Genetics and Barriers to Successful

Epilepsy Management Dec 4, 2011

Samuel F Berkovic MD FRS Epilepsy Research Centre

University of Melbourne

American Epilepsy Society | Annual Meeting

Disclosure

Name of Commercial

Interest

Bionomics Inc

Athena Diagnostics

Type of Financial

Relationship

Licensing by University of Melbourne for

genetic tests in Epilepsy

American Epilepsy Society | Annual Meeting

Learning Objectives

• Appreciate increasing clinical relevance of genetics in epilepsy diagnosis

• Understand management implications of genetics: Treatment and Counseling

• Review progress in pharmacogenomics including genetics of pharmaco-resistance

American Epilepsy Society | Annual Meeting

Jumping Barriers with Genetics

• Discovering the cause of refractory epilepsy is critical to management

• Genetics is unraveling the cause of many epilepsies of hitherto unknown etiology

• By reaching a specific diagnosis

Realistic treatment expectations can be set

Treatment and counseling are tailored

Patient and family are empowered

Closure is reached

Jumping Barriers with Genetics

• Genetic diagnosis is a commonplace consideration especially in pediatric epilepsy

• Gene testing is part of initial workup in many cases

• Hesitancy to embrace genetics needs education

Physicians: lack of genetic literacy

Patients: stigma, lack of understanding

Genes for Epilepsies: Big picture 2011

– Ion channel subunits

• Voltage-gated (Sodium, Potassium)

• Ligand-gated (Nicotinic, GABA)

– Non-ion channel genes (GLUT1; LGI1 etc)

– Genetic heterogeneity for rare monogenic disorders

– Pleiotropic expression of individual genes

Complex Epilepsies (majority of cases)

– Common variants (GWAS) – none identified

– Rare variants – some identified

Monogenic Epilepsies (largely dominant, uncommon/rare)

Genes for Epilepsies: Big picture 2011

Hidden Genetics of „Sporadic‟ Epilepsy

• Under-ascertainment of family history

• „Genetic‟ ≠ „familial‟

• Lack of family history expected in complex disorders

• Not expected – Importance of de novo mutagenesis

Severe childhood encephalopathies

Dravet syndrome (sodium channel SCN1A)

Copy Number Variations (CNVs)

Other single gene disorders

Copy Number Variation • Unexpected deletions/duplications in normals

• Large deletions found in neurodevelopmental disorders

• Essential investigation in epilepsy + ID or autism

• Determining significance can be challenging

• Del15q ~1% of GGE (Helbig et al 2009)

• De novo or inherited (Dibbens et al, 2009)

• Paradox of “severe” mutation

contributing to polygenic disease

• Comorbidity with autism, ID,

schizophrenia

(Redon et al; Nature 2006)

Case 1: Ruby 16 months

• Normal birth and perinatal period

• 8 months: 3 min convulsive seizure with focal features,

cluster of 10 focal seizures over 3 days associated with fever

• 11 months further cluster

• Every 3 months recurrent seizures, often with fever, clusters

and rare episodes of status

• Concern re development (compared to older brother)

• Normal MRI; interictal EEG no diagnostic features

What is the Diagnosis?

Case 1: Ruby 16 months

Jumping the Barrier with genetics Family History: mother had “febrile convulsions”

Seizures until age 11 years – febrile & afebrile

Completed grade 10; borderline intellect

What is the Diagnosis?

PCDH19 mutation (Protocadherin 19)

• Female only (X-linked dominant, male sparing)

• Familial or Sporadic

PCDH19 female limited epilepsy

• Onset 6m-3yr

• Seizure semiology

•Febrile seizures, Focal seizures, Generalized seizures

•Clustered focal seizures

•Status epilepticus

• Intellect varies from normal to severe ID

• Early development often normal with later regression

• Autistic spectrum features common

• Epilepsy severity: “Dravet-like” to very mild

Importance in Management

Genetic counseling

Prognosis

Case 2: Robert 20 years

Intellectually disabled male brought by his carer

Poorly controlled nocturnal seizures

No useful history…….

Multiple forms to fill in……

Jumping the Barrier with genetics

History from mother

Normal infant

Multiple febrile seizures, some long

Never the same after 6m vaccination…

Refractory seizures, regression

Diagnosis?? Dravet Syndrome

Missense mutation in SCN1A

Case 2: Robert 20 years

• Previously normal infant; seizures from ~ 6 mths

– Hemiclonic or generalized seizures

– Status epilepticus, often with fever

– Frequent convulsive seizures

• Other seizure types by 1- 4 years

• Development plateaus

• Regression

• MRI non-specific

• EEG patterns variable

• Surprisingly normal early

• Generalized and focal epileptiform discharges

• Diffuse slowing

Case 2: Robert 20 years

Dravet: Recognition in adults (Jansen et al 2006)

Early history is the key

Characteristic evolution

Tonic-clonic seizures; especially nocturnal

Other seizures less prominent

Ataxia, pyramidal signs

Evolution of crouch gait

Importance in Management

Closure; relief of lifelong guilt

Genetic counseling

Avoid lamotrigine, carbamazepine

Late change to Rx helps (Catarino et al Brain 2011)

Epileptic Encephalopathies

“The epileptic activity itself may contribute to

severe cognitive and behavioral impairments

above and beyond what might be expected

from the underlying pathology alone (e.g.,

cortical malformation), and that these can

worsen over time” Berg et al. Epilepsia 2010

Epileptic Encephalopathies Jumping the Barrier with genetics

• Group of severe early childhood epileptic encephalopathies • Previously, causes largely unknown (minority surgical)

• De novo mutations now clearly the major known cause

Copy number variation (~ 5 %)

SCN1A (Dravet)

PCDH19 (girls; Dravet-like and others)

ARX (boys; X-linked spasms and others)

CDKL5 (mainly girls; spasms)

STXBP1 (Ohtahara syndrome and others)

KCNQ2, PLCB1 etc

• ~ 30% currently solvable, new technology will make this

rapid and inexpensive

Pharmacogenetics

• Prediction of drug response or side effects based on genetic

markers

• “Personalized Medicine”

• Challenges in Epileptology

– Prediction of pharmaco-resistant epilepsy

– Prediction of particular drug response

– Prediction of idiosyncratic side effects

– Rapid testing – demand for rapid treatment

Prediction of Pharmaco-resistant Epilepsy

• Are there genetic factors determining outcome or

pharmaco-resistance distinct from those determining

epilepsy syndrome?

• Strongly suspected but not definitively known!

• Remarkably difficult to test

– Problems in defining & measuring pharmaco-resistance (Kwan et al Epilepsia 2010)

– Clinical measures determining heritability hard to study

and separate from genes for etiology

– Some evidence from animal models

Molecular Studies of Pharmaco-resistance

• Many attempts using association study approach

• Superficially simple, but numerous methodological issues

– Definition of pharmaco-resistance

– Retrospective treated samples convenient, but suboptimal

– Sample size

– Population stratification

– Heterogeneity of practice patterns (Johnson et al Ep Behav 2011)

• Exciting claim for role of the multi-drug transporter ABCB1

not confirmed, despite multiple studies

• Genome wide approaches now being implemented

– Promising results from multi-SNP machine-learning approaches

(Petrovski et al 2009)

Case 4 Miranda • 22 year old woman, first convulsion

• ? Focal dyscognitive seizures for 6 months

• Right temporal epileptiform discharges

• No known antecedents, Normal MRI

Jumping the Barrier with genetics

Han Chinese background

Decision on use of carbamazepine

HLA-B*1502 testing

Pharmacogenetics

• Robust findings in prediction of carbamazepine

sensitivity

• Strong association in Han Chinese with Stevens–

Johnson syndrome and HLA-B*1502

• Initially described in Taiwan (Chung et al. Nature 2004)

• Subsequently confirmed in other SE Asian populations

(Hong Kong, Thailand, India)

• FDA alert

Pharmacogenetics

• HLA-B*1502 screening effective in preventing SJS in Taiwan

• Different risk factors in other populations

March 2011

Impact on Clinical Care and Practice

• Role of genetics in epilepsy underestimated

• De novo genetic epilepsies increasingly important

• Benefits of specific Genetic Diagnosis

Realistic treatment expectations can be set

Avoid unnecessary or invasive investigation

Treatment and counseling are tailored

Patient and family are empowered

Closure is reached with challenging epilepsy

• Pharmacogenetics has arrived as a practical tool