THE BIOCHEMISTRY OF
EPILEPSY
Mike Potes, Austin Fernstrum, Sydney Bruestle
What is Epilepsy Group of related disorders
Not just one diseaseConcentration: Idiopathic Generalized Epilepsy
A person that has more than one spontaneous seizure classified with epilepsyA 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
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
Forms of Partial Seizure
Simple Partial Seizureone specific part of brainNo loss in consciousness
Complex Partial SeizureLarger part of brainLoss in consciousness
Secondarily generalized SeizureBegins as partial Seizure then becomes
generalized
Forms of Generalized Seizure Generalized Tonic Clonic Seizure
All age groupsLoss of consciousness
Different phases of Tonic Clonic Seizure.(Epilepsyclassroom.com)
Causes of Epilepsy
Imbalance of Inhibitory Neurotransmitter and Excitatory Neurotransmitter
Mutations in Specific genesProteins of Voltage-gated and ligand-gated
ion channels Epileptogenesis Brain Lesions Chemical Stimulation
Causes of Epilepsy
Seizure TriggerFactor that can cause a seizure in a personTriggers include:
○ Alcohol○ Drugs○ Flashing Lights○ Diseases○ Sleep Deprivation
Neurotransmitters in Epilepsy Serotonin
Acetylcholine
GABA
Formation of Serotonin
Synthesis from Tryptophan Central Nervous System
Regulation of mood, appetite, sleep, and muscle contraction
Modulation used in antidepressants
Themedicalbiochemistrypage.org
Formation of Acetylcholine Synthesis from Acetyl-CoA and Choline Central Nervous System
Neuromodulator Peripheral nervous system
Activates Muscles
Themedicalbiochemistrypage.org
Formation of GABA
Synthesis from Glutamine Central Nervous System
Inhibitory NeurotransmitterCause Hyperpolarization
Themedicalbiochemistrypage.org
Synapse
Nicerweb.com
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.
Synapse
Nicerweb.com
Genes Behind Epilepsy
CACNB4Voltage-dependent L-type calcium
channel subunit beta-4 ProteinMediate the influx of Calcium ions into
the cell
Sequence of CACNB4 protein
1 mssssyakng tadgphspts qvargtttrr srlkrsdgst tstsfilrqg sadsytsrps61 dsdvsleedr eairqereqq aaiqleraks kpvafavktn vsycgalded vpvpstaisf121 dakdflhike kynndwwigr lvkegceigf ipsplrleni riqqeqkrgr fhggkssgns181 ssslgemvsg tfratptsta kqkqkvtehi ppydvvpsmr pvvlvgpslk gyevtdmmqk241 alfdflkhrf dgrisitrvt adislakrsv lnnpskraii ersntrssla evqseierif301 elarslqlvv ldadtinhpa qliktslapi ivhvkvsspk vlqrliksrg ksqskhlnvq361 lvaadklaqc ppemfdvild enqledaceh lgeyleaywr athttsstpm tpllgrnlgs421 talspyptai sglqsqrmrh snhstenspi errslmtsde nyhnerarks rnrlssssqh481 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
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.
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
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
Treatment of Epilepsy
AnticonvulsantsTreat seizuresTreat bi-polar disordersMood stabilizerssuppress the rapid, excessive firing of
neuronsAlthough the different types of epilepsy vary
greatly, in general, medications can control seizures in about 70% of patients
Drug Therapy
AldehydesParaldehydeHypnotic, Clear liquidInjection, Oral, RectalDoes not suppress breathing
Drug Therapy
StiripentolPossible cause in increase of GABA
productionGel capsule, or dry mixadjunctive therapy with sodium valproateIncrease in plasma concentrations
Drug Therapy
BarbituratesDepress the Central Nervous SystemIncrease the flow of chloride ions across the
neuronal membraneReduce the chance of action potential
generation
Treatment of Epilepsy
Severing the Corpus Callosum:a broad transverse nerve tract connecting
the two cerebral hemispheres
http://www.youtube.com/watch?v=lfGwsAdS9Dchttp://www.mult-sclerosis.org/corpuscallosum.html
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.
Questions
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 β4-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.google&_acct=C000062079&_version=1&_urlVersion=0&_userid=4019097&md5=906957c74b4af3bd5b1d367cf5038db7&searchtype=a
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=D19R6GB101S
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&_sort=d&_docanchor=&view=c&_acct=C000062079&_version=1&_urlVersion=0&_userid=4019097&md5=b6f9f77c26b3617a86fc5368685b279c&searchtype=a