Idiopathic Epilepsies with a Complex Mode of Inheritance

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1 Epdlepsia, 4O(Suppl. 3):12-16, 1999 Lippincott Williams & Wilkins, Philadelphia 0 International League Against Epilepsy Idiopathic Epilepsies with a Complex Mode of Inheritance Jose M. Serratosa Epilepsy Unit, Neurology Servicd, Fundacidn Jirnknez Diaz Hospital, Madrid, Spain In the last decade, major advances have been made in the understanding of the molecular bases of simple mendelian genetic epilepsies (1). However, epilepsies following a simple mendelian pattern of inheritance are rare, and most common human genetic epilepsies (most idiopathic epilepsies) follow a complex mode of inheritance. The idiopathic epilepsies, those for which there is no detectable underlying cause other than a possible hereditary predisposition (2), account for almost 50% of all epilepsies. According to the International League Against Epilepsy (Commission on Classification and Terminology), idiopathic epilepsies are defined by agerelated onset, clinical and electroencephalographic characteristics, and a presumed genetic etiology (2). The presumed genetic etiology of the idiopathic epilepsies may be difficult to prove in many cases, making the effort necessary to map and clone the responsible genes a considerable task. Informative families containing enough affected members to be useful for linkage analysis are not common, and other methods that require a high number (in the hundreds) of affected individuals (such as nonparametric sib-pair analysis) may be necessary to map and clone the responsible genes. The main problems associated with the genetic dissection of complex traits are incomplete penetrance, phenocopies, genetic heterogeneity, bilineality due to high frequency of diseasecausing alleles, and polygenic inheritance (3). Besides the problems inherent in complex traits, genetic analysis of the epilepsies is limited by the difficulties related to the definition of affectedness in a disorder characterized by paroxysmal events. There is now evidence supporting the hypothesis that most idiopathic epilepsies are caused by the interaction of a few gene variants, which by themselves are not sufficient to cause an epilepsy phenotype (1,4). Environmental factors may also have some influence in the epilepsy phenotype. Because of the difficulties in mapping epilepsy genes responsible for common epilepsies, most mapping efforts have been directed to mapping and clon- Address correspondence and reprint requests to Dr. J. M. Serratosa at Epilepsy Unit, Neurology Service, Fundacidn Jim6nez Diaz Hospital, Avda. Reyes Catdlicos, 2E Madrid, Spain. serratosa@ jet.es ing genes responsible for epilepsies following simple mendelian inheritance. However, because of the high incidence of the idiopathic epilepsies, the characterization of the genes involved in complex epilepsies is becoming a high priority of epilepsy research. IDIOPATHIC GENERALIZED EPILEPSIES The idiopathic generalized epilepsies (IGEs) (2) for which a genetic cause is widely accepted account for 39-59% of all epilepsies (5). Juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), and epilepsy with generalized tonicxlonic seizures only (related or not to the sleep-wake cycle) are estimated to account for most of the genetically determined IGEs. According to previous reports, JME accounts for % of all epilepsies; epilepsy with generalized tonic-clonic seizures (related or not to the sleep-wake pattern), for %; CAE, for %; and JAE, for 3-7.5% of all epilepsies (6). The genetics of the common IGEs is discussed, as well as the genetic aspects of some rare syndromes that are also IGEs, although some are not included as such in the last classification, either because they were not described when the classification in use was introduced or because they constitute a heterogenous group composed of both idiopathic and cryptogenic syndromes. Childhood and juvenile absence epilepsy The genetics of CAE was first studied by Lennox (7) and by Metrakos and Metrakos (8,9). Lennox (7) found a concordance rate of 66% for the 3-Hz spike-wave pattern and an 84% concordance rate for absence seizures of the petit mal type in monozygous twins. Metrakos and Metrakos (8,9) concluded that the EEG showing a relatively good background pattern but with interspersed paroxysmal, bilaterally synchronous bursts of cycles per second spike-wave complexes was inherited as an autosomal dominant trait with age-dependent penetrance. They also observed that additional factors, environmental and genetic, interacted to precipitate the clinical seizures. Doose et al. (10) suggested that the epilepsies associated with the 3-Hz spike-wave absences were inherited through the interaction of several genes 12

2 IDIOPATHIC EPILEPSIES WITH COMPLEX INHERITANCE 13 and that the onset and course of the epilepsy may be affected by exogenous factors. More recent studies confirmed a high rate of concordance in monozygous twins for CAE and JAE (11,12). A clear pattern of inheritance is not present in the absence epilepsies, suggesting a complex mode of inheritance. In a study of a large group of families of CAE probands (13,14), we concluded that, although CAE is the most common epilepsy syndrome in family members of CAE probands, other IGE syndromes also are present. No evidence of linkage to chromosome 6p was found in a subgroup of 12 families that were studied with chromosome 6p DNA markers. Similar findings have been reported by Sander et al. (15), who excluded linkage to the human leukocyte antigen (HLA) region in chromosome 6p in 44 families ascertained through CAE or JAE probands. However, these investigators reported positive lod scores for a subgroup of 14 families in which a JME patient was present. They concluded that the putative chromosome 6p locus for JME did not contribute to a major gene effect to the expression of JAE or CAE in families ascertained through CAE or JAE patients who did not include JME patients (16). However, the JME 6p locus would confer genetic susceptibility to a broad spectrum of IGEs in the presence of affected members with JME (15). A family composed of affected members with CAE or epilepsy with generalized tonic-clonic seizures and asymptomatic individuals with bilateral synchronous high-voltage slow waves has been reported to be linked to chromosome 3p (16). CAE with tonic-clonic seizures and EEG 3- to 4-Hz spike and multispike-slow wave complexes appears to be linked to chromosome 8q24 (17), a finding previously described in families with different types of IGE (18). These findings could not be replicated by Sander et al. by using 38 multiplex families of probands with common IGE syndromes. In fact, these authors could exclude linkage to chromosome 8q24 (19). In 1977, Jeavons (20) described the syndrome of eyelid myoclonia with absence, a type of photomyoclonic epilepsy consisting of brief seizures precipitated by eye closure. Seizures are characterized by palpebral myoclonias, loss of consciousness, and upward deviation of the eyeballs with EEG 3-Hz spike-wave complexes. De- Marco (21) reported this syndrome in two monovular twins who started seizures at age 4.5 years, suggesting a genetic etiology for this syndrome. Juvenile Myoclonic Epilepsy Family studies of JME have resulted in conflicting results regarding the mode of inheritance of JME. Polygenic (22), digenic (recessive-dominant or recessiverecessive) (23), single-gene autosomal dominant (24), and recessive models (25) have been proposed. This is probably due to diverse interpretations of what, in fact, is a complex trait. There have been descriptions of individual JME families that appear to be clearly influenced by a major autosomal recessive (25) or dominant gene (26). In the families of JME patients, affected family members usually express different IGE syndromes such as CAE, JAE, or epilepsy with generalized tonic-clonic seizures only (27-30). Some asymptomatic family members show the typical 4- to 6-Hz polyspike-wave complexes in their EEGs (26,30). Initial linkage studies reported evidence of linkage to chromosome 6p by using HLA and Bf as markers (30). The clinical phenotype for this 6p epilepsy locus consisted of myoclonic seizures, generalized tonic-clonic or clonic-tonic-clonic seizures, absences, and asymptomatic individuals with diffuse 4- to 6-Hz polyspike-wave complexes. Maximal lod scores were obtained by using a recessive mode of inheritance with 60% penetrance. Subsequently, other studies reported similar findings (26,28,3 1). Linkage to chromosome 6p markers could not be reproduced by Whitehouse et al. of the London group (29). This group recently reported linkage to chromosome 15q in a study comprising 34 families containing two or more individuals with JME (32). A maximal multipoint lod score of 4.42 was obtained at a point 1.7 cm telomeric to marker D15S144. In this study, 25 of 27 sib pairs had identical haplotypes by descent in one or both chromosomes in a chromosome 15 region. Haplotype-sharing analysis allowed placing the candidate gene region in a 15.1-cM region on chromosome 15q. This region contains a gene encoding the 017 subunit of the nicotinic cholinergic receptor (CHRNA7). Interestingly, a transgenic mouse deficient in this subunit has generalized hypersynchronous 4- to 7-Hz sharp wave activity on the EEG, similar to the EEG abnormalities found in JME patients. This study also provided evidence in favor of genetic heterogeneity for JME, as two pedigrees were unlinked to chromosome 15q. However, a recent study by Sander et al. (33) provided further evidence of a JME locus in chromosome 6p. This locus would confer susceptibility to idiopathic generalized seizures in the majority of German families of JME patients. In this study, the region containing the 6p gene was proposed to lie in a 10-cM region in chromosome 6p between HLA-DQ and marker D6S1019. The recombinations used to narrow the JME gene region were deduced from families in which linkage to chromosome 6p was assumed on the basis of individual family lod scores between 0.24 and Because JME is a complex genetic disease and genetic heterogeneity is present, the use of these recombinants to narrow the JME gene region may have resulted in misleading localization. However, the proposed gene region is very close to a translocation breakpoint we found in a family with IGE (Serratosa et al., unpublished observation). These two findings favor the existence of an IGE gene close and centromeric to the HLA region in Epilepsia, Vol. 40, Suppl

3 14 J. M. SERRATOSA chromosome 6p. One explanation for the different results obtained in the analysis of JME families may well be ethnic variation of interacting polygenic effects, as Sander et al. indicated (33). In different populations the weight of the diverse genes involved in the JME phenotype is probably not the same. Thus linkage studies will yield different results in different populations (as in fact has happened). Epilepsy with generalized tonic-clonic seizures only Pure grand ma1 epilepsy may account for as much as 5-10% of all epilepsies (34). The incidence of epilepsy in close family members is 3.8%, similar to that in other IGEs with absence or myoclonic seizures (34). The epilepsy syndromes in family members suggest a close relation between epilepsy with generalized tonic-clonic seizures on awakening and other forms of IGE. There is some evidence that grand ma1 on awakening may be conditioned by the JME-1 6p locus, whereas grand ma1 unrelated to the sleep-wake cycle is not (35). Benign myoclonic epilepsy of infancy This rare condition is characterized by brief bouts of generalized myoclonic seizures occurring in normal children during the first or second year of life (36). No other seizure types are involved, although generalized tonicclonic attacks may occur later in life. EEG recordings show brief bursts of generalized spike-wave complexes during the early stages of sleep. A family history of seizures or epilepsy is noted frequently. This syndrome is included under the IGE heading in the International League Against Epilepsy classification (2) and might represent their earliest expression. Gastaut (37) suggested that benign myoclonic epilepsy in infants is probably the infantile equivalent of juvenile myoclonic epilepsy. The two syndromes would represent different expressions of IGE at different stages of brain maturation. Myoclonic-astatic epilepsy Doose (38,39) described the syndrome of epilepsy with myoclonic-astatic seizures, which accounts for only 1-2% of childhood epilepsies and involves a strong genetic predisposition. Onset is between ages l and 5 years but can be as early as during the first year. Development is normal in most cases, with no neurologic deficits. Myoclonic, astatic, myoclonic-astatic, absence, generalized tonic, and generalized tonic-clonic seizures may occur in this syndrome, but focal seizures or atypical absences do not. The EEG shows bilateral hypersynchronous discharges of irregular spike-wave and polyspikewave complexes, usually superimposed on 4- to 7-Hz background activity. Doose and Baier (40) emphasized the importance of hereditary pathogenic factors and proposed a polygenic mode of inheritance. Generalized epilepsy with febrile seizures plus A generalized epilepsy syndrome characterized by febrile seizures followed by diverse epilepsy phenotypes was recently described by Scheffer and Berkovic (41). Generalized epilepsy with febrile seizures plus was defined by these authors as febrile seizures extending beyond 6 years of age, with or without associated afebrile generalized tonic-clonic seizures, who [sic] do not have one of the recognized syndromes. The phenotype of generalized epilepsy with febrile seizures plus would comprise, according to Scheffer and Berkovic, a spectrum of clinical epilepsy phenotypes including febrile convulsions; frequent generalized tonic-clonic seizures not always associated with fever (febrile seizures plus or FS+), in some cases followed by absences (FS+ and absences), myoclonic (FS+ and myoclonic seizures), or atonic seizures (FS+ and atonic seizures), and the syndrome of myoclonic-astatic epilepsy. The inheritance of the seizure disorder seems to be complex because in only a minority of families does a gene appear to be the major gene. In these families, inheritance is consistent with an autosomal dominant mode of inheritance with incomplete penetrance. As in JME, families in which a gene acts as a major highly penetrant gene are only rarely seen. Bilineality, incomplete penetrance, and the possible influence of acquired factors suggested a complex mode of inheritance. A mutation in the pl subunit gene of the voltage-gated sodium channel (SCN1 B) has been recently described in a family with generalized epilepsy with febrile seizures plus (42). No other mutations have been found in sporadic or familial cases of generalized epilepsy or in families with febrile seizures. IDIOPATHIC PARTIAL EPILEPSIES Benign epilepsy of childhood with centrotemporal spikes and benign epilepsy of childhood with occipital spikes appear to be idiopathic partial epilepsies with a complex mode of inheritance. Bray and Wiser (439) first called the attention on the importance of genetic factors in this syndrome and the related EEG pattern. In a study of 19 patients, they reported centrotemporal spikes in 36% of the siblings and seizures in 12%. Heigbe1 et al. (45,46) found centrotemporal spikes in 34% of the siblings of patients with benign epilepsy of childhood with centrotemporal spike and seizures in 15%. The EEG pattern associated with benign epilepsy of childhood with centrotemporal spikes appears to be inherited following an autosomal dominant pattern with agedependent penetrance. An attractive hypothesis is that the gene mutation responsible for the centrotemporal spike EEG pattern is not sufficient to express the clinical phenotype of benign epilepsy of childhood with centrotemporal spikes and other gene mutations are probably needed for the full clinical picture to be expressed. How- Epilepsia, Val. 40, Suppl. 3, 1999

4 IDIOPATHIC EPILEPSIES WITH COMPLEX INHERITANCE 15 ever, nongenetic factors could also play a role because twin studies have shown low concordance rates. In a study of twins with benign epilepsy of childhood with centrotemporal spikes, Berkovic et al. (1 1) found no concordance for seizures or EEG abnormalities in monozygous pairs. Linkage to the fragile X site and to the two loci responsible for benign familial neonatal convulsions (EBN1 and EBN2) has been ruled out (47,48). The genetics of benign epilepsy of childhood with occipital spikes has been less well studied. This syndrome appears to be genetically related to benign epilepsy of childhood with centrotemporal spikes. REFERENCES 1. Berkovic SF. Genetics of epilepsy syndromes. In: Engel J Jr, Pedley TA, eds. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven, 1997: Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30: Lander E, Schork N. Genetic dissection of complex traits. Science 1994;265: Andermann E. Multifactorial inheritance of generalized and focal epilepsy. In: Anderson VE, Hauser WA, Penry JK, Sing CF, eds. Genetic basis of the epilepsies. New York: Raven Press, 1982: Hauser WA, Hesdorffer DC, eds. Epilepsy: frequency, causes and consequences. New York: Demos, Serratosa JM, Delgado-Escueta AV. Juvenile myoclonic epilepsy. In: Wyllie E, ed. The treatment of epilepsy: principles and practice. Philadelphia: Lippincott-Raven, 1992: Lennox WG. The heredity of epilepsy as told by relatives and twins. JAMA 1951 ;6: Metrakos K, Metrakos JD. Genetics of convulsive disorders I. Introduction, problems, methods, and base lines. Neurology 1960; 10: Metrakos K, Metrakos JD. Genetics of convulsive disorders 11: genetic and electroencephalographic studies in centrencephalic epilepsy. Neurology 1961;11: Doose H, Gerken T, Hortsmann T, Volzke E. Genetic factors in spike-wave absences. Epilepsia 1973;14: Berkovic SF. Howell RA, Hay DA, Hopper JL. Epilepsies in twins. In: Wolf P, ed. Epileptic seizures and syndromes. London: John Libbey, 1994: Berkovic SF. Howell RA, Hay DA, Hopper JL. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol 1998;43: Serratosa JM. GenBtica clinica y molecular de la epilepsia con ausencias en la infancia. Thesis, Universidad Autdnoma de Madrid, Serratosa JM, Delgado-Escueta AV, Liu A, et al. Exclusion of linkage between DNA markers in the juvenile myoclonic epilepsy locus of chromosome 6p and childhood absence epilepsy [Abstract]. Epilepsia 1993;34(suppl 2): Sander T, Hildman BC, Janz D, et al. The phenotypic spectrum related to the human epilepsy susceptibility gene EJMl. Ann Neurol 1995;38: Zara F, Labuda M, Garofalo PG, et al. Unusual EEG pattern linked to chromosome 3p in a family with idiopathic generalized epilepsy. Neurology 1998;s 1: Fong GCY, Shah PU, Gee M, et al. Childhood absence epilepsy with tonic-clonic seizures and EEG 3-4 Hz spike and multispikeslow wave complexes: linkage to chromosome 8q24. Am J Hum Genet 1998;63: Zara F, Bianchi A, Avanzini A, et al. Mapping of genes predis- posing to idiopathic generalized epilepsy. Hum Mol Genet 1995:4: Sander T, Kretz R, Schulz H, Sailer U, et al. Replication analysis of a putative susceptibility locus (EGI) for idiopathic generalized epilepsy on chromosome 8q24. Epilepsia 1998;39: Jeavons PM. Nosological problems of myoclonic epilepsies in childhood and adolescence. Dev Med Child Neurol 1977; 19: DeMarco P. Eyelid myoclonia with absences (EMA) in two monovular twins. Clin Electroencephalogr 1989;20: Tsuboi T, Christian W. On the genetics of primary generalized epilepsy with sporadic myoclonias of impulsive petit mal: a clinical and electroencephalographic study of 399 probands. Hum Genet : Greenberg DA, Delgado-Escueta AV, Maldonado HM, Widelitz H. Segregation analysis of juvenile myoclonic epilepsy. Genet Epidemiol 1988;5: Greenberg DA, Delgado-Escueta AV. The chromosome 6p epilepsy locus: exploring mode of inheritance and heterogeneity through linkage analysis. Epilepsia 1993;34(suppl 3): Panayiotopoulos CP, Obeid T. Juvenile myoclonic epilepsy: an autosomal recessive disease. Ann Neurol 1989;25: Serratosa JM, Delgado-Escueta AV, Medina MT, Zhang Q, Iranmanesh R, Sparkes, RS. Clinical and genetic analysis of a large pedigree with juvenile myoclonic epilepsy. Ann Neurol 1996;39: Delgado-Escueta AV, Greenberg D, Weissbecker K, et al. Gene mapping in the idiopathic generalized epilepsies: juvenile myoclonic epilepsy, childhood absence epilepsy, epilepsy with grand ma1 seizures on awakening, and early childhood myoclonic epilepsy. Epilepsia 1990;31(suppl 3): Durner M, Sander T, Greenberg DA, et al. Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology 1991 ;41: Whitehouse WP, Rees M, Curtis D, et al. Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myoclonic epilepsy: no evidence for an epilepsy locus in the HLA region. Am J Hum Genet 1993;53: Greenberg DA, Delgado-Escueta AV, Widelitz, et al. Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6. Am J Med Genet 1988;31: Weissbecker KA, Dumer M, Janz D, et al. Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6. Am J Med Genet l991;38: Elmslie FV, Rees M, Williamson MP, et al. Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. Hum Mol Genet 1997;6: Sander T, Bockenkamp B, Hildman T, et al. Refined mapping of the epilepsy susceptibility locus EJMl on chromosome 6. Neurology 1997 ;49: Janz D. Pitfalls in the diagnosis of grand ma1 on awakening. In: Wolf P, ed. Epileptic seizures and syndromes. London: John Libbey, 1994: Greenberg D, Durner M, Resor S, Rosenbaum D, Shinnar S. The genetics of idiopathic generalized epilepsies of adolescent onset: differences between juvenile myoclonic epilepsy and epilepsy with random grand ma1 and with awakening grand mal. Neurology 1995;45: Dravet C, Bureau M, Roger I. Benign myoclonic epilepsy in infants. In: Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P, eds. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbev Eurotext. 1985: Gastaut H. Individualisation des epilepsies dites binignes ou fonctionelles aux differents ages de la vie. Rev EEG Neurophysiol 1981;11: Doose H. Myoclonic astatic epilepsy of early childhood. In: Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P, eds. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey Eurotext, 1985: Doose H, Gerken H, Leonhardt R, Volzke E, Volz C. Centrencephalic myoclonic astatic petit mal. Neuropiidiatrie 1970;2: Epilepsia, Vol. 40, Suppl. 3, 1999

5 16 J. M. SERRATOSA 40. Doose H, Baier WK. Epilepsy with primarily generalized myoclonic astatic seizures: a genetically determined disease. Eur J Pediutr 1987;146: Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes. Bruin 1997;120: Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel pl subunit gene SCNlB. Nut Genet 1998;19:36& Bray FP, Wiser WC. Evidence for a genetic etiology of temporal central abnormalities in focal epilepsy. N Engl J Med 1964;271: Bray FP, Wiser WC. Hereditary characteristics of familial temporal central focal epilepsy. Pediatrics 1965;30: Heijbel J, Blom S, Rasmuson M. Benign epilepsy of childhood with centrotemporal EEG foci: a genetic study. Epilepsiu 1975;16: Blom S, Heijbel J. Benign epilepsy of childhood with centrotemporal spikes. In: Beck-Mannagetta G, Anderson VE, Doose H, Janz D, eds. Genetics of the epilepsies. Berlin: Springer-Verlag. 1989: Neubauer BA, Moises HW, Lassker U, Waltz S, Diebold U, Stephani U. Benign childhood epilepsy with centrotemporal spikes and electroencephalography trait are not linked to EBNl and EBN2 of benign neonatal familial convulsions. Epilepsiu 1997;38: Rees M, Diebold U, Parker K, Doose H, Gardiner RM, Whitehouse WP. Benign childhood epilepsy with centrotemporal spikes and the focal sharp wave trait is not linked to the fragile X region. Neuropediufrics 1993;24: Epilepsia, Vol. 40, Suppl. 3, 1999