guides antiseizure medication selection• SCN1A & Dravet – clobazam, valproic acid,

ketogenic diet, cannabidiol, stiripentol, fenfluramine• AVOID sodium channel drugs

• SLC2A1 – ketogenic diet, triheptanoin

• KCNQ2, KCNQ3 – oxcarbazepine / carbamazepine, ezogabine

• SCN8A – sodium channel blockers, high-dose

• SCN2A – sodium channel blockers, zonisamide

• PCDH19 – clobazam

Benefits of Testing

• Guides antiseizure medication selection• CHRNA3, CHRNB2, CHRNA4 – oxcarbazepine /

carbamazepine, zonisamide, nicotine

• TSC1/2 – everolimus, vigabatrin, cannabidiol

• KCNT1 – quinidine

• POLG1 – avoid valproic acid

• TPP1 – cerliponase alfa

Benefits of Testing

Areas of Active Research

• Genotype / phenotype prediction

• Antiseizure medication profiles

• Gene discovery• Re-analysis of clinical whole exomes

• Gene-specific RCTs

• Novel pathogenic mechanisms• Whole genome sequencing

Areas of Active ResearchGene-Specific RCTs: SCN2A

Wolff M, et al. Brain. 2017.

Novel Pathogenicity Mechanisms

Ishiura H, et al. Nat Genet. 2018.

A Glimpse into the Future

• Modifier genes• Polygenic inheritance

• Personalized mutation modeling

• Gene discovery of “benign” epilepsy syndromes

• Exomes as common as MRI in seizure evaluation

Any questions?Thanks for listening!