Evan J. Fertig, MD

Introduction

A common question is epilepsy inherited? How and when?

Genetics is “the study of heredity”

This talk will therefore be about the genetics of epilepsy

Overview A Brief History of Epilepsy

Genetics

Basic concepts of genetics

What are my child’s chances of getting epilepsy?

Genetic Testing. Worth it?

The future: Pharmacogenetics

History of Epilepsy Genetics

Hippocrates (400 B.C.E.) On the Sacred Disease

Recognized epilepsy could be inherited

Through history this has been another burden for person w epilepsy

Photograph and EEG of Constance and Kathryn, identical twins both w/ childhood absence epilepsy, both with seizure onset at age 6 years!

Vadlamudi, L. et al. Neurology 2004;62:1127-1133

Concordance rate for epilepsy inIDENTICAL vs. FRATERNAL Twins

Epilepsy or not

Same Different Concordance Rate

Identical

Twins

29 109 0.35

Fraternal

Twins

11 214 0.09

essexcc.gov.ukpublications.nigms.nih.gov

Study YearNumber of

probandsNumber of

offspring

Affected

N %

Conrad 1937 519 1,568 70 4.5

Alstrom 1950 897 339 10 3.0

Harvald 1951 162 252 11 4.4

Lennox 1951 4,231 1,237 34 2.7

Tsuboi and Endo 1977 263 506 12 2.4

Annegers et al. 1978 336 687 25 3.6

Janz and Scheffner 1980 384 672 24 3.6

Beck-Mannagetta et al.

1989 427 840 39 4.6

*Probands (parents) had any kind of epilepsy; single seizures were excluded.

Source: Beck-Mannagetta and Janz 1991 (12).

Risk for epilepsy in children of parents with epilepsy (any type)

Peas, Genes, and DNA

18561953

The Structure of the Genome

Genome

Chromosome

Genes, Protein, and Disease

Gene Protein

Neuron Nih.gov

Mutation

Cell

What We Know Today

Epilepsy frequently does have a genetic basis

Hundreds of inherited conditions have seizures as feature

Only a few of these conditions have seizures as their ONLY feature

How do Genetic Factors cause Epilepsy? Chromosomal abnormalities

Genes involved in BRAIN FORMATION (migration)

Genes involved in BRAIN METABOLISM

Genes involved in BRAIN COMMUNICATION (ion channel function)

Chromosomal Abnormalities

Chromosome Abnormality

http://ghr.nlm.nih.gov/handbook/illustrations/ringchromosome.jpg

Brain Formation: Genes are GPS for the Developing Brain

eurekalert.org

Brain Communication

http://www.niaaa.nih.gov/NR/rdonlyres/9E5D5B9F-C28E-49F2-A925-33886A82E4D5/0/synapsebetween_neurons.gif

Brain Metabolism

Gene (DNA)

Enzyme

MutationToxic

Metabolite

Substrate, eg. Fat

So, how is Epilepsy Inherited?

SIMPLE INHERITANCEWith “STRONG” GENES

COMPLEX INHERITANCEWith “WEAK” GENES

“Strong” Genes

Are biologically very important. Therefore “bad” strong genes have obviously “bad” effects

Strong Genes are rare

However when they occur in a family, the can occur very commonly in the family tree

Simple Inheritance (Mendel)

shinerama.naitsa.ca

Epilepsy Genes and Simple Inheritance There are very few “strong” epilepsy

genes out there (sharks)

Over 10 have been identified to date

“Strong” genes account for very few cases of epilepsy

Known Major Epilepsy GenesGene Syndrome Yr Discovered

CHRNA4 ADNFLE 1995

KCNQ2 BFNS/(myokymia) 1998

KCNQ3 BFNS 1998

SCN1B GEFS+ 1998

SCN1A GEFS+/(SMEI) 2000

CHRNB2 ADNFLE 2000

GABRG2 CAE/FS/GEFS+ 2001

SCN2A GEFS+/(BFNIS) 2001

GABRA1 ADJME 2002

LGI1 ADPEAF 2002

CLCN2 JME 2003

EFHC1 JME 2004

Weak Genes and Complex Inheritance

Weak genes may not be powerful enough to cause epilepsy alone, but may be an influencing factor, with other genes or environment stimuli

“Runs in the Family”

Most medical diseases, e.g. high blood pressure

Reasons for Complex Inheritance No single gene causes the disease in the

family

Many bad “weak” genes cause the disease School of piranha Ion channel polymorphisms and idiopathic

generalized epilepsy

Environmental factors contribute • Smoking with alpha-1-antitrypsin mutation

increases risk of early emphysema

What does this all mean for the patient with epilepsy?

Question: Can predict if a child will have epilepsy?

Answer: Most times we can only give very rough odds

Case study: Counseling risk

33 year old woman with epilepsy is planning to get pregnant, but she first wants to know…

“What’s the chance my child will have seizures?”

Winawer, Epilepsia, 2005

Assessing Risk: Patient FactorsExclude Non-Genetic Causes of Epilepsy Central nervous system infection

Stroke Brain Trauma Alcohol Brain tumors Degenerative Disease

(Parkinson’s Disease) Static Conditions from birth

Hauser WA, Epilepsia, 1993;34:453-68.

Classification of Seizures

GeneralizedGeneralized FocalFocal

FocusFocus

Patient Factors: Determine Seizure Type and Epilepsy Syndrome

She first noted bilateral muscle jerks riding on a school bus at age 15

First GTC at age 16 preceded by jerks

Normal exam Generalized polyspike wave on

EEG superimposed on normal background

Epilepsy well-controlled on LTG

DIAGNOSIS?

Assessing Risk: Family Factors

Questions to ask about family members with epilepsy

1) Seizure type or types2) Triggering factors (fever, alcohol)3) Other nongenetic risk factors4) Age of onset

Winawer, Epilepsia, 2005

Case study: Family History

Winawer, Epilepsia, 2004

GTC upon awakening

Juvenile Myoclonic Epilepsy

Genetic risk to offspringRisk Factors based on Parent

Parent Gender: Maternal effect (2.8-8.7%) Father (1.0-3.6%)

Age of onset < 20 (2-6%) 20+ (1.0-2.8%)

Increases with # of affected

Generalized spike wave on EEG (4-6%)

Winawer, Epilepsia, 2004

Effect of Parent Seizure Type

Winawer, Shinnar 2005

So what do we tell her? Generalized epilepsy, Juvenile

Myoclonic Epilepsy

A remote relative has IGE, no first degree relatives: Likely Complex

Gene testing not possible at this point for syndromes with complex inheritance

Winawer, 2004

The bottom line….

Population risk to offspring: 1%

Patient factors Mom has epilepsy: 6% Early onset: 6% GSW EEG: 6% Myoclonic Seizures: 4-8%

> 90% chance child will be seizure free

Mom has another question…

“If my child gets epilepsy, will it be worse than mine? Will she be developmentally delay from the epilepsy?

Does epilepsy syndrome “breed true”?

Identical vs. Fraternal twinsIdentical Twins

29 twins had epilepsy

25/29 had same type of epilepsy

Fraternal Twins

11 concordant for epilepsy

1/11 concordant for seizure type and syndrome

Henriksen, Corey et al. Epilepsia 1999-from Shlomo Shinnar, AES, 2004

Epilepsy Syndromes in Concordant and Discordant Identical Twins

Syndrome Concordant Discordant

Idiopathic Generalized

12 9

Idiopathic

Localization-Related

2 3

Symptomatic

Generalized0 2

Symptomatic

Localization-Related

3 53

Undetermined 8 43

Henriksen, Corey et al. Epilepsia 1999-from Shlomo Shinnar, AES, 2004

Epilepsy Syndrome, Same or Different in a Child?

Syndromes do not always “breed true” but most often do!

The most heritable epilepsies tend also to be benign (childhood absence epilepsy)

Exceptions to be aware of….. Tuberous

Sclerosis

Rare genetic cause of epilepsy w/ other features

•Child can be more severely affected than the parent

Role of Genetic Testing

There are no official guidelines for when and who should be tested

Most often there is complex inheritance and there is no definite genetic test to send

Many genetic tests are very expensive and may not be covered by insurance

Role of Genetic Testing (Continued) Patients with epilepsy associated with

developmental delays or other features may benefit from other types of genetic test:

Microscopic examination of the chromosomes

Metabolic tests- Blood tests to see how some genes are functioning

MRI and other clinical features might suggest other genetic tests

Role of Genetic Tests

For some patients, genetic testing is very important

To help guide medical therapy (eg, decide what drugs to avoid)

Determine the long term prognosis Family planning

Pharmacogenetics: The Future

Initiating seizure medications What drug? What dose?

New onset epilepsy: 40-50% won’t respond to seizure medication

Pharmacogenetics- Use individual genetic variation to predict response

How Pharmacogenetics works in theory

Genes influence how well each seizure medication “bind” to their targets (where they work) in the brain

Genes (eg. in the liver) influence how much seizure medication reaches the brain Too little: Seizures Too much: Side effects

Conclusion

Advances in epilepsy genetics will alter how we treat epilepsy from diagnosis to treatment

More research remains to be done!

Have multiple family members with epilepsy? Consider joining a research study