Epilepsiu, 33(5): 8 14-8 16, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy
Possible Association of Juvenile Myoclonic Epilepsy with HLA-DRw6 *?Martha Durner, ?Dieter Janz, $Juergen Zingsem, and "David A. Greenberg *Department of Psychiatry, Mount Sinai Medical Center, New York, New York, {J.S.A.; %Department of Neurology, and SBIuthank, Klinikum Rudolf Virchow, Free University of Berlin, Berlin, Germany
Summary: Juvenile myoclonic epilepsy (JME) is a clearly defined subform of idiopathic generalized epilepsy with a high aggregation of epilepsy in family members. With the HLA-system used as a genetic marker, a linkage between JME and the HLA region was demonstrated. Linkage with the HLA region suggests that JME may be associated with an HLA-antigen. An association could indicate that the gene lies in the HLA region and is in linkage disequilibrium with one of the HLA-antigens. Eightyeight unrelated patients with JME were typed for the
HLA-A and HLA-B locus, 77 were typed for the HLA-C locus, and 76 were typed for the DR locus. The antigen frequency was compared with those of healthy blood donors. The highest difference was noted in the frequency of DRw6 (39.5% in patients vs. 22.1% in controls). This weak association is open to question because DRw6 is known to split into DRwl3 and DRw14. Key Words: Juvenile myoclonic epilepsy-Genetics-HLA antigensHLA-DRw6 antigen.
Juvenile myoclonic epilepsy (JME) is a common form of idiopathic generalized epilepsy, comprising -8% of all epilepsies (Janz et al., 1989). It is clearly distinguishable from other forms of epilepsy by the symptoms of sudden, consciously experienced, short bilateral myoclonic jerks of the upper limbs, appearing mainly in the morning after awakening. During these jerks, the EEG shows polyspike and waves. Most patients also have generalized tonicclonic seizures (GTCS), and one third also have absence seizures (Janz et al., 1989). These clear clinical features, a lack of obvious exogenous factors (Janz, 1969), and a high genetic predisposition (Tsuboi and Christian, 1973; Janz, 1985) make this subform of epilepsy ideal for genetic studies. JME has been shown to be linked to the HLA region on chromosome 6 (Greenberg et al., 1988, 1989; Durner et al., 1991; Weissbecker et al., 1991). Linkage is a phenomenon observed in families and is defined by the cosegregation of two genes, in this case the HLA gene and the disease gene. Association, on the other hand, is a phenomenon observed at the population level. A disease or trait is said to
be associated with a marker when that marker is observed more often in the population with the trait than in the general population. An association can exist without evidence of linkage. Because JME is linked to the HLA region of chromosome 6, association of JME with an allele of the HLA locus might provide a clue to the locus of JME in relation to other HLA loci. We examined the evidence for an association of JME with an allele of the HLA complex.
PATIENTS AND METHODS Eighty-eight unrelated patients with JME were tested for the HLA-A and HLA-B locus, 77 patients were tested for the HLA-G locus, and 76 were tested for the DR locus. For typing, the microlymphotoxicity test of the technique of the NationaI Institutes of Health (NIH) was used. Antigens tested were (Antigens in parentheses indicate a subsplit of the previous antigen): A locus: 1, 2, 3, 9 (23,24), 10 (25,26,34), 11, 19 (29,30,31,32,33), 28 (68,69), 36, 43, 66 B locus: 5 (51,52), 7, 8, 12 (44,45), 13, 14 (64,65), 15 (62,63), 16 (38,39), 17 (57,58), 18,21 (49,50), 22 (54,55,56), 27, 35, 37, 40 (60,61), 41, 42, 46, 47, 48, 53, 59, 67, 70 (71,72), 73 C locus: 1, 2, 3, 4, 5, 6, 7, 8 DRlocus: 1, 2, 3, 4, 5 (11,12), 6, 7, 8, 9, 10
Received August 1991; revision accepted April 1992. Address correspondence and reprint requests to Dr. M. Durner at Department of Psychiatry, Mount Sinai Medical Center, Box 1229, One Custave L. Levy Place, New York, NY 10029, U.S.A.
814
815
HLA - D Rw ~ASSOCIATION WITH JME
All HLA typing was performed by the Bloodbank of the Klinikum Rudolf Virchow, Free University of Berlin (Professor Dr. R. Eckstein, Director). The allele frequencies of healthy blood donors of the Bloodbank were used as controls.
between patients and controls was observed with DRw6. Of 76 patients, 30 (39.47%) as compared with 166 of 750 controls (22.13%) expressed the DRw6 antigen, for a chi-square value of 11.47, corresponding to p = 0.00035 before correction and pc = 0.028 after correction.
Statistical methods The phenotypic antigen frequencies were compared between patients and controls by chi-square test. Fisher’s exact test was used for rare antigens. We tested for 75 antigens (+ four times blank), which led to 79 separate tests. We corrected the p-value for multiple tests by multiplying by the numbers of tests performed, according to the Bonferroni inequality method (pc).
DISCUSSION The linkage studies showed that a gene for JME is close to the HLA region but did not indicate whether this gene is centromeric (proximal toward the centromer), telomeric (distal of HLA), or within the HLA region. There was no clear evidence for a recombination in the HLA-haplotype. The HLA region is an area where a strong linkage disequilibrium exists. (Linkage disequilibrium is a phenomenon whereby alleles at neighboring loci on the same chromosome occur more often in common than is expected.) Therefore, an association could be explained by the disease gene being in linkage disequilibrium with a specific antigen. Diseases that have been mapped to areas in the HLA region have demonstrated a very strong association with some HLA alleles. Congenital adrenal hyperplasia resulting from 2 1-hydroxylase deficiency is strongly associated with HLA-BW47. The frequency of HLA-A3 and, to a lesser degree, of HLA-B7 and HLA-B14 is greatly increased in patients with idiopathic hemochromatosis (Tiwari and Terasaki, 1985). This weak association between JME and HLA-DRw6 may indicate that the gene for JME is close to the HLA area, but not directly in it. It is unfortunate that the suggested association of DRw6 with JME is open to question. DRw6 is known to split into DRwl3 and DRw14, indicating that some serologic similarities exist between those
RESULTS The comparison showed no chi-square value of phenotypic antigen frequencies >2.4 with any allele of the HLA-A and HLA-C locus. Of the HLA-B alleles, only Bw62 was observed slightly more frequently in patients (15 of 88 = 17.1%) than in controls (100 of 974 = 10.3%). The calculated chisquare value was 3.84, and the p-value was not significant after correction. At the DR locus (Table l), DR9 occurred more often in patients (6.0 vs. 2.5%) than did DRwll (22.4 vs. 9.3%). DR5 is known to split into DRll and DR12. Of the DR5+ controls, 15% could not be assigned to either DRwl1 or DRwl2. In contrast, all DR5 patients could be typed unambiguously for DR11 or DR12. Therefore, we used the reference numbers of the IXth histocompatibility workshop (Baur et al., 1984). The observed frequency of DRwll was 23.1%, which is similar to the frequency in JME patients. The greatest difference in the antigen frequencies +
TABLE 1. HLA-DR frequencies in patients with JME and controls HLA-DR DR-0 DR-1 DR-2 DR-3 DR-4 DR-5 DR-6 DR-7 DR-8 DR-9 DR-10 DR-11 DR-12
Absolute frequencies ______ Patients Controls 9 18 22 14 14 0 30 15 4 5 1
17 3
123 155 24 1 170 162 113 166 171 58 19 9 70 36
Relative frequencies Patients
Controls
Chi-square
pc-Value
11.8 23.7 29.0 18.4 18.4 0.0 39.5 19.7 5.3 6.6 1.3 22.4 4.0
16.4 20.7 32.1 22.7 21.6 15.1 22.1 22.8 7.7 2.5 1.2 9.3 4.8
1.07 0.38 0.32 0.72 0.42 -a 11.47 0.37 0.61 4.00 0.00 -a -n
NS NS NS NS NS 0.03 NS NS NS NS
JME, juvenile myoclonic epilepsy. Described in text. Epilepsia, Vol. 33, No. 5 , 1992
M . DURNER ET AL.
816
two more recently defined antigens. In any case, two genetically different alleles code for DRwl3 and DRwl4. Because we cannot determine whether patients with DRw6 are positive for DRwl3 or DRwl4, we cannot rule out the possibility of a stronger association with one of the two antigens. On the other hand, this increase in DRw6 frequency may result from a slight (but not significant) increase in both antigens. Further studies are needed with special emphasis on typing for DRwl3 and DRw14 to solve this problem. Molecular techniques may help differentiate these two splits. By concentrating on these specific antigens, we can drastically reduce the problem of multiple testing. These studies should also include antigens from the DP or DQ locus because an association with one of the antigens from these loci also is still possible. Acknowledgment: This study was supported by grants from the Deutsche Forschungsgemeinschaft a n d NIH Grant No. NS27941.
REFERENCES Baur MP, Neugebauer M, Deppe H , et al. Population analysis on the basis of deduced haplotypes from random families. In: Albert ED, Baur MP, Mayr WR, eds. Histocompatihility testing 1984. Berlin: Springer, 1984:333-41. Durner M, Sander T, Greenberg DA, et al. Localisation of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology 1991;41: 16.51-5. 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;31: 18592. Greenberg DA, Delgado-Escueta A V , Widelitz H , et al. Strengthened evidence for linkage of juvenile myoclonic epilepsy to HLA and BF. Abstracts of the Xth International Human Gene Mapping Workshop. Cytogenet Cell Genet 1989;51:1008. Janz D. Die Epilepsien. Spezielle Pathologie und Therapie. Stuttgart: Thieme, 1969. lanz D. Epilepsy with impulsive petit ma1 (juvenile myoclonic epilepsy). Acta Neurol Scand 1985;72:449-59. lanz D, Durner M, Beck-Mannagetta G, et al. Family studies on the genetics of juvenile myoclonic epilepsy. In: BeckMannagetta G , Anderson VE, Doose H , Janz D, eds. Genetics of the epilepsies. New York: Raven Press, 1989:43-52. ’iwari JL, Terasaki PI, eds. HLA and disease associations. New York: Springer, 1985. ’suboi T, Christian W. On the genetics of primary generalized epilepsy with sporadic rnyoclonias of impulsive petit ma1 type. Humangenetik 1973;19:155-82. Veissbecker K, Durner M, Janz D, et al. Confirmation of linkage between a juvenile myoclonic epilepsy-locus and the HLA region of chromosome 6. Am J Med Genet 1991;38:32-6.
ilepsia, Voi. 33, No. 5 , 1992
aSUME L‘Cpilepsie myoclonique juvenile (EMJ) est une forme cliniquement bien dkfinie d’epilepsie generalisee idiopathique, dans laquelle il existe une agregation importante de cas d’epilepsie dans les familles. En utilisant le systeme HLA comrne marqueur gCnktique, il a 6t6 dCmontrC une liaison entre 1’EM.l et la region HLA. Cette liaison suggere qu’il peut y avoir une association entre I’EMJ et un des antigenes HLA. Une telle association pourrait indiquer que le gene est situe dans la region HLA et qu’il est en dCsCquilibre de liaison avec I’un des antigenes du systeme HLA. Quatre vingt-huit patients, sans lien de parente, prtsentant une EMJ ont benCficiC d’un typage des locus HLA A et B, 77 du locus C et 76 du locus DR. La frCquence des antigenes etait comparke a celle observee chez des donneurs de sang sains. La difference la plus importante a Ctt constatee dans la frkquence du groupe DRw6 (39.5% des patients contre 22.1% des contr6les). Cette association faible peut &re remise en cause, car I’on sait que DRw6 peut &re sCparC en DRwl3 et DRwl4. (P. Genton, Mur.seille)
RESUMEN La Epilepsia Mioclonica Juvenil (JME) se define como una subforma de epilepsia idiopatica generdlizada con una elevada agregacion de epilepsia en la familia. Utilizando el sistema HLA como marcador genetic0 se ha demostrado un acoplamiento entre la JME y la region del HLA. Este acoplamiento sugiere que puede existir una asociacion entre la JME y el antigen0 HLA. Esta asociacibn podria indicar que el gene se asienta en la region del HLA y est&en acoplamiento en desequilibrio con uno de 10s antigenos HLA. En 88 pacientes no relacionados entre si con la JME se han tipificado el HLA-A y el locus-9, en 77, el locus-C y en 76, el locus-DR. Se ha comparado la frecuencia de antigenos con la obtenida en donantes de sangre normales. La diferencid mas elevada aparecio en la frecuencia del DRw6 (39.5% en 10s enfermos y 22.1% en 10s controles). Esta dCbil asociacion es cuestionable porque se sabe que el DRw6 se divide en DRw 13 y DRwl4. (A. Porterd-Sinchez, Mudrid)
ZUSAMMENFASSUNG Juvenile Myoclonische Epilepsie (JME) oder Epilepsie mit Impulsiv Petit ma1 (IPM) ist eine klar definierte Unterform idiopathisch gneralisierter Epilepsie mit einer hohen familiaeren Haeufung. Mit Hilfe des IILA-Systems als genetischen Marker konnte eine Kopplung zwischen JME und der HLA-Region nachgewiesen werden. Eine Kopplung mit der HLA-Region legt die Moeglichkeit einer Assoziation von JME mit einem HLAAntigen nahe. Eine Assoziation koennte einen Hinweis dafuer geben, dass das Gen sich in der HLA-Region befindet und im Kopplungsungleichgewicht mit einem der HLA-Antigene ist. Acht-und-achtzig unverwandte Patienten mit JME wurden fuer den HLA-A und B-locus typisiert, 77 fuer den C-locus, und 76 fuer den DR-locus. Die Antigenhaeufigkeit wurde mit der von gesunden Blutspendern verglichen. Der groesste Unterschied fand sich in der Haeufigkeit von DRw6 (39.5% in Patienten vs. 22.1% in Kontrollen). Diese schwache Assoziation ist nicht ganz eindeutig, da bekannt ist, dass DRw6 sich in DRwl3 und DRw14 aufsplittet. (Translation supplied b y authors)
Possible Association of Juvenile Myoclonic Epilepsy with HLA-DRw6 *?Martha Durner, ?Dieter Janz, $Juergen Zingsem, and "David A. Greenberg *Department of Psychiatry, Mount Sinai Medical Center, New York, New York, {J.S.A.; %Department of Neurology, and SBIuthank, Klinikum Rudolf Virchow, Free University of Berlin, Berlin, Germany
Summary: Juvenile myoclonic epilepsy (JME) is a clearly defined subform of idiopathic generalized epilepsy with a high aggregation of epilepsy in family members. With the HLA-system used as a genetic marker, a linkage between JME and the HLA region was demonstrated. Linkage with the HLA region suggests that JME may be associated with an HLA-antigen. An association could indicate that the gene lies in the HLA region and is in linkage disequilibrium with one of the HLA-antigens. Eightyeight unrelated patients with JME were typed for the
HLA-A and HLA-B locus, 77 were typed for the HLA-C locus, and 76 were typed for the DR locus. The antigen frequency was compared with those of healthy blood donors. The highest difference was noted in the frequency of DRw6 (39.5% in patients vs. 22.1% in controls). This weak association is open to question because DRw6 is known to split into DRwl3 and DRw14. Key Words: Juvenile myoclonic epilepsy-Genetics-HLA antigensHLA-DRw6 antigen.
Juvenile myoclonic epilepsy (JME) is a common form of idiopathic generalized epilepsy, comprising -8% of all epilepsies (Janz et al., 1989). It is clearly distinguishable from other forms of epilepsy by the symptoms of sudden, consciously experienced, short bilateral myoclonic jerks of the upper limbs, appearing mainly in the morning after awakening. During these jerks, the EEG shows polyspike and waves. Most patients also have generalized tonicclonic seizures (GTCS), and one third also have absence seizures (Janz et al., 1989). These clear clinical features, a lack of obvious exogenous factors (Janz, 1969), and a high genetic predisposition (Tsuboi and Christian, 1973; Janz, 1985) make this subform of epilepsy ideal for genetic studies. JME has been shown to be linked to the HLA region on chromosome 6 (Greenberg et al., 1988, 1989; Durner et al., 1991; Weissbecker et al., 1991). Linkage is a phenomenon observed in families and is defined by the cosegregation of two genes, in this case the HLA gene and the disease gene. Association, on the other hand, is a phenomenon observed at the population level. A disease or trait is said to
be associated with a marker when that marker is observed more often in the population with the trait than in the general population. An association can exist without evidence of linkage. Because JME is linked to the HLA region of chromosome 6, association of JME with an allele of the HLA locus might provide a clue to the locus of JME in relation to other HLA loci. We examined the evidence for an association of JME with an allele of the HLA complex.
PATIENTS AND METHODS Eighty-eight unrelated patients with JME were tested for the HLA-A and HLA-B locus, 77 patients were tested for the HLA-G locus, and 76 were tested for the DR locus. For typing, the microlymphotoxicity test of the technique of the NationaI Institutes of Health (NIH) was used. Antigens tested were (Antigens in parentheses indicate a subsplit of the previous antigen): A locus: 1, 2, 3, 9 (23,24), 10 (25,26,34), 11, 19 (29,30,31,32,33), 28 (68,69), 36, 43, 66 B locus: 5 (51,52), 7, 8, 12 (44,45), 13, 14 (64,65), 15 (62,63), 16 (38,39), 17 (57,58), 18,21 (49,50), 22 (54,55,56), 27, 35, 37, 40 (60,61), 41, 42, 46, 47, 48, 53, 59, 67, 70 (71,72), 73 C locus: 1, 2, 3, 4, 5, 6, 7, 8 DRlocus: 1, 2, 3, 4, 5 (11,12), 6, 7, 8, 9, 10
Received August 1991; revision accepted April 1992. Address correspondence and reprint requests to Dr. M. Durner at Department of Psychiatry, Mount Sinai Medical Center, Box 1229, One Custave L. Levy Place, New York, NY 10029, U.S.A.
814
815
HLA - D Rw ~ASSOCIATION WITH JME
All HLA typing was performed by the Bloodbank of the Klinikum Rudolf Virchow, Free University of Berlin (Professor Dr. R. Eckstein, Director). The allele frequencies of healthy blood donors of the Bloodbank were used as controls.
between patients and controls was observed with DRw6. Of 76 patients, 30 (39.47%) as compared with 166 of 750 controls (22.13%) expressed the DRw6 antigen, for a chi-square value of 11.47, corresponding to p = 0.00035 before correction and pc = 0.028 after correction.
Statistical methods The phenotypic antigen frequencies were compared between patients and controls by chi-square test. Fisher’s exact test was used for rare antigens. We tested for 75 antigens (+ four times blank), which led to 79 separate tests. We corrected the p-value for multiple tests by multiplying by the numbers of tests performed, according to the Bonferroni inequality method (pc).
DISCUSSION The linkage studies showed that a gene for JME is close to the HLA region but did not indicate whether this gene is centromeric (proximal toward the centromer), telomeric (distal of HLA), or within the HLA region. There was no clear evidence for a recombination in the HLA-haplotype. The HLA region is an area where a strong linkage disequilibrium exists. (Linkage disequilibrium is a phenomenon whereby alleles at neighboring loci on the same chromosome occur more often in common than is expected.) Therefore, an association could be explained by the disease gene being in linkage disequilibrium with a specific antigen. Diseases that have been mapped to areas in the HLA region have demonstrated a very strong association with some HLA alleles. Congenital adrenal hyperplasia resulting from 2 1-hydroxylase deficiency is strongly associated with HLA-BW47. The frequency of HLA-A3 and, to a lesser degree, of HLA-B7 and HLA-B14 is greatly increased in patients with idiopathic hemochromatosis (Tiwari and Terasaki, 1985). This weak association between JME and HLA-DRw6 may indicate that the gene for JME is close to the HLA area, but not directly in it. It is unfortunate that the suggested association of DRw6 with JME is open to question. DRw6 is known to split into DRwl3 and DRw14, indicating that some serologic similarities exist between those
RESULTS The comparison showed no chi-square value of phenotypic antigen frequencies >2.4 with any allele of the HLA-A and HLA-C locus. Of the HLA-B alleles, only Bw62 was observed slightly more frequently in patients (15 of 88 = 17.1%) than in controls (100 of 974 = 10.3%). The calculated chisquare value was 3.84, and the p-value was not significant after correction. At the DR locus (Table l), DR9 occurred more often in patients (6.0 vs. 2.5%) than did DRwll (22.4 vs. 9.3%). DR5 is known to split into DRll and DR12. Of the DR5+ controls, 15% could not be assigned to either DRwl1 or DRwl2. In contrast, all DR5 patients could be typed unambiguously for DR11 or DR12. Therefore, we used the reference numbers of the IXth histocompatibility workshop (Baur et al., 1984). The observed frequency of DRwll was 23.1%, which is similar to the frequency in JME patients. The greatest difference in the antigen frequencies +
TABLE 1. HLA-DR frequencies in patients with JME and controls HLA-DR DR-0 DR-1 DR-2 DR-3 DR-4 DR-5 DR-6 DR-7 DR-8 DR-9 DR-10 DR-11 DR-12
Absolute frequencies ______ Patients Controls 9 18 22 14 14 0 30 15 4 5 1
17 3
123 155 24 1 170 162 113 166 171 58 19 9 70 36
Relative frequencies Patients
Controls
Chi-square
pc-Value
11.8 23.7 29.0 18.4 18.4 0.0 39.5 19.7 5.3 6.6 1.3 22.4 4.0
16.4 20.7 32.1 22.7 21.6 15.1 22.1 22.8 7.7 2.5 1.2 9.3 4.8
1.07 0.38 0.32 0.72 0.42 -a 11.47 0.37 0.61 4.00 0.00 -a -n
NS NS NS NS NS 0.03 NS NS NS NS
JME, juvenile myoclonic epilepsy. Described in text. Epilepsia, Vol. 33, No. 5 , 1992
M . DURNER ET AL.
816
two more recently defined antigens. In any case, two genetically different alleles code for DRwl3 and DRwl4. Because we cannot determine whether patients with DRw6 are positive for DRwl3 or DRwl4, we cannot rule out the possibility of a stronger association with one of the two antigens. On the other hand, this increase in DRw6 frequency may result from a slight (but not significant) increase in both antigens. Further studies are needed with special emphasis on typing for DRwl3 and DRw14 to solve this problem. Molecular techniques may help differentiate these two splits. By concentrating on these specific antigens, we can drastically reduce the problem of multiple testing. These studies should also include antigens from the DP or DQ locus because an association with one of the antigens from these loci also is still possible. Acknowledgment: This study was supported by grants from the Deutsche Forschungsgemeinschaft a n d NIH Grant No. NS27941.
REFERENCES Baur MP, Neugebauer M, Deppe H , et al. Population analysis on the basis of deduced haplotypes from random families. In: Albert ED, Baur MP, Mayr WR, eds. Histocompatihility testing 1984. Berlin: Springer, 1984:333-41. Durner M, Sander T, Greenberg DA, et al. Localisation of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients. Neurology 1991;41: 16.51-5. 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;31: 18592. Greenberg DA, Delgado-Escueta A V , Widelitz H , et al. Strengthened evidence for linkage of juvenile myoclonic epilepsy to HLA and BF. Abstracts of the Xth International Human Gene Mapping Workshop. Cytogenet Cell Genet 1989;51:1008. Janz D. Die Epilepsien. Spezielle Pathologie und Therapie. Stuttgart: Thieme, 1969. lanz D. Epilepsy with impulsive petit ma1 (juvenile myoclonic epilepsy). Acta Neurol Scand 1985;72:449-59. lanz D, Durner M, Beck-Mannagetta G, et al. Family studies on the genetics of juvenile myoclonic epilepsy. In: BeckMannagetta G , Anderson VE, Doose H , Janz D, eds. Genetics of the epilepsies. New York: Raven Press, 1989:43-52. ’iwari JL, Terasaki PI, eds. HLA and disease associations. New York: Springer, 1985. ’suboi T, Christian W. On the genetics of primary generalized epilepsy with sporadic rnyoclonias of impulsive petit ma1 type. Humangenetik 1973;19:155-82. Veissbecker K, Durner M, Janz D, et al. Confirmation of linkage between a juvenile myoclonic epilepsy-locus and the HLA region of chromosome 6. Am J Med Genet 1991;38:32-6.
ilepsia, Voi. 33, No. 5 , 1992
aSUME L‘Cpilepsie myoclonique juvenile (EMJ) est une forme cliniquement bien dkfinie d’epilepsie generalisee idiopathique, dans laquelle il existe une agregation importante de cas d’epilepsie dans les familles. En utilisant le systeme HLA comrne marqueur gCnktique, il a 6t6 dCmontrC une liaison entre 1’EM.l et la region HLA. Cette liaison suggere qu’il peut y avoir une association entre I’EMJ et un des antigenes HLA. Une telle association pourrait indiquer que le gene est situe dans la region HLA et qu’il est en dCsCquilibre de liaison avec I’un des antigenes du systeme HLA. Quatre vingt-huit patients, sans lien de parente, prtsentant une EMJ ont benCficiC d’un typage des locus HLA A et B, 77 du locus C et 76 du locus DR. La frCquence des antigenes etait comparke a celle observee chez des donneurs de sang sains. La difference la plus importante a Ctt constatee dans la frkquence du groupe DRw6 (39.5% des patients contre 22.1% des contr6les). Cette association faible peut &re remise en cause, car I’on sait que DRw6 peut &re sCparC en DRwl3 et DRwl4. (P. Genton, Mur.seille)
RESUMEN La Epilepsia Mioclonica Juvenil (JME) se define como una subforma de epilepsia idiopatica generdlizada con una elevada agregacion de epilepsia en la familia. Utilizando el sistema HLA como marcador genetic0 se ha demostrado un acoplamiento entre la JME y la region del HLA. Este acoplamiento sugiere que puede existir una asociacion entre la JME y el antigen0 HLA. Esta asociacibn podria indicar que el gene se asienta en la region del HLA y est&en acoplamiento en desequilibrio con uno de 10s antigenos HLA. En 88 pacientes no relacionados entre si con la JME se han tipificado el HLA-A y el locus-9, en 77, el locus-C y en 76, el locus-DR. Se ha comparado la frecuencia de antigenos con la obtenida en donantes de sangre normales. La diferencid mas elevada aparecio en la frecuencia del DRw6 (39.5% en 10s enfermos y 22.1% en 10s controles). Esta dCbil asociacion es cuestionable porque se sabe que el DRw6 se divide en DRw 13 y DRwl4. (A. Porterd-Sinchez, Mudrid)
ZUSAMMENFASSUNG Juvenile Myoclonische Epilepsie (JME) oder Epilepsie mit Impulsiv Petit ma1 (IPM) ist eine klar definierte Unterform idiopathisch gneralisierter Epilepsie mit einer hohen familiaeren Haeufung. Mit Hilfe des IILA-Systems als genetischen Marker konnte eine Kopplung zwischen JME und der HLA-Region nachgewiesen werden. Eine Kopplung mit der HLA-Region legt die Moeglichkeit einer Assoziation von JME mit einem HLAAntigen nahe. Eine Assoziation koennte einen Hinweis dafuer geben, dass das Gen sich in der HLA-Region befindet und im Kopplungsungleichgewicht mit einem der HLA-Antigene ist. Acht-und-achtzig unverwandte Patienten mit JME wurden fuer den HLA-A und B-locus typisiert, 77 fuer den C-locus, und 76 fuer den DR-locus. Die Antigenhaeufigkeit wurde mit der von gesunden Blutspendern verglichen. Der groesste Unterschied fand sich in der Haeufigkeit von DRw6 (39.5% in Patienten vs. 22.1% in Kontrollen). Diese schwache Assoziation ist nicht ganz eindeutig, da bekannt ist, dass DRw6 sich in DRwl3 und DRw14 aufsplittet. (Translation supplied b y authors)
