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Juvenile Myoclonic Epilepsy (JME) accounts for almost 12% of all epilepsies and is one of the most frequent forms of genetic generalized epilepsies. Genetic studies have revealed that mutations in EFHC1 (EF-hand containing one) account for 3 to 9% of all cases around the world. This gene encodes a protein that is not an ion channel, and several studies have tried to find its cellular role. In this article, we review the various functions that have been proposed for this protein. Interestingly, all of them could affect brain development at different steps, suggesting that the developmental assembly of neural circuits may play a prominent role in JME. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

Heterozygous mutations in Myoclonin1/EFHC1 cause juvenile myoclonic epilepsy (JME), the most common form of genetic generalized epilepsies, while homozygous F229L mutation is associated with primary intractable epilepsy in infancy. Heterozygous mutations in adolescent JME patients produce subtle malformations of cortical and subcortical architecture, whereas homozygous F229L mutation in infancy induces severe brain pathology and death. However, the underlying pathological mechanisms for these observations remain unknown. We had previously demonstrated that EFHC1 is a microtubule-associated protein (MAP) involved in cell division and radial migration during cerebral corticogenesis. Here, we show that JME mutations, including F229L, do not alter the ability of EFHC1 to colocalize with the centrosome and the mitotic spindle, but act in a dominant-negative manner to impair mitotic spindle organization. We also found that mutants EFHC1 expression disrupted radial and tangential migration by affecting the morphology of radial glia and migrating neurons. These results show how Myoclonin1/EFHC1 mutations disrupt brain development and potentially produce structural brain abnormalities on which epileptogenesis is established.

many of the milder forms of epilepsy, the genetic contribution is made up of many factors that each contributes little to the disease risk. This is called multifactorial inheritance. Juvenile myoclonic epilepsy (JME) is thought to be inherited in amultifactorial mode. So, while genetic factors are largely to blame for the condition, we encountermany sporadic cases, in addition to families with multiple affected members with JME and families with both JME and other forms of epilepsy. Genetic research is aimed at finding genetic factors that contribute to disease risk. If the genetic factor has a large effect, genetic testing can be used for diagnosis and prognosis and, maybe, for treatment. In multifactorial disorders, such as JME, the aims are more fundamental: understanding the biology of the disorder by placing the genes that contribute in a network that makes sense. The quality of the research into multifactorial traits depends on many factors: first, a correct diagnosis; next, knowledge of ethnicity of the patients and the healthy people we used to compare them with; and, finally, the quality of the lab work and the statistical analysis. In this talk, I will discuss what is known about the multifactorial genetics of JME and what is done to move forward. I will dedicate time to the question as to why knowledge of ethnicity is important in this type of studies.