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