1. Mike Potes, Austin Fernstrum, Sydney Bruestle

2. What is Epilepsy  Group of related disorders Not just one disease Concentration: Idiopathic Generalized Epilepsy  A person that has more than one spontaneous seizure classified with epilepsy A seizure is the physical manifestation of a sudden disruption of orderly communication between neurons in the brain Many forms of seizures. Epilepsy type is determined from area of disruption and length of abnormal activity

3. Two Types of Seizures  Partial Seizure Affect one specific area in one hemisphere of brain Can cause loss of consciousness Symptoms ○ Twitching and repetitive actions ○ A “daydream” appearance  Generalized Seizure Seizure that affects both hemispheres of brain Loss of consciousness A partial seizure can manifest to a generalized seizure Symptoms: ○ Falling to floor ○ Repetitive muscle contraction Stiffening and relaxation of muscles ○ Blank stares

4. Forms of Partial Seizure  Simple Partial Seizure one specific part of brain No loss in consciousness  Complex Partial Seizure Larger part of brain Loss in consciousness  Secondarily generalized Seizure Begins as partial Seizure then becomes generalized

5. Forms of Generalized Seizure  Generalized Tonic Clonic Seizure All age groups Loss of consciousness Different phases of Tonic Clonic Seizure. (Epilepsyclassroom.com)

6. Causes of Epilepsy  Imbalance of Inhibitory Neurotransmitter and Excitatory Neurotransmitter  Mutations in Specific genes Proteins of Voltage-gated and ligand-gated ion channels  Epileptogenesis  Brain Lesions  Chemical Stimulation

7. Causes of Epilepsy  Seizure Trigger Factor that can cause a seizure in a person Triggers include: ○ Alcohol ○ Drugs ○ Flashing Lights ○ Diseases ○ Sleep Deprivation

8. Neurotransmitters in Epilepsy  Serotonin  Acetylcholine  GABA

9. Formation of Serotonin  Synthesis from Tryptophan  Central Nervous System Regulation of mood, appetite, sleep, and muscle contraction Modulation used in antidepressants Themedicalbiochemistrypage.org

10. Formation of Acetylcholine  Synthesis from Acetyl-CoA and Choline  Central Nervous System Neuromodulator  Peripheral nervous system Activates Muscles Themedicalbiochemistrypage.org

11. Formation of GABA  Synthesis from Glutamine  Central Nervous System Inhibitory Neurotransmitter Cause Hyperpolarization Themedicalbiochemistrypage.org

12. Synapse Nicerweb.com

13. Our hypothesis  Seizures are caused by the hyper- excitability of neurons producing a subsequent spread of excitation throughout a brain area due to the voltage-gated calcium channels staying open too long causing excessive neurotransmitter release.

14. Synapse Nicerweb.com

15. Genes Behind Epilepsy  CACNB4 Voltage-dependent L-type calcium channel subunit beta-4 Protein Mediate the influx of Calcium ions into the cell

16. Sequence of CACNB4 protein  1 mssssyakng tadgphspts qvargtttrr srlkrsdgst tstsfilrqg sadsytsrps 61 dsdvsleedr eairqereqq aaiqleraks kpvafavktn vsycgalded vpvpstaisf 121 dakdflhike kynndwwigr lvkegceigf ipsplrleni riqqeqkrgr fhggkssgns 181 ssslgemvsg tfratptsta kqkqkvtehi ppydvvpsmr pvvlvgpslk gyevtdmmqk 241 alfdflkhrf dgrisitrvt adislakrsv lnnpskraii ersntrssla evqseierif 301 elarslqlvv ldadtinhpa qliktslapi ivhvkvsspk vlqrliksrg ksqskhlnvq 361 lvaadklaqc ppemfdvild enqledaceh lgeyleaywr athttsstpm tpllgrnlgs 421 talspyptai sglqsqrmrh snhstenspi errslmtsde nyhnerarks rnrlssssqh 481 srdhyplvee dypdsyqdty kphrnrgspg gyshdsrhrl  A mutation at amino acid 104 where a cysteine is replaced by a phenylalanine has been shown to disrupt the normal function of calcium channels in the brain

17. Additional Intron in CACNB4  A 535 BP intron between the first two exons of the CACNB4 gene. The exons are designated at 1A and 1B. In human mutation R482X, the protein is condensed in the middle of a domain that interacts with the C-terminus of the a1A subunit.

18. Premature Termination Mutation (R482X mutation)  The mutation generates a pre-mature stop codon  This eliminates part of the interaction domain for the alpha1 subunit  This mutation causes the deletion of two consensus phosphorylation sites

19. C104F Mutation  A subject family exhibited idiopathic generalized epilepsy  Variation in exon 3  Sequence analysis confirmed heterozygosity (two different alleles for the same gene) for a G T transversion  Resulted in the replacement of cysteine residue 104 by phenylalanine (C104F mutation).  Phenylalanine is hydrophobic  Unaffected members of a family do not carry the mutation

20. Treatment of Epilepsy  Anticonvulsants Treat seizures Treat bi-polar disorders Mood stabilizers suppress the rapid, excessive firing of neurons Although the different types of epilepsy vary greatly, in general, medications can control seizures in about 70% of patients

21. Drug Therapy  Aldehydes Paraldehyde Hypnotic, Clear liquid Injection, Oral, Rectal Does not suppress breathing

22. Drug Therapy  Stiripentol Possible cause in increase of GABA production Gel capsule, or dry mix adjunctive therapy with sodium valproate Increase in plasma concentrations

23. Drug Therapy  Barbiturates Depress the Central Nervous System Increase the flow of chloride ions across the neuronal membrane Reduce the chance of action potential generation

24. Treatment of Epilepsy  Severing the Corpus Callosum: a broad transverse nerve tract connecting the two cerebral hemispheres  http://www.youtube.com/watch?v=lfGwsAdS9Dc http://www.youtube.com/watch?v=lfGwsAdS9Dc http://www.mult-sclerosis.org/corpuscallosum.html

25. Conclusion  Seizures are caused by the hyper-excitability of neurons producing a subsequent spread of excitation throughout a brain area due to mutation in the voltage-gated ion channels. Anticonvulsant drugs are used to suppress the rapid, excessive firing of neurons reducing the amount of seizures.

26.  Questions

27. Citations  Epilepsy Foundation. “An introduction into Epilepsy”, Copyright 2008. Accessed 11/1/2010. Epilepsyclassroom.com  NicerWeb. “ Synaptic Illustration”, Accessed 11/1/10. http://bio1152.nicerweb.com/Locked/media/ch48/synapse.html  The Biochemistry Page. “Table of Neurotransmitters”, Last updated 3/24/2010. Accessed 11/1/2010. http://themedicalbiochemistrypage.org/nerves.html#ach  YouTube. “Severed Corpus Callosum”. Accessed 11/1/2010. http://www.youtube.com/watch?v=lfGwsAdS9Dc  American Journal of Human Genetics. “Coding and Noncoding Variation of the Human Calcium-Channel β 4 -Subunit Gene CACNB4 in Patients with Idiopathic Generalized Epilepsy and Episodic Ataxia”, Updated May 2000. Accessed 11/1/2010. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B8JDD-4RDPT5C- 8&_user=4019097&_coverDate=05%2F31%2F2000&_rdoc=1&_fmt=high&_orig=search&_origin =search&_sort=d&_docanchor=&view=c&_searchStrId=1524679629&_rerunOrigin=scholar.googl e&_acct=C000062079&_version=1&_urlVersion=0&_userid=4019097&md5=906957c74b4af3bd5 b1d367cf5038db7&searchtype=a http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B8JDD-4RDPT5C- 8&_user=4019097&_coverDate=05%2F31%2F2000&_rdoc=1&_fmt=high&_orig=search&_origin =search&_sort=d&_docanchor=&view=c&_searchStrId=1524679629&_rerunOrigin=scholar.googl e&_acct=C000062079&_version=1&_urlVersion=0&_userid=4019097&md5=906957c74b4af3bd5 b1d367cf5038db7&searchtype=a

28. Citations II  WebMD. “Treatment for Epilepsy”, Copyright 2010. Accessed 11/1/2010. http://www.webmd.com/epilepsy/treating-epilepsy  Molecular Biology Intelligence Unit. “Voltage Gated Calcium Channels”. Copyright 2005. Accessed 11/1/2010 http://books.google.com/books?id=7RqevZ02RaYC&pg=PA248&lpg=PA248&dq=R482X+mutation&source=bl& ots=F7fD4qSZoz&sig=sZ1kfhFLQwq4YK8rIyWTtmEU7ec&hl=en&ei=QPPRTPbZFsTangfCzsmnDA&sa=X&oi= book_result&ct=result&resnum=4&ved=0CCUQ6AEwAw#v=onepage&q=R482X%20mutation&f=false  National Center for Biotechnology Information. “voltage-dependent L-type calcium channel subunit beta-4 isoform b [Homo sapiens]”, Copyright 2010. Accessed 11/2/2010. http://www.ncbi.nlm.nih.gov/protein/54607064?report=genbank&log$=prottop&blast_rank=1&RID=D19R6GB10 1S http://www.ncbi.nlm.nih.gov/protein/54607064?report=genbank&log$=prottop&blast_rank=1&RID=D19R6GB10 1S  University of Washington. “Barbiturates”, Accessed 11/2/2010. http://faculty.washington.edu/chudler/barb.html  The Journal of Biological Chemistry. “The Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the Subunit of a Calcium Channel”, Copyright 2010. Accessed 11/2/2010. http://www.jbc.org/content/271/10/5768.full  The Lancet. “Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial “ Copyright 2000. Accessed 11/2/2010. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-41PVXX3- 1D&_user=4019097&_coverDate=11%2F11%2F2000&_rdoc=1&_fmt=high&_orig=search&_origin=search&_so rt=d&_docanchor=&view=c&_acct=C000062079&_version=1&_urlVersion=0&_userid=4019097&md5=b6f9f77c 26b3617a86fc5368685b279c&searchtype=a