Evan J. Fertig, MD. Introduction A common question is epilepsy inherited? How and when? Genetics...
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Transcript of Evan J. Fertig, MD. Introduction A common question is epilepsy inherited? How and when? Genetics...
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)
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)
Brain Communication
http://www.niaaa.nih.gov/NR/rdonlyres/9E5D5B9F-C28E-49F2-A925-33886A82E4D5/0/synapsebetween_neurons.gif
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
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.
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
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
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