Is Epilepsy Inherited? A Guide for Patients and their Families

1
Is Epilepsy Inherited?A Guide for Patients and
their Families

• Evan J. Fertig, MD

2
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

3
Overview

• A Brief History of Epilepsy Genetics
• Basic concepts of genetics
• What are my childs chances of getting epilepsy?
• Genetic Testing. Worth it?
• The future Pharmacogenetics

4
The first question Why do we think Epilepsy has
aGenetic Basis?
5
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

6
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 2004621127-1133
7
Concordance rate for epilepsy inIDENTICAL vs.
FRATERNAL Twins
essexcc.gov.uk
publications.nigms.nih.gov
Epilepsy or not Same Different Concordance Rate
Identical Twins 29 109 0.35
Fraternal Twins 11 214 0.09
Henriksen, Corey et al. Epilepsia 1999 -Data
combined from US and Norwegian Twin Registries
8
Risk for epilepsy in children of parents with
epilepsy (any type)
Study Year Number of probands Number of offspring Affected Affected
Study Year Number of probands Number of offspring 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. Probands (parents) had any kind of epilepsy single seizures were excluded. Probands (parents) had any kind of epilepsy single seizures were excluded. Probands (parents) had any kind of epilepsy single seizures were excluded. Probands (parents) had any kind of epilepsy single seizures were excluded. Probands (parents) had any kind of epilepsy single seizures were excluded.
Source Beck-Mannagetta and Janz 1991 (12). Source Beck-Mannagetta and Janz 1991 (12). Source Beck-Mannagetta and Janz 1991 (12). Source Beck-Mannagetta and Janz 1991 (12). Source Beck-Mannagetta and Janz 1991 (12). Source Beck-Mannagetta and Janz 1991 (12).
9
SOME BASICS Of GENETICS
10
Peas, Genes, and DNA
1953
1856
11
The Structure of the Genome
Genome
Chromosome
GENE
davidmaybury.ie
http//
12
Genes, Protein, and Disease
Protein
Gene
Cell
Mutation
Neuron Nih.gov
13
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

14
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)

15
Chromosomal Abnormalities
16
Chromosome Abnormality
http//ghr.nlm.nih.gov/handbook/illustrations/ring
chromosome.jpg
17
Brain Formation Genes are GPS for the Developing
Brain
eurekalert.org
18
Brain Communication
http//www.niaaa.nih.gov/NR/rdonlyres/9E5D5B9F-C28
E-49F2-A925-33886A82E4D5/0/synapsebetween_neurons.
gif
19
Brain Metabolism
Gene (DNA)
Enzyme
Substrate, eg. Fat
Mutation
Toxic Metabolite
20
So, how is Epilepsy Inherited?
Vs.
SIMPLE INHERITANCE With STRONG GENES
COMPLEX INHERITANCE With WEAK GENES
21
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

22
Simple Inheritance (Mendel)
shinerama.naitsa.ca
23
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

24
Known Major Epilepsy Genes
Gene 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
25
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

26
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

27
OK BUT WHATs My Childs Risk of Epilepsy?
28
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

29
Case study Counseling risk

• 33 year old woman with epilepsy is planning to
  get pregnant, but she first wants to know
• Whats the chance my child will have seizures?

Winawer, Epilepsia, 2005
30
Assessing Risk Patient FactorsExclude
Non-Genetic Causes of Epilepsy

• Central nervous system infection
• Stroke
• Brain Trauma
• Alcohol
• Brain tumors
• Degenerative Disease (Parkinsons Disease)
• Static Conditions from birth

Hauser WA, Epilepsia, 199334453-68.
31
Classification of Seizures
Generalized
Focal
Focus
32
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?
33
Assessing Risk Family Factors

• Questions to ask about family members with
  epilepsy
• 1) Seizure type or types
• 2) Triggering factors (fever, alcohol)
• 3) Other nongenetic risk factors
• 4) Age of onset

Winawer, Epilepsia, 2005
34
Case study Family History
GTC upon awakening
Juvenile Myoclonic Epilepsy
Winawer, Epilepsia, 2004
35
Genetic risk to offspringRisk Factors based on
Parent

• Parent Gender
• Maternal effect (2.8-8.7)
• Father (1.0-3.6)
• Age of onset
• lt 20 (2-6)
• 20 (1.0-2.8)
• Increases with of affected
• Generalized spike wave on EEG (4-6)

Winawer, Epilepsia, 2004
36
Effect of Parent Seizure Type
Winawer, Shinnar 2005
37
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
38
The bottom line.

• Population risk to offspring 1
• Patient factors
• Mom has epilepsy 6
• Early onset 6
• GSW EEG 6
• Myoclonic Seizures 4-8
• gt 90 chance child will be seizure free

39
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?

40
Identical vs. Fraternal twins

• Identical 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
41
Epilepsy Syndromes in Concordant and Discordant
Identical Twins
Syndrome Concordant Discordant
Idiopathic Generalized 12 9
Idiopathic Localization-Related 2 3
Symptomatic Generalized 0 2
Symptomatic Localization-Related 3 53
Undetermined 8 43
Henriksen, Corey et al. Epilepsia 1999 -from
Shlomo Shinnar, AES, 2004
42
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)

43
Exceptions to be aware of..

• Tuberous Sclerosis
• Rare genetic cause of epilepsy w/ other features

• Child can be more severely affected than the
  parent

44
GENETIC TESTING
45
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

46
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

47
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

48
GENETICS ANDTHERAPY
49
Pharmacogenetics The Future

• Initiating seizure medications
• What drug?
• What dose?
• New onset epilepsy 40-50 wont respond to
  seizure medication
• Pharmacogenetics- Use individual genetic
  variation to predict response

50
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

51
(No Transcript)
52
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

53
Thank you