Genetic mearch in epilepsy: The Itahan League against Epilepsy contribution

R. Canget, B. dalla Bernardina: G. Avanzini3, F. Vigevano4, C.A. TassinarP (LICE Committee) Italian League against Epilepsy (LICE) Genetic Collaborative Group Centro Epilessia, Ospedale S. Paolo, Milano Cattedra Neuropsichiatria Infantile, Verona lstituto Neurologico “C. Besta”, Milano Servizio Neuropsichiatria Infantile, Ospedale Meijer, Firenze Clinica Neurologica, Ospedale Bellaria, Bologna CollaborativeGroup: A. Bianchi (Coordinator) A. Tiezzi, G. Buzzi, C. Fani, P. Zolo (Organizer Centre) A. Antonelli, S. Binelli, D.Buti, M.P. Canevini, A. Carullo, C. Ciarmatori, G. Coppola, P. d’Alessandro, M.R. de Feo, S. di Donatok Ch. Durisotti, C.F. Roso, A. Francia, C.A. Galirnberti, R. G., P. Garofalo, P.G. Rossi, C. lani, R. Mai, M. Manfredi, N. Margiotta, R. Massetani, S. Mazza, 0. Mecarelli, A. Parrneggiani, A. Pascotto, S. Ricci, R. Rocchi, G. Romano, A. Saltarelli, M. Santucci, G. Sideri, L. Specchio, A. Tartara, C. Tiacci, G. Vatti, P. Vigliano, L. Volpi

Introduction The genetic factor plays an important role in the determination of the epileptic phenotype and it assumes a primary biological value in the idiopathic epileptic syndromes, both partial and generalized. The achievements of the recent years in the molecular genetics field have steered the research towards the location of the chromosomic site of the epileptic syndromes. The greatest difficulty in this research is the genetic heterogeneity of the epilepsy and of the epileptic seizures (1,2). Indeed the study of experimental epilepsy and of the animal genetic models show that there are several potential sites of genetic influence on the neuronal excitability threshold (3, 4). Moreover the epileptic seizure as phenotypical expression may be found in 163 diseases, with one of the

Address: R. Canger Lega ltaliana Contro d’epilessia Via A. Fogazzaro 37 20135Milano Italy

three major patterns of Mendelian inheritance (autosomal dominant, autosomal recessive and X-linked recessive): seizures can also be found in chromosomal abnormality syndromes and in pathologies with mitochondrial inheritance (5, 6 ) . An evaluation of the epileptic syndromes according to the International Classification (7) shows some forms, like West syndrome (WS), where a phenotypic homogeneity corresponds with different diseases with a different genetic locus. Also in the more homogeneous epileptic syndromes, as in Juvenile Myoclonic Epilepsy (JME) a very different phenotypic expression can be found with the presence, in addition to the myoclonic jerks on awakening, typical absences, tonic clonic seizures (GTCS) and photosensitivity (8). The first results of the molecular research and of the linkage analysis single out heterogeneity in Benign Familial Neonatal Convulsions (BFNC), the only form with a Mendelian transmission pattern of autosomal dominant type (9). The mode of inheritance is an interesting question too; the most reliable is the multifactorial mode of transmission, where one or more genes combined with environmental factors cause the disease. But this mode appears to be insufficient if we consider that familial risk is greater for the EEG pattern than for epilepsy and that the 47

R. Canger offsprings of epileptic mothers have a greater risk than those of epileptic fathers (10, 1 1). The problems raised ask for a common strategy both in clinical and in genetic research. Clinical research has to address itself towards a better definition of the epileptic phenotype. Indeed the singling out of clinical subforms within the epileptic syndromes, as for example, the idiopathic West syndrome within the West syndrome, may permit the definition of more homogeneous epileptic forms in regard to clinical signs, prognosis and inheritance. Such a seizure disorder may represent more reliable phenotypic models for molecular genetic studies. In the effort to define homogeneous clinical subforms a great contribution may be made by the clinical genetic studies on twins, on families and on EEG patterns. The genetic strategy for the singling out of the chromosomal locus of epilepsy should not neglect the traditional cytogenetic methods, both with the study of greater chromosomal abnormalities, where association with specific genetic EEG patterns have been observed (12, 13), and the new cytogenetic techniques which allow the characterization of micro duplications and micro deletions (14). And lastly, it is important to carry on the molecular genetic study by linkage analysis that recently permitted the individuation of a linkage between JME and the short arm (region p21.3) of Chromosome 6 (15-17), a linkage between BFNC and the long arm Chromosome 20 (18) and the location of a gene responsible for the Progressive myoclonic epilepsy of Unverricht-Lundborg, on Chromosome 21 (region q22.3) (19).

Italian Multicentric Study on Genetic Epilepsy The Italian League Against Epilepsy (LICE) decided to take part in the study on the genetics of the epilepsies in a collaborative project that, at the moment, involves 20 Italian Centres (20, 21). Our multicentre study, started in 1989, gave the opportunity of creating of a Data-bank (Epilepsy Centre of Arezzo) of families with more than one case of genetic epilepsy. The biological material of all the members of the families singled out, is stored in a DNA-bank (Besta Institute, Milan). The study provides the collection of families containing three or more members affected by genetic epilepsy, either with the same form or with associated ones. Eligible families are those with at least three probands in three or two generations, or families with two probands if a third member has a genetic EEG pattern or families with two probands if a Mendelian genetic non neurological disease is associated with the genetic epilepsy. The eligible forms of epilepsy are: BFNC; Febrile Convulsions (FC); Childhood Absence Epilepsy (CAE); 48

Juvenile Absence Epilepsy (JAE); JME; Epilepsy with Tonic Clinic seizures (ETCS); Benign Childhood Epilepsy with Centro-Temperal Spike (BCECTS). The design of the study provides a homogeneous standard for the clinical and EEG evaluation of the family members. The clinical and EEG diagnosis of every family member is verified by an ‘ad hoc’ committee and discussed in special meetings of the LICE. Every form has been classified according to the International Classification of the Epileptic syndromes (7) with the exception of the ETCS, where it has been considered, along with the forms with Tonic Clonic Seizures on awakening, and the idiopathic forms with sleep and with random Tonic Clonis Seizures (22). Specific attention has been given to the diagnosis of epilepsy with cases of TCS: particularly to the age of onset in order to exclude the cases with BCECTS, to the presence in childhood of Absence seizures and thereafter of TCS (diagnosed as CAE) and to the presence of myoclonic jerks on awakening in addition to TCS (diagnosed as JME). Every member, affected or not, had a routine EEG recording with specific activations (hyperventilation, intermittent photic stimulation). At present 25 families have their biological material deposited in the DNA-bank; the pedigrees of 74 families are in the Data-bank.

Molecular genetics studies A collaborative study with the Epilepsy Centre and the Genetics Institute of Berlin (Proffessor Janz and Dr Sander) was started in order to examine by linkage analysis families with cases of CAE. The biological material of every family with at least one case of CAE in the Italian DNA-bank has been sent to the German centre. The study is in progress and, at present, the results have not yet been published.

Study on the concordance of clinical forms in the samefamily A correct definition of the phenotype with epilepsy and of the individualization of clinically homogeneous subforms in the genetic research is vitally important. A contribution to this problem may come from the analysis of concordance of clinical forms among the affected cases in the same family. In our clinical study (23,24) every family with at least three members affected by an idiopathic form of epilepsy, in one or more generations, was evaluated. In total 74 families, with 295 affected members (148 males, 147 females) have been analyzed. The mean number of affected people in each family was 4 (range 310). The most represented clinical forms were FC (34.5%) and the ETCS (28%)

Genetic Research in Epilepsy Table I.

StudyGeneralData.

Familiesno.74 Affected

Total:295 (m=148;f=147) Forfamily mean:4 (3-10)

No

Phenotype

- Febrileconvulsions: - Benignchildhoodepilepsy -

-

101

(34.5%)

14 49 20 a2

(4.7%) (16.6%) (6.7%) (27.a~~) (2.7%) (3.0%) (4.0%)

wbcentretemporalspike: Childhoodabsenceepilepsy: Juvenilemyoclonicepilepsy: Epilepsywlhtonicclonicseizures: Wleridiopahicepilepsies: Parhalsymptomakxpilepsy: Benignneonatalfmilialconculsion:

a 9 12

The group ‘Other Idiopathic Epilepsies’ (8 cases) comprised: Childhood epilepsy with occipital paroxysms (N=l), Benign myoclonic epilepsy in infancy (N=2); Juvenile Absence Epilepsy (N=3), Idiopathic West syndrome (N= 1) and Epilepsy with myoclonic-astatic seizures (N=l). Two families with BNFC were considered separately because of its Mendelian inheritance: one family had one member with ETCS and the other had one case with BCECTS. In 25% of the remaining 72 families there was only one clinical form of epilepsy among the affected members (9 families with FC, 3 with CAE, 2 with JME and 4 with ETCS); 14% of the families had a prevalent clinical form, i.e. only one member had a different seizure type (3 FC, 1 BCECTS, 2 CAE, 1 JME, 3 ETCS); 36% had two clinical forms and as much as 25% of the families had three types of epilepsy. Table II.

Theconcordanceof theclinicalform of epilepsyamongtheaffectedmembers inthefamily.

Familieswithoneclinicalform: Febrilewnvulsions: Childhoodabsenceepilepsy: Juvenilemyoclonicepilepsy: Epilepsywlhtonicclonicseizures: FamilieswiVloneprevailingform: Febiileconwlsims: Benignchildhoodepilepsy wbcenb-o-temporal spike: Childhoodabsenceepilepsy: Juvenilemyoclonicepilepsy: Epilepsywlhtonicclonicseizures: 3

1a (25.0%) 9 3 2 4 10(13.9%) 3 1 2 1

The analysis of concordance of clinical form in the relatives of probands with FC, BCECTS, CAE, JME and ETCS allowed some observations. There is concordance for the same clinical form and for the prevalent clinical form only in 39% of the families with three or more cases of idiopathic epilepsy, while 6 1 % have two or three forms in the same family. We have not found complete concordance in either of the two families with BFNC. Our study showed a high representation (respectively 35% and 39%) of ETCS in affected parents of probands with CAE and JME, but we found a rare association between CAE and JME, as opposed to findings in literature (25-27). FC and ETCS are the forms more diffusely represented in our families and they seem to manifest themselves with a common phenotypic expression. Nevertheless this trend is more evident in the affected second degree relatives, while in the first degree relatives (siblings, parents) we have found a high concordance either for FC or for ETCS. Moreover we have 12 families only withcases of FC and 7 families with only ETCS. Also in CAE and JME there is, at least in the first degree relatives a high concordance and the presence of the same clinical form in 4 families with CAE and in 3 families with JME. The low number of cases of BCECTS (7 families) does not allow specific observations except for the high presence of FC (44.5%) in the affected members of the families. We may therefore hypothesize that there are genetically transmitted clinically homogeneous subforms and other subforms that may be associated with different epileptic syndromes. At present there is no evidence that these different expressions corresponds with the clinical differentiation of the various syndromes. It is noteworthy also that the higher level of clinical concordance is found in the target family with first degree relatives and tends to assume a different phenotypic expression in the other relatives. Future developments in research In order to complete these first clinical results, we started a study on clinical concordance in epileptic twins. The aim of this study is to give a contribution to the clinical evaluation of the different epileptic syndromes in the affected twins in order to individuate homogeneous syndromic subforms in idiopathic epilepsy (CAE, JME, ETCS) and the possible identification of new forms of idiopathic epilepsy.

Familieswbtwoclinicalforms: Familieswiththreeclinicalforms: 72(100%) FamilieswthBenignneonatalfamilialconvulsions:

2

49

R. Canger References. 1.

2. 3. 4.

5. 6.

7.

8.

9.

10.

I I. 12.

13.

14. 15.

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Anderson VE. Hauser WA. Rich SS. Genetic heterogeneity in the epilepsies. In: Delgado-Escueta AV et al. eds. Basis mechanisms of the epilepsies: molecular and cellular approaches. (Advances in Neurol) New York Raven Press 1944: 44: 59-74. Bird TD. Genetic considerations in childhood epilepsy. Epilepsia 1987: 28 (suppl I): S71-81. Seyfried TN. Glaser GH. A review of mouse mutants as genetic models of Epilepsy. Epilepsia 1985: 26: 143.50. Dichtrr MA. Cellular mechanism of epilepsy and potential new treatment strategies. Epilepsia 1989: 30: S3- I?. McKusick VA ed. Mendelian Inheritance in Man. 8th edn. Baltimore. Johns Hopkins University Press: 1988. Anderson VE, Hauser WA, Olafsson E, Rich SS. Genetic aspects of the epilepsies. In: Sillanpaa M et al. eds. Paediatric Epilepsy. Wrightson Biomedical Pub1 Lts. 1990: 37-56. Commission on Classification and Terminology of the ILAE. Proposal for revised classification of Epilepsies and Epileptic Syndromes. Epilepsia 1989: 30 (4): 389-99. Janz D. Juvenile Myoclonic Epilepsy. In: Dam M et al. eds. Comprehensive Epileptology. New York Raven Press 1990: 17185. Ryan SG. Wiznitzer M, Hollman G. Torres MC. Szekeresova M. Schneider S. Benign Familial Neonatal Convulsions: evidence for clinical and genetic heterogeneity. Ann Neurol 1991: 29: 469-73. Tsuboi T. Christian W. Epilepsy. A clinical. EEG and statistical study of 446 patients. Neurol Series. Springer. Berlin Heidelberg. 1976. Blandfort M. Tsuboi T. Vogel F. Genetic counseling in the epilepsies. Hum Genet 1987: 76: 303-31. Musumeci SN. Colognola RM, Fem R et al. Fragile-X syndrome: a particular epileptogenic EEG pattern. Epilepsia 1988: 29: 41-7. Guemni R, Bureau M. Mattei MG. Battaglia A. Galland MC. Roger J. Trisomy I2p Syndrome: A chromosomal disorder associated with generalized 3-Hz spike and wave discharges. Epilepsia 1990: 3 1 (5): 557-66. Leppert MF. Gene mapping and other tools for discovery. Epilepsia 1990: 31 (SUPPI3): SI 1-8. Greenberg DA, Delgado-Escueta AV. Widelitz H et al. Juvenile myoclonic epilepsy (JME) may be linked to the Bf and HLA loci on human chromosome 6. Am J Med genet 1988: 3 1 : 185-92.

16. Delgado-Escueta AV, Greenbeg DA, Treiman Let al. Mapping the gene for Juvenile Myoclonic Epilepsy. Epilepsia 1989: 30 (Suppl4): S8- 18. 17. Weissbecker KA, Durner M, Janz D, Scaramelli A, Sparkas RS, Spencer MA. Confirmation of linkage between Juvenile Myoclonic Epilepsy locus and the HLA region of chromosome 6. Am J Med Genet 1991: 38: 32-6. 18. Leppert M, Anderson VE, Quattlebaum T et al. Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature 1989: 337: 647-8. 19. Lehesjoki AE. Koskiniemi M, Sistonen Pet al. Localization ofagene for progessive myoclonus epilepsy to chromosome 2 lq22. Proc Natl Acad Sci USA 1991: 88: 3696-9. 20. Bianchi A. Studio multicentrico italiano sulk epilessie genetiche. Boll Lega It Epil 1989: 66/67: 17-21. 21. Bianchi A. Fani C and LICE collaborative group. Italian Multicentric study on genetic epilepsies. Epilepsia 1990: 31 (6): 8 13-4. 12. Wolf P. Epilepsy with grand ma1 on awakening. In: RogerJet al. eds. Epileptic syndromes in infancy. childhood and adolescence, London. Pans: John Libbey Eurotext 1985: 259-71. 13. Bianchi A. Tiezzi A. Fani C. Buzzi G et al. Concordance of clinical forms in families with several members of Idiopathic Epilepsies. Epilepsia 1991: 3 3 1 ) : 63. 21. Italian League against Epilepsy genetic collaborative group. The concordance of clinical forms of epilepsy in families with several affected members. Epilepsia (in press). 3. Janz D. Durner M. Beck-Mannagetta G. Pantazis G . Family studies o n the genetics of Juvenile Myoclonic Epilepsy. (Epilepsy with Impulsive Petit Mal). In: Beck-Mannagettd G et al. eds. Genetic of the epilepsies. Berlin Heidelberg, New York Springer Verlag 1989: 43-66. 16. Jan7 D. Beck-Mannagetta G. Syndrome idiopathischer generalisierter Epilepsien Unierschiede und Gemeinsamkeiten. Epilepsie-Blatter 1990: 3: 63-9. 17. Delgado-Escueta AV. Greenberg DA. Weissbecker KA et al. Gene mapping in the Idiopathic Generalized Epilepsies: Juvenile Myoclonic Epilepsy. Childhood Absence Epilepsy, Epilepsy with Grand Ma1 Seizures and Early Childhood Myoclonic Epilepsy. Epilepsia 1990: 31 (Suppl 3): S19-19.

Genetic research in epilepsy: the Italian League against Epilepsy contribution.

Genetic mearch in epilepsy: The Itahan League against Epilepsy contribution R. Canget, B. dalla Bernardina: G. Avanzini3, F. Vigevano4, C.A. Tassinar...
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