2. The genetics of human epilepsy.
2.1. Causes of epilepsy:
Because epilepsy is unknown. The word epilepsy does not bring up anything about the cause or severity of epileptic seizures, some individual cases caused by hereditary factors, but can likewise result from head injuries caused by blows to the head, stroke, infection, high fever or tumors (Marieb, 2006), It has been observed that heredity (genes) plays an important role in many causes of epilepsy in children is very immature, but could be a factor for citizens of all ages. For example, not everyone has a serious injury in the header (a clear cause for seizures) puts epilepsy (Fisher, et al., 2006).
In this point are several cases of epilepsy, which is common to different age groups; (1) is during the neonatal period and infancy are the most common causes of hypoxic ischemic brain disease, CNS infections, injuries, congenital malformations of the central nervous system and metabolic disorders. 2. end infant and early childhood that most frequent febrile seizures can be caused by CNS infections and childhood are injury.3.In well defined epilepsy syndrome usually complied. (4) In adolescence and adulthood the causes (Lowenstein, 2005).
2.2. Mutations in the Gene Encoding Cystatin B in Progressive Myoclonus Epilepsy (EPM I).
Epilepsy is a heterogeneous disorder, the 3% of the world population (Scheuer, et al., 1990) affected. Although the Etiology the most Epilepsies Unkwon Genetic factor’s role a key Role in disease. Genetic link has based for several inherited Epilepsies and in one case a mutation in one of Gene has been identified (Greenberg, et al., 1988). Progressive myoclonus epilepsy refers to a heterogeneous group of heavy Lnhertede marked epilepsy with Myoclonic seizures, is one of the five recognized progressive myoclonus members of this group, Unverricht-Lundborg type of epilepsy (EPM1) (Unverrich, et al., 1895). This form of epilepsy is an autosoma1 inherited recessive disease with strong stimulus sensitive Myoclonic and tonic clonic seizures between early at the age of 6 and 15, as well as a variable interest rate of progression between and within the family (Koskiniemi, et al., 1974) .
Linkage analysis first isolated the gene for the EPMl to a region of 2 million base pairs on human Chromosolne 21 between the DNA markers of CBS and CDlS (Lehesjoki, et al., 1993). Us, Poles imbalance and recombination to refine breakpoint mapping with Finnish EPMl patients, the position of the gene in a region between markers, D21S2040 and D21S1259 allows founder effects and the history of the Finnish population bottlenecks (fig. 1) (Virtaneva, et al., 1993).
Fig. 1. Physical mapping information used in positional cloning of the gene of progressive myoclonus epilepsy (EPMI). The upper line shows an eco R restriction map of the 175 kb region on chromosome 21q22. 3 flanked by DNA markers, D21S2040 and D2151259 (from left to right telomeric direction) oriented in the centromere shows that breakpoint was by pushrods imbalance and recombination mapping, contain the gene encoding EPMl.
The gene squence encoding Cystatin B General by evidence expressing, a probe from the cDNA, Clolle recognizes a mRNA approx. 0.8 kb in length in all tissues examined (fig. 2A). These results the measurement of mRNA levels in the Lymuhoblastoid cell lines, then he as an initial screen for changes in the Cystatin B gene in people (Pennacchio, et al., 1996) was used. On the Northern (RNA) patches, lymphoblastoid cells of affected by a Finnish family, an American family (fig. 2B). And were only two other families (Lehesjoki, et al., 1996) MRNA levels of Cystatin B, in a pristine, individual Noncarrier (fig. 2B) and parents support the EPMl patients (fig. 2 b). These results suggest that the gene encoding the Cystatin B from these individuals is mutated in a way, that this results in lower amounts of mRNA tires, that these mutations have a primary at EPM1 role.
Fig. 2. Messenger RNA analysis of the gene encoding cystatin B in affected and unaffected individuals.
(A) A 500-bp Cystatin B cDNA probe was hybridized to the RNA blots. Each track 2 g Polyadenylated mRNA contain including 1, heart, by eight human tissues (ClonTech, Palo Alto, California), 2, brain; 3, placenta; 4, Lung; 5, liver; 6, skeletal muscle; 7, kidney; and 8, pancreas. The size of the Cystatin B mRNA is less than 1 kb, which is consistent with the 642 bp that original full length cDNA sequence in described. (B)
) The same probe was on RNA hybridized blots with 20 pg of total RNA from lymphoblastoid cell lines (top); 1 and 9 are untouched Noncarrier controls; 2 to 5 are from a Finnish family with EPMl, including 2, carrier father; 3, carrier mother; 4, affected child; and 5, affected child; and 6 to 8 are an American family, including 6, carrier father; 7, carrier mother; and 8, affected child. A human p-actin probe was hybridized to the same Northern blot to assess the approximate quantity of RNA loaded per lane (lower panel).
Encoding Cystatin B by the persons interested. Because we first found out the complete nucleotide sequence of the human gene from an entire chromosome (fig. 3) only cDNA and not genomic sequence information to exist. This sequence revealed that the gene 2500 base pairs (bp) in duration and takes three small exons 98-amino acid coding protein, whose ripening mRNA and amino acid sequence were previously known (Machleidt, et al., 1985). Sequence comparison identified two mutations in the gene encoding Cystatin B in these individuals. One is a G-C TRANS version at the last nucleotide of intron 1, change the Sequence of the 3' splice site AG dinucleotide It seems in this position in almost all introns (fig. 3 and 4A) (Breathnach and Chambon, 1994).
The second mutation, the alleles of the Cystatin B gene from two four generate CGA, TGA, families has been found, a stop codon changes translation to amino acid position 68, 3' splice site mutation destroys a recognition site for the restriction enzyme ”fA-1, which allows us a simple test alleles in large numbers, to develop non-affected persons (fig. 4) the screen. We found independent no Mutant alleles for the fluoroscopy 190 chromosomes for this change in 95.
Fig. 3. The genomic sequence of the gene encoding human cystatin B. Uppercase letters for nucleotides indicate the component parts of the gene present in the mature MRNA transcript, and lowercase letters designate the 5' flanking region, the two introns, and the 3' flanking region. Amino acids in the cystatin B protein are indicated below the base sequence (Lehesjoki, et al. ,1996). Underlined bases designate potential Spl binding sites in the 5' flanking region. Only portions of the two introns, which are 1445 and 325 bp in length, are shown; 5' and 3' untranslated regions are indicated by 5' UTR and 3' UTR, respectively. The two mutations we identified in this study are designated by boxes, where the mutant sequence is shown above the wild-type sequence.
2.3. Voltage-gated ion channels.
Genetic discoveries in recent years show the central role of ion channels in the pathophysiology of idiopathic epilepsies. With monogenic inheritance associated with mutations in genes encoding subunits of voltage gated ion channels, ligand portals. Voltage gated ion channels, mutations Na +, K + Cl2 + channels associated with generalized epilepsy and seizure syndromes patterns in infants (Ingrid, et al., 2003).
2.3.1. Voltage-gated ion channels: Na+ channels:
The NA + channel consists of a pore-forming ” subunit and regulatory ” subunits, and there are 11 known a subunits and three ” subunits (Isom, 2002). In the idiopathic Epilepsies were mutations of three na +-channel subunits identified. Generalized epilepsy with febrile seizures-in addition to (GEFS +) is a case of the complexity, which include phenotype-genotype connections (Scheffer, 1997). This clinical disorder includes a selection of phenotypes that can happen in a single family: including the normal febrile seizures (FS), in which seizures happen with fever from 3 months to 6 years; Febrile seizures, can also happen in which seizures without fever or febrile seizures to keep, on following 6 years old; and Myoclonic astatic epilepsy and severe Myoclonic epilepsy from the outset (SMEI).Four GEFS+ qualities have been recognized to date: SCN1A, SCN2A and SCN1B, which encode the ”1-, ”2- what's more, ”1-subunits of the Na+ channel, individually, and GABRG2, which encodes the ”2-subunit of the GABAA receptor (Escayg, 2001) and (Wallace, 2001).
2.3.1. a. Sodium voltage-gated channel Beta 1-subunit (SCN1B).
The same change in the quality, that the ”1 subunit of NA +-channel, SCN1B, coded was in two large, irrelevant Australian families, an English family with GEFS + (Wallace, 1998) and recognized (Wallace, 2002). The conversion of cysteine, tryptophan (C121W) contains a putative disulfide span in the extracellular space of the ”1 subunit and channel gating energy influenced.
These mutations are to allow passage of an increased sodium current, which would lead to a greater depolarization during the action potential and an increased tendency to fire repetitive bursts, fig. 4, (Bernard, et al., 2003).
2.3.2. Voltage-gated ion channels: K+ channels.
KCNQ2 and KCNQ3
KCNQ2 transformations represent the dominant part in patients with benign familial Neonatal seizures (BFNS) and malformations in KCNQ3 are just a few of the sexes (Biervert, 1998) and (Hirose, 2000) represented. A KCNQ2 transformation in a BFNS family reported Myokymia (automatic compression of skeletal muscle) has in later life (Dedek, 2001). In-vitro thinks about show loss of normal capacity by mutant K+ channels (Biervert, 1998). KCNQ2 and KCNQ3 ordinarily partner to frame heteromeric channels that underlie the M-current. The M-current is in charge of settling the resting layer potential and is, in this way, imperative in controlling neuronal sensitivity (Jentsch, 2000) and (Cooper and Jan, 2003). Investigations of KCNQchannel capacity in rodent hippocampal cells in the early postnatal period demonstrate that these channels go about as the prevalent inhibitory framework amid the principal week of life, when GABA-interceded neurotransmission switches from excitatory to inhibitory capacity (Okada, 2003) These discoveries might clarify the time-course and abatement that is common in BFNS.
Mutations in KCNQ2 and KCNQ3, which both encode potassium channels, are associated with benign familial neonatal convulsions These mutations, which appear to decrease the potassium outflow underlying the long-lasting ‘M- current,’ are likely to cause a loss of spike-firing adaptation and therefore an increase in neuronal firing frequency, (fig. 4), (Bernard, et al., 2003).
Fig. 4. Examples of Ion-Channel Dysfunction Associated with Inherited Forms of Epilepsy.
2.3.3. Voltage-gated ion channels: Ca2+ channels.
These models involve largely missing epilepsy with Ataxia is a rare combination in human Epilepsies. There were two reports of mutations in genes, which encode subunits in a few patients with idiopathic Ca2 channel generalized epilepsy, but without functional. These reports before you their meaning must be confirmed as epilepsy Genes will be accepted( Escayg, 2000) and (Jouvenceau, 2001).
2.3.4. Voltage-gated ion channels: Cl- channels.
CLCN2 encodes the ClC-2 Cl2 channel that is expressed widely distributed in brain and is considered important for the conservation the low intracellular concentration of Cl2, the indispensable for the GABA-mediated inhibition. More recently, heterozygous The CLCN2 mutations were detected in three, relatively small families with heterogeneous, idiopathic generalized Epilepsies (Haug, 2003). These mutations can cause that Loss of normal function and Cl2 affects discharge, the intracellular accumulation of CL would result. That would reduce transmembrane gradient Cl2 and the inhibitory GABA-mediated response (Haug, 2003). CLCN2 is expected to be a susceptibility gene in this family (i.e. A several genes that contribute to epilepsy in each each).
2.4. Epilepsy Risk Factors.
2.4.1. Head Injury.
Injured in the head. Attacks 7 days after onset of a Head injury or seizures occur during the period Recovery from this insult were classified by. the term of the head injured. Examples of the latter could also seizures occur 14 days after a head injury but in connection with inappropriate secretion Antidiuretic hormone.
2.4.2. Cerebrovascular insults.
Seizures, the within 7 days of an acute insult Occlusive or hemorrhagic or in conjunction with progression or extension of the the primary insult were categorized as cerebrovascular Insults.
2.4.3. CNS infection.
Seizures, during the Course of CNS active infection were categorized the term CNS infection. Further evidence for Infection at the time of the seizure either by laboratory Test or clinical symptoms were asked in this category.
2.4.4. Metabolic Disturbances.
Disorders that alter levels of various metabolic substances in the body sometimes result in seizures. Change levels of renal sodium or calcium or magnesium (electrolyte imbalance), with increased blood urea (would) or changes that occur with kidney failure, low blood sugar (hypoglycemia) or high blood sugar (hyperglycemia), low level of oxygen in the brain (decrease) and severe liver disease (liver failure) and associated toxins (Allen, et al., 1991).
References.
Bernard S., Chang, M. D., Daniel H., & Lowenstein, M. D. (2003). Mechanisms of disease, Epilepsy. The new england journal of medicine. 349(4), 1257-66.
Biervert, C. (1998).A potassium channel mutation in neonatal human epilepsy. Science. 279(4), 403’406.
Cooper, E.C. and Jan, L. Y. (2003). M-channels: neurological diseases, neuromodulation, and drug development. Arch. Neurol. 60(2), 496’500.
Dedek, K. (2001).Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K + channel. Proc. Natl.Acad. Sci. U. S. A., 98(4), 12272’12277.
Escayg, A. (2000). Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am. J. Hum. Genet. 66(3), 1531’1539.
Escayg, A. (2001). A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus’and prevalence of variants in patients with epilepsy. Am. J. Hum. Genet. 68(4), 866’873.
Haug, K. (2003). Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.Nat. Genet. 33(6), 527’532.
Fisher, R. S., Emde, V. B., & Blume, W. (2005). Epileptic seizures and epilepsy: definition proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia, 46(4), 470-72.
Hirose, S. (2000).A novel mutation of KCNQ3 (c.925T! C) In a Japanese family with benign familial neonatal convulsions. Ann.Neurol.47(10), 822’826.
Ingrid, E., Scheffer, & Samuel, F., & Berkovic, W. (2003).The genetics of human epilepsy. Journal of Pharmacological Sciences, 42(8), 428-433.
Isom, L. L. (2002) The role of sodium channels in cell adhesion. Front. Journal of Bioscience, 7(3), 12’23.
Jentsch, T. J. (2000).Neuronal KCNQ potassium channels: physiology and role in disease. Nat. Rev. Neurosci. 1(2), 21’30.
Jouvenceau, A. (2001). Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358(13),801’807.
Koskiniemi, M., Donner, M., Majuri, H., Haltia, M., & Norio, R. (1979). Epilepsia. Clin. Genet. 15(2), 382.
Lowenstein, D. H., Kasper, D. L., Braunwald, E., Fauci, A. S., Hauser, S. L., Longo, D. L., & Jameson, J.(2005). Seizures and epilepsy. Harrison's principles of internal medicine. USA: McGraw-Hill Companies Inc, 16( 4), 2357-72.
Marieb, E. N. (2006). Human anatomy and physiology. New Delhi Pearson Education Inc and Dorling Kindersley Publishing Inc, 6(3),430-88.
Mukhopadhyay, H. K., Kandar, C., Sanjay, K. D., Lakshmikanta, G., & Gupta, K. (2012). Epilepsy and its Management: A Review. Journal of PharmaSciTech, 1(2), 20-26.
Okada, M. (2003).Age-dependent modulation of hippocampal excitability by KCNQ-channels. Epilepsy Res., 53(4), 81’94.
Scheffer, I. E. and Berkovic, S.F. (1997). Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Journal of Brain, 120(10), 479’490.
Unverricht, H., Myoclonie, D. (1891). The Human Genome Data Base Project, Johns Hopkins University, Baltimore, MD. 1(2), 1- 28.
Wallace, R. H. (1998). Febrile seizures and generalized epilepsy associated with a mutation in the Na + channel beta1 subunit gene. SCN1B. Nat. Genet. 19(5), 366’370
Wallace, R. H. (2001). Mutant GABA (A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat. Genet. 28(4), 49’52.
Wallace, R. H. (2002). Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit. SCN1B. Neurology 58(6), 1426’1429.
Allen, H. W., John, F., & Kurland, T. (1991). Prevalence of Epilepsy in Rochester, Minnesota: 1940-1980. International League Against Epilepsy. 32(4), 429-445.