Transcript Dr. Evan Fertig - Epilepsy Life Links

IS EPILEPSY INHERITED?
A GUIDE FOR PATIENTS
AND THEIR FAMILIES
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 in
IDENTICAL vs. FRATERNAL Twins
publications.nigms.nih.gov
essexcc.gov.uk
Epilepsy or
not
Same
Different
Concordance
Rate
Identical
29
109
0.35
11
214
0.09
Twins
Fraternal
Twins
Risk for epilepsy in children of
parents with epilepsy (any type)
Affecte
d
Study
Number of
probands
Year
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.
Source: Beck-Mannagetta and Janz 1991 (12).
Peas, Genes, and DNA
1953
1856
The Structure of the Genome
Genome
Chromosome
Genes, Protein, and Disease
Gene
Protein
Cell
Mutation
Neuron Nih.gov
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)
Mutation
Enzyme
Toxic
Metabolite
Substrat
e, eg.
Fat
So, how is Epilepsy
Inherited?
SIMPLE INHERITANCE
With “STRONG” GENES
COMPLEX INHERITANCE
With “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 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
2001
GEFS+/(BFNIS)
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 Factors
Exclude 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
Generalized
Focal
Focus
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 types
2) Triggering factors (fever, alcohol)
3) Other nongenetic risk factors
4) Age of onset
Winawer, Epilepsia, 2005
Case study: Family History
GTC upon awakening
Juvenile Myoclonic Epilepsy
Winawer, Epilepsia, 2004
Genetic risk to offspring
Risk 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 twins
Identical Twins
 29 twins had
epilepsy
 25/29 had same
type of epilepsy
Henriksen, Corey et al. Epilepsia 1999
-from Shlomo Shinnar, AES, 2004
 Fraternal Twins
 11 concordant for
epilepsy
 1/11 concordant for
seizure type and
syndrome
Epilepsy Syndromes in Concordant and
Discordant Identical Twins
Syndrome
Concordant
Discordant
Idiopathic
Generalized
12
9
Idiopathic
2
3
0
2
3
53
8
43
LocalizationRelated
Symptomatic
Generalized
Symptomatic
LocalizationRelated
Undetermined
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