Eyelid myoclonia with absences meets GEFS+

Running in the family. Eyelid myoclonia with absences (EMA) is a rare generalized epilepsy syndrome characterized by brief episodes of myoclonic jerks that are often accompanied by an upward deviation of the eyeballs and an extension of the head. The EEG shows generalized spike-wave discharges during these episodes, and most patients are highly photosensitive. Therefore, it would be natural to think of EMA as related to other classical generalized epilepsies including Childhood Absence Epilepsy or Juvenile Myoclonic Epilepsy. Now, a recent paper in Epilepsia shows that the families of patients with EMA tell a slightly different story.

EMA. Eyelid myoclonia with absences is a peculiar epilepsy syndrome. Its main feature, eyelid myoclonias, are characteristic, brief seizures with blinking of the eyelids. These brief episodes are not always directly identified as seizures and might be interpreted as tics by parents. However, if these episodes are captured on EEG, the epileptic origin becomes clear quite quickly. These episodes are invariably accompanied by generalized epileptic discharges. Some epileptologists regard these seizures as an extreme form of photosensitivity, and all patients with EMA are photosensitive. There is strong evidence from twin studies that EMA has a genetic component as also seen in other generalized epilepsies.

GGE, cGGE and GEFS+. The terminology to classify generalized epilepsies has recently changed. The epilepsies formerly referred to as Idiopathic Generalized Epilepsies are now considered Generalized Genetic Epilepsies (GGE), even though the term IGE is still commonly used. In additional to the classical GGEs including Childhood Absence Epilepsy, Juvenile Myoclonic Epilepsy and others, the GGEs also comprise the Genetic Epilepsies with Febrile Seizures Plus (GEFS+). GEFS+ is a familial epilepsy syndrome characterized by a wide range of phenotypes of fever-related epilepsies. One classical presentation of Febrile Seizures Plus (FS+), for example, is febrile seizures that persist beyond the age of six years. Gene identification has been particularly successful in GEFS+, and SCN1A, SCN1B and GABRG2 are established genes for familial fever-related epilepsies. Dravet Syndrome can be considered an extreme form of GEFS+, even though most mutations in SCN1A arise de novo.

EMA and GEFS+. Prior to seeing Lynette Sadleir’s poster at AES last year, I wouldn’t have thought that there was any connection between EMA and GEFS+. This work has now been published in Epilepsia and deals with an interesting observation in the families of patients with EMA. The authors characterized the epilepsy phenotypes in the families of 18 patients with EMA. They found a positive family history in 15/18 families including affected first-degree relatives in 12/18 patients (67%), with 34 affected relatives in total. Classical GGE phenotypes were only seen in 5/34 relatives, while GEFS+ phenotypes were observed in 16/34 relatives. 7/15 families had a typical GEFS+ patterns, while 3/15 families were classical GGE families. In summary, GEFS+ phenotypes outnumber cGGE phenotypes by a factor of three in the families of patients with EMA. The authors compare their finding with published cGGE/IGE families and find that this ratio is significantly different from what we know from cGGE/IGE families, where cGGE/IGE phenotypes vastly outnumber GEFS+ phenotypes.

Family history of some of the patients with Eyelid Myoclonia with Absences (EMA). In the families of patients with EMA, there is a surprising abundance of phenotypes consistent with the GEFS+ spectrum (Genetic Epilepsy with Febrile Seizures Plus).

Family history of some of the patients with Eyelid Myoclonia with Absences (EMA). In the families of patients with EMA, there is a surprising abundance of phenotypes consistent with the GEFS+ spectrum (Genetic Epilepsy with Febrile Seizures Plus).

What does this mean? The genetic etiology of EMA is virtually unknown. The current paper by Sadleir and collaborators now emphasizes that there might be some surprises down the road when the genetic architecture of this rare epilepsy syndrome is unraveled. Even though we have recently discussed that the art form of clinical epilepsy genetics is in steep decline, papers like this help us get oriented in the maze of epilepsy phenotypes prior to embarking on genetic studies.

8 thoughts on “Eyelid myoclonia with absences meets GEFS+

  1. Pingback: FS and FS+ are two distinct diseases, as suggested by twins | Beyond the Ion Channel

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  3. I pray you and others pursue the genome and genetic link. My 13 yr old son has EMA (onset at 4), myself (Dad) and Mom have no epilepsy…neither my wife’s parents or my parents had epilepsy …but my Brother’s daughter had epilepsy…and wife’s cousin family tree has a child with absence. Its similar to the top example where a more recessive gene appears possibly in play.

    • Dear Matt,
      thank you for your comment and I hope that your son and you family is doing well despite the burden of epilepsy. From the genetic perspective, EMA is still a poorly understood epilepsy and several research networks worldwide are currently trying to find the causative genes. The finding that EMA is often found in families with a particular familial epilepsy syndrome called GEFS+ was an interesting finding that nobody really expected. We hope that this might help us figure out what the possible candidate genes might be.

  4. Pingback: Mutation intolerance – why some genes withstand mutations and others don’t | Beyond the Ion Channel

  5. Pingback: From unaffected to Dravet Syndrome – extreme SCN1A phenotypes in a large GEFS+ family | Beyond the Ion Channel

  6. Pingback: CACNA2D2, the ducky mouse, and what it takes to be an epilepsy gene | Beyond the Ion Channel

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