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December 12 Highlight and Commentary

Epilepsy genetics: Complexity unmasked, conundrums revealed

Stogmann et al. studied 61 patients with idiopathic generalized epilepsy syndromes for mutations in the EFHC1 gene and detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3'UTR (2014t>c). Mutations in this gene may underlie different epilepsy syndromes.

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Epilepsy genetics: Complexity unmasked, conundrums revealed

Commentary by Samuel F. Berkovic, MD

Molecular genetics has transformed the diagnosis and understanding of numerous single gene disorders. This success has rarely been duplicated in common neurologic disorders with complex inheritance.

Idiopathic generalized epilepsies, including the common syndrome of juvenile myoclonic epilepsy (JME), are a good example. In 1988 a locus for JME on chromosome 6p was reported.¹ The finding was replicated by some but not others, it was said to be specific to JME by some but not all, there was debate as to the precise location and number of loci for JME on chromosome 6, and no causative gene was definitively identified. Frustratingly, such inconsistency across laboratories is usual in complex disorders.

Finally, in 2004, a consortium led by Japanese and US investigators found mutations in the gene EFHC1 on chromosome 6 in a few JME families.² This was an important advance, but the frequency of families with mutations could not account for the positive linkage signals. Stogmann et al.³ now report mutations in an independent Austrian sample, in sporadic (as opposed to familial) cases and in a wider spectrum of phenotypes, including other forms of idiopathic generalized epilepsy and one case of temporal lobe epilepsy. The case for these mutations being causative is not completely conclusive since functional studies of mutant channels have not yet been carried out. Nonetheless, their findings strengthen the case for EFHC1 contributing to the complex inheritance of idiopathic epilepsies.

Conundrums remain in terms of reconciling the early linkage studies and determining the attributable risk of EFHC1 mutations in particular epilepsies. The function of EFHC1 is unclear; roles in apoptosis² and ciliary function⁴ have been proposed. Importantly, EFHC1 is not known to have a direct or indirect role in ion channel function, as opposed to other confirmed idiopathic epilepsy genes.

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References

1. Greenberg DA, Delgado-Escueta AV, Widelitz H, et al. Juvenile myoclonic epilepsy may be linked to the Bf and HLA loci on human chromosome 6. Am J Med Genet 1988;31:185–192.[Medline]
2. Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet 2004;36:842–849.[Medline]
3. Stogmann E, Lichtner P, Baumgartner C, et al. Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations. Neurology 2006;67:2029–2031.[Abstract/Free Full Text]
4. King SM. Axonemal protofilament ribbons, DM10 domains and the link to juvenile myoclonic epilepsy. Cell Motil Cytoskeleton 2006;63:245–253.[Medline]

This Article Full Text (PDF) Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Related Article