Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy

Deb K. Pal, Martina Durner, Irene Klotz, Elisa Dicker, Shlomo Shinnar, Stanley Resor, Jeffrey Cohen, Cynthia Harden, Solomon L. Moshe, Karen Ballaban-Gill, Edward B. Bromfield, David A. Greenberg

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Abstract

Background: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. Methods: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. Results: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. Conclusions: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.

Original languageEnglish (US)
Pages (from-to)92-98
Number of pages7
JournalBrain and Development
Volume28
Issue number2
DOIs
StatePublished - Mar 2006

Fingerprint

Juvenile Myoclonic Epilepsy
Seizures
Absence Epilepsy
Myoclonic Epilepsy
Chromosomes, Human, Pair 6
Sex Ratio
Sex Characteristics

Keywords

  • Genetics
  • Idiopathic generalized epilepsy
  • Parent-of-origin
  • Phenotype

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Neurology

Cite this

Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy. / Pal, Deb K.; Durner, Martina; Klotz, Irene; Dicker, Elisa; Shinnar, Shlomo; Resor, Stanley; Cohen, Jeffrey; Harden, Cynthia; Moshe, Solomon L.; Ballaban-Gill, Karen; Bromfield, Edward B.; Greenberg, David A.

In: Brain and Development, Vol. 28, No. 2, 03.2006, p. 92-98.

Research output: Contribution to journalArticle

Pal, DK, Durner, M, Klotz, I, Dicker, E, Shinnar, S, Resor, S, Cohen, J, Harden, C, Moshe, SL, Ballaban-Gill, K, Bromfield, EB & Greenberg, DA 2006, 'Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy', Brain and Development, vol. 28, no. 2, pp. 92-98. https://doi.org/10.1016/j.braindev.2005.05.009
Pal, Deb K. ; Durner, Martina ; Klotz, Irene ; Dicker, Elisa ; Shinnar, Shlomo ; Resor, Stanley ; Cohen, Jeffrey ; Harden, Cynthia ; Moshe, Solomon L. ; Ballaban-Gill, Karen ; Bromfield, Edward B. ; Greenberg, David A. / Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy. In: Brain and Development. 2006 ; Vol. 28, No. 2. pp. 92-98.
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abstract = "Background: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. Methods: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. Results: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95{\%} CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8{\%} vs. 7.0{\%}, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6{\%} vs. 1.6{\%}, P=0.01), but not myoclonic seizures. Conclusions: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.",
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T1 - Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy

AU - Pal, Deb K.

AU - Durner, Martina

AU - Klotz, Irene

AU - Dicker, Elisa

AU - Shinnar, Shlomo

AU - Resor, Stanley

AU - Cohen, Jeffrey

AU - Harden, Cynthia

AU - Moshe, Solomon L.

AU - Ballaban-Gill, Karen

AU - Bromfield, Edward B.

AU - Greenberg, David A.

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N2 - Background: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. Methods: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. Results: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. Conclusions: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.

AB - Background: Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy (IGE) with complex inheritance. Previous studies have suggested maternal inheritance and female excess in IGEs but have not been specific for JME. We investigated evidence for maternal inheritance, female excess and patterns of familial seizure risk in a well-characterized sample of JME families. Methods: We ascertained 89 families through a JME proband and 50 families through a non-JME IGE proband. JME families were divided into those with and without evidence of linkage to the EJM1 susceptibility locus on chromosome 6. We analyzed transmission in 43 multigenerational families, calculated the adjusted sex ratio for JME, and looked for evidence of seizure specific risk in 806 family members. Results: We found evidence for preferential maternal transmission in both EJM1-linked and unlinked families (2.7:1), evidence even more marked when potential selection factors were excluded. The adjusted female: male risk ratio was very high in JME (RR=12.5; 95% CI: 1.9-83.7). Absence seizures in JME probands increased the overall risk of seizures in first degree relatives (15.8% vs. 7.0%, P=0.011), as well as first-degree relatives' specific risk of absence seizures (6% vs. 1.6%, P=0.01), but not myoclonic seizures. Conclusions: We have confirmed the finding of maternal inheritance in JME, which is not restricted to JME families linked to the EJM1 locus. The striking female excess in JME may relate to anatomical and/or endocrine sexual dimorphism in the brain. Evidence for independent inheritance of absence and myoclonic seizures in JME families reinforces a model in which combinations of loci confer susceptibility to the component seizure types of IGE.

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KW - Phenotype

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