Epilepsy Benchmark IB1
Benchmark Area I: Understanding basic mechanisms of epileptogenesis
Section B: Continue the progress of identifying the genes predisposing to epilepsy
Specific Benchmark 1: Create and enhance national research collaborations between physicians, human geneticists, and families to identify and clone
the gene of pedigrees with monogenic epilepsy syndromes.
2005 Report submitted by Benchmark Steward(s):
Ruth Ottman, Ph.D. (Columbia University)
Background of the benchmark goal:
Discovery of genes that raise risk for monogenic epilepsy syndromes provides important information about basic mechanisms
of epileptogenesis. This information could lead to the development of new treatments or mechanisms to prevent onset of seizures
in some individuals. Most of the work is carried out by single research groups, rather than through collaborative efforts,
although the work involved is necessarily collaborative because it requires input from clinicians, geneticists, and families.
Current status of field:
Researchers in the U.S. and elsewhere have continued intensive efforts to identify epilepsy genes in families with Mendelian
forms of epilepsy. These groups are also actively researching the range of phenotypic manifestations of mutations in the
identified genes, and the prevalence of mutations in different populations. A major limitation is the scarcity of families
with Mendelian modes of transmission. Also, few researchers have the expertise or funding resources to collect data from
such families when they are identified. Over the last few years, the rate of gene identification in Mendelian forms of epilepsy
seems to have slowed somewhat, and efforts to study genetically complex epilepsies have increased, with a profusion of publication
of allelic association studies. None of these studies has produced a consistently replicated finding.
Efforts to ensure that epilepsy clinicians remain aware of the importance of genetic research are continuing. At the American
Epilepsy Society meetings, a genetics Special Interest Group was initiated 2003, and the Annual Course was on genetics in
2004. At the 2003 International Epilepsy Congress in Lisbon, genetics was a dominant theme, with two plenary sessions (Presidential
Symposium: Genetics of Epilepsy in the Third Millenium, and Epilepsy in the Post Genomic Era: Focus on the Genetics of Inhibition
and three parallel sessions (Genetic Counseling in the Epilepsies, Genetics of Epilepsy in the Mediterranean Region, and Inclusion
of Genetic Information Concerning Etiology of Epilepsy Syndromes in Axis 4 of ILAE’s Proposed Scheme). Also in Lisbon, an
informal workshop was held for attendees interested in genetics; this was organized by Elving Anderson and intended to create
or reinforce networks, to enhance collaboration.
The Epilepsy Foundation Gene Discovery Project is a good potential source of families. However, although several investigators
have been approved to use it, only two have actually done so, and only one is continuing to do so. The explanation for this
is unclear – one possibility is that investigators prefer to ascertain families from their own epilepsy centers, to maximize
clinical information on the cases. The Foundation has not devoted much effort to maintaining the database over the last year,
partly because the person responsible for this job left the Foundation, and her replacement did not make it a priority. Due
to the apparent lack of interest by investigators, they are evaluating whether or not to continue the project. Drs. Noebels
and Ottman strongly advised them to continue.
Top priorities for next 5-10 years:
- Continue efforts to identify families with Mendelian forms of epilepsy, clinically characterize them, and identify the genes
- Strengthen efforts to educate clinicians and patients to ensure that adequate family histories are taken and research contacts
made when they are likely to be fruitful.
- Strengthen referral networks to ensure that researchers learn about families that could be of interest
Roadblocks to progress:
- Most epileptologists are too busy to collect the detailed family history data needed for this type of study. They are uncertain
which families are of interest, and do not know whom to contact when they find potentially interesting families.
- Families with Mendelian modes of inheritance are extremely rare. We need to cast a very wide net to identify them, nationally
- Although epilepsy genetics requires input from clinicians, geneticists, and people with epilepsy, resistance to collaboration
sometimes slows progress in gene identification. This is especially true for geneticists, for whom discovery of a gene is
a major success accompanied by great recognition. Hence competition has sometimes interfered with collaboration.
- Bergmann C, Zerres K, Senderek J, et al. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation
with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 2003;126:1537-1544.
- Berkovic SF, Izzillo P, McMahon JM, et al. LGI1 mutations in temporal lobe epilepsies. Neurology 2004;62:1115-1119.
- Berkovic SF, Serratosa JM, Phillips HA, et al. Familial partial epilepsy with variable foci: clinical features and linkage
to chromosome 22q12. Epilepsia 2004;45:1054-1060.
- Chan EM, Bulman DE, Paterson AD, et al. Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22.
J Med Genet 2003;40:671-675.
- Chan EM, Young EJ, Ianzano L, et al. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet 2003;35:125-127.
- Cho YW, Motamedi GK, Laufenberg I, et al. A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental
retardation. Arch Neurol 2003;60:1625-1632.
- Claes L, Ceulemans B, Audenaert D, et al. De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy.
Hum Mutat 2003;21:615-621.
- Combi R, Dalpra L, Malcovati M, Oldani A, Tenchini ML, Ferini-Strambi L. Evidence for a fourth locus for autosomal dominant
nocturnal frontal lobe epilepsy. Brain Res Bull 2004;63:353-359.
- Coppola G, Castaldo P, Miraglia del Giudice E, et al. A novel KCNQ2 K+ channel mutation in benign neonatal convulsions and
centrotemporal spikes. Neurology 2003;61:131-134.
- de Falco FA, Striano P, de Falco A, et al. Benign adult familial myoclonic epilepsy: genetic heterogeneity and allelism with
ADCME. Neurology 2003;60:1381-1385.
- Dedek K, Fusco L, Teloy N, Steinlein OK. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense
mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res 2003;54:21-27.
- Fertig E, Lincoln A, Martinuzzi A, Mattson RH, Hisama FM. Novel LGI1 mutation in a family with autosomal dominant partial
epilepsy with auditory features. Neurology 2003;60:1687-1690.
- Foncke EM, Klein C, Koelman JH, et al. Hereditary myoclonus-dystonia associated with epilepsy. Neurology 2003;60:1988-1990.
- Fujiwara T, Sugawara T, Mazaki-Miyazaki E, et al. Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable
childhood epilepsies with frequent generalized tonic-clonic seizures. Brain 2003;126:531-546.
- Fukuma G, Oguni H, Shirasaka Y, et al. Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core
severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB). Epilepsia 2004;45:140-148.
- Greenberg DA, Cayanis E, Strug L, et al. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized
epilepsy. Am J Hum Genet 2005;76:139-146.
- Gu W, Brodtkorb E, Steinlein OK. LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures. Ann
- Gu W, Sander T, Becker T, Steinlein OK. Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy.
- Guerrini R, Moro F, Andermann E, et al. Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin
gene mutations. Ann Neurol 2003;54:30-37.
- Guerrini R, Parmeggiani L, Marini C, Brovedani P, Bonanni P. Autosomal dominant cortical myoclonus and epilepsy (ADCME) with
linkage to chromosome 2p11.1-q12.2. Adv Neurol 2005;95:273-279.
- Haug K, Warnstedt M, Alekov AK, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic
generalized epilepsies. Nat Genet 2003;33:527-532.
- Kamiya K, Kaneda M, Sugawara T, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable
epilepsy and mental decline. J Neurosci 2004;24:2690-2698.
- Leniger T, Kananura C, Hufnagel A, Bertrand S, Bertrand D, Steinlein OK. A new Chrna4 mutation with low penetrance in nocturnal
frontal lobe epilepsy. Epilepsia 2003;44:981-985.
- Leppert MF, Singh NA. Nonsyndromic seizure disorders: epilepsy and the use of the internet to advance research. Annu Rev Genomics
Hum Genet 2003;4:437-457.
- Lossin C, Rhodes TH, Desai RR, et al. Epilepsy-associated dysfunction in the voltage-gated neuronal sodium channel SCN1A.
J Neurosci 2003;23:11289-11295.
- Marini C, Harkin LA, Wallace RH, Mulley JC, Scheffer IE, Berkovic SF. Childhood absence epilepsy and febrile seizures: a family
with a GABA(A) receptor mutation. Brain 2003;126:230-240.
- McLellan A, Phillips HA, Rittey C, et al. Phenotypic comparison of two Scottish families with mutations in different genes
causing autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia 2003;44:613-617.
- Michelucci R, Poza JJ, Sofia V, et al. Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations,
and genetic heterogeneity in seven European families. Epilepsia 2003;44:1289-1297.
- Moulard B, Darcel F, Mignard D, et al. FOunder effect in patients with Unverricht-Lundborg disease on reunion island. Epilepsia
- Nabbout R, Gennaro E, Dalla Bernardina B, et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology
- Nakayama J, Hamano K, Iwasaki N, et al. Mutation analysis of the leucine-rich, glioma inactivated 1 gene (LGI1) in Japanese
febrile seizure patients. Neuropediatrics 2003;34:234-236.
- Noebels JL. The biology of epilepsy genes. Annu Rev Neurosci 2003;26:599-625.
- Ottman R, Winawer MR, Kalachikov S, et al. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology
- Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg DA. BRD2 (RING3) is a probable major susceptibility gene for
common juvenile myoclonic epilepsy. Am J Hum Genet 2003;73:261-270.
- Patterson EE, Mickelson JR, Da Y, et al. Clinical characteristics and inheritance of idiopathic epilepsy in Vizslas. J Vet
Intern Med 2003;17:319-325.
- Pizzuti A, Flex E, Di Bonaventura C, et al. Epilepsy with auditory features: a LGI1 gene mutation suggests a loss-of-function
mechanism. Ann Neurol 2003;53:396-399.
- Ranta S, Topcu M, Tegelberg S, et al. Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients
is allelic to Northern epilepsy. Hum Mutat 2004;23:300-305.
- Rozycka A, Skorupska E, Kostyrko A, Trzeciak WH. Evidence for S284L mutation of the CHRNA4 in a white family with autosomal
dominant nocturnal frontal lobe epilepsy. Epilepsia 2003;44:1113-1117.
- Saez-Hernandez L, Peral B, Sanz R, et al. Characterization of a 6p21 translocation breakpoint in a family with idiopathic
generalized epilepsy. Epilepsy Res 2003;56:155-163.
- Sander T, Windemuth C, Schulz H, et al. Exploration of a putative susceptibility locus for idiopathic generalized epilepsy
on chromosome 8p12. Epilepsia 2003;44:32-39.
- Sheen VL, Topcu M, Berkovic S, et al. Autosomal recessive form of periventricular heterotopia. Neurology 2003;60:1108-1112.
- Siddiqui A, Kerb R, Weale ME, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter
gene ABCB1. N Engl J Med 2003;348:1442-1448.
- Simpson MA, Cross H, Proukakis C, et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function
mutation of GM3 synthase. Nat Genet 2004;36:1225-1229.
- Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet 2004;36:842-849.
- Tan NC, Mulley JC, Berkovic SF. Genetic association studies in epilepsy: "the truth is out there". Epilepsia 2004;45:1429-1442.
- Weale ME, Depondt C, Macdonald SJ, et al. Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A:
implications for linkage-disequilibrium gene mapping. Am J Hum Genet 2003;73:551-565.