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Purpose: Eyelid myoclonia with absences (EM) is an uncommon type of absence seizure associated with a variety of epilepsy syndromes. The syndrome of epilepsy with EM (EMA) has been proposed to denote the onset of frequent EM induced by eye closure and photic stimulation beginning in childhood. The clinical genetics of EMA has not been well characterized, although a family history of seizures is not infrequent.
Methods: Individuals with EMA were ascertained by referral and through the investigators’ clinical practices. All available family members were assessed for seizures using a validated seizure questionnaire. Electroclinical data were obtained on each proband and all affected family members; pedigrees were constructed. Families were analyzed for phenotypic patterns.
Key Findings: Eighteen individuals with EMA were recruited. A history of seizures was found in 34 relatives in 15 (83%) of 18 families. In terms of epilepsy syndromes, 9 relatives from 7 of 15 families had febrile seizures. Two relatives had EMA. Classical genetic generalized epilepsy (GGE) syndromes were seen in five relatives: two generalized tonic–clonic seizures alone, two childhood absence epilepsy (CAE), and one juvenile myoclonic epilepsy (JME). Genetic epilepsy with febrile seizures plus (GEFS+) phenotypes occurred in 16 relatives. On review of the epilepsy syndromes within each family, seven families had a pattern consistent with GEFS+, whereas three families had classical GGE.
Significance: The clinical genetics of EMA is suggestive of complex inheritance with shared genetic determinants overlapping with both classical GGE and GEFS+. The epilepsy syndromes in relatives of probands with EMA differ from those found in families of probands with CAE, supporting the concept that patients with EMA have a syndrome that is distinct from CAE. This presumably reflects different genetic components contributing to their genetic architecture.
Eyelid myoclonia with absences (EM) is a rare type of absence seizure (Appleton et al., 1993; Panayiotopoulos et al., 1996; Covanis, 2005). The seizures are brief lasting 1.5–6 s with repetitive, often rhythmic, fast (4–6 Hz) myoclonic jerks of the eyelids with simultaneous upward deviation of the eyeballs and extension of the head (Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996a; Panayiotopoulos et al., 1996; Loiseau et al., 2002; Capovilla et al., 2009). Alteration of awareness varies markedly (Appleton et al., 1993). The ictal electroencephalography (EEG) shows high-amplitude generalized spikes and polyspikes and slow waves at a frequency of 3–6 Hz (Appleton et al., 1993; Caraballo et al., 2009). This seizure type has been reported in a variety of epilepsy syndromes including childhood absence epilepsy (CAE) and juvenile myoclonic epilepsy (JME), and in association with intellectual disability such as in Dravet syndrome and individuals with chromosomal rearrangements (Ferrie et al., 1996).
Although there has been some debate about whether a specific syndrome exists with the hallmark of EM, Jeavons and others have recognized a group of children with onset of frequent EM associated with photosensitivity and eye closure who may later develop generalized tonic–clonic seizures (Jeavons, 1977; Appleton et al., 1993; Giannakodimos & Panayiotopoulos, 1996a; Panayiotopoulos et al., 1996; Loiseau et al., 2002; Capovilla et al., 2009). This syndrome of epilepsy with eyelid myoclonia with absences (EMA) occurs in children aged 2–14 years (peak 6–8 years) and is a genetic (idiopathic) generalized epilepsy (GGE) (Capovilla et al., 2009). Photosensitivity is always present, although it decreases with age and antiepileptic drug (AED) exposure. Patients usually experience generalized tonic–clonic seizures (GTCS) after EM (Giannakodimos & Panayiotopoulos, 1996b; Panayiotopoulos, 2005). Results of examination and neuroimaging are normal (Panayiotopoulos, 2005). Most individuals are in the normal cognitive range, although borderline intellectual functioning and intellectual disability may occur (Scuderi et al., 2000; Covanis, 2005; Sevgi Demirci & Saygi, 2006; Capovilla et al., 2009; Striano et al., 2009). EMA is considered a life-long condition and can be difficult to treat (Panayiotopoulos, 2005; Striano et al., 2009) .
Evidence for a genetic basis for EMA has been drawn from studies describing concordant monozygotic twins and epilepsy in relatives of patients with EMA (Giannakodimos & Panayiotopoulos, 1996a; Parker et al., 1996; Striano et al., 2002; Adachi et al., 2005; Yang et al., 2008; Caraballo et al., 2009). In general, studies have obtained the familial information from the index case rather than by explicitly studying each family member (Giannakodimos & Panayiotopoulos, 1996a; Striano et al., 2002; Capovilla et al., 2009; Caraballo et al., 2009). There is, however, one study reporting the familial phenotypes in four families selected on the basis of two family members with EMA (Parker et al., 1996).
Herein we perform detailed phenotyping of all available family members and analyze the phenotypic patterns in families of probands with EMA.
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GGEs fall into two major groups; the classical genetic generalized epilepsies (cGGEs), and genetic epilepsy with febrile seizures plus (GEFS+) (Scheffer & Berkovic, 1997; Singh et al., 1999; Marini et al., 2004). The cGGEs are the best recognized GGEs and include the well-defined epilepsy syndromes of CAE, JAE, JME, and GTCS alone (Marini et al., 2004). GEFS+ is characterized by phenotypic heterogeneity within families with a range of phenotypes including FS, FS+, MAE, and Dravet syndrome, as well as other epilepsies in which febrile seizures are a prominent feature (Scheffer & Berkovic, 1997; Singh et al., 1999). Family studies have suggested that these two major groups are distinct and contributed to by different susceptibility genes (Scheffer & Berkovic, 1997; Singh et al., 1999; Marini et al., 2004).
EMA is believed to have a genetic etiology (Giannakodimos & Panayiotopoulos, 1996a; Parker et al., 1996; Striano et al., 2002; Adachi et al., 2005; Yang et al., 2008; Capovilla et al., 2009; Caraballo et al., 2009). Little is known about the family history of seizures in probands with EMA. In the only previous study in which the relatives were directly interviewed, 14 of 18 probands had a family history, but the only families that were phenotyped were the four with relatives who also had EMA. Only three possibly affected relatives were studied, and further information was gleaned from the probands’ family (Parker et al., 1996). In these “EMA enriched” families, 11 affected relatives had GGE.
Here, we studied the families of 18 probands with EMA and phenotyped all available affected family members. Fifteen (83%) of 18 probands with EMA had family members with seizures, with a total of 34 affected relatives, of which 26 had adequate data for phenotyping. Our finding of 83% of probands having a positive family history is similar to previous reports that range from 40–78% (Giannakodimos & Panayiotopoulos, 1996a; Parker et al., 1996; Striano et al., 2002; Capovilla et al., 2009; Caraballo et al., 2009). In contrast to our phenotyping methods, many studies have not directly asked the relatives and have relied on reports from the probands’ families (Giannakodimos & Panayiotopoulos, 1996a; Striano et al., 2002; Capovilla et al., 2009; Caraballo et al., 2009).
Our families showed different patterns, with three having exclusively cGGE syndromes, and seven having exclusively GEFS+ phenotypes. This provides a more representative picture of the phenotypic spectrum associated with EMA than previous studies that have limited their phenotyping to families in which two individuals had EMA (Parker et al., 1996).
Syndromes in relatives
Looking at the syndromes in affected relatives, we found that the most common phenotype in relatives was FS in 9 (35%) of 26 of affected relatives; a further 6 had FS as part of a more complex phenotype. cGGE syndromes occurred in 5 (19%) of 26, and GEFS+ syndromes (excluding FS syndrome) in 7 (27%) of 26 of affected relatives. The remaining four had the following: EMA (2), myoclonic epileptic encephalopathy (1), focal epilepsy (1), and a single unprovoked seizure.
Differentiation into specific subgroups of cGGE, GEFS+, and GGE was based on the data available in each family. Where affected relatives had clearcut cGGE, the family was called cGGE, as previously EMA has been considered as part of the absence epilepsy syndrome group (family D, H). If there was no cGGE and a relative had FS, we called this GEFS+ (family E, J, O). There were larger families with clearer patterns consistent with GEFS+ (family G, I, L, M) or cGGE (family N). In families with just EMA or non-cGGE, we have called them GGE in order not to bias our analysis (family A, F). We acknowledge that the data emerging from the small families is open to debate, but the large families show a more compelling picture of the familial epilepsy syndrome. Ongoing clinical and molecular genetic studies will elucidate these relationships further.
The epilepsy syndromes in our families of probands with EMA were different from those observed in families of probands with cGGEs (Marini et al., 2004). The EMA probands were significantly more likely to have relatives with GEFS+ (62% vs. 23%) and less likely to have relatives with cGGE (19% vs. 73%). They also had less syndromic concordance (8%) compared to probands with CAE (42%), JAE (46%), or JME (32%). The reasons for this comparative lack of syndromic concordance is not clear, but may relate to GEFS+ susceptibility genes being more important in this syndrome than in the cGGE, and GEFS+ being a more heterogeneous familial epilepsy syndrome. Photosensitivity susceptibility genes may be important for EMA to occur in a GEFS+ family, and in general GEFS+ families have a low rate of photosensitivity (unpublished data Scheffer IE).
Although the syndrome of EMA has not been recognized as a distinct epilepsy syndrome in the ILAE organization of the epilepsies (Berg et al., 2010), debate continues as to whether it should be regarded as a specific epilepsy syndrome (Striano et al., 2009). Some regard individuals with EM to be part of CAE or JAE/JME depending on the age of onset (Striano et al., 2009). Here, we have looked at EMA and compared the family history with CAE. Relatives of probands with EMA are different from relatives of probands with CAE, as fewer family members have CAE (8% vs. 42%) and more have FS or FS+ (46% vs. 15%; Table 4, Marini et al., 2004). Our findings showing the absence of CAE in relatives of probands with EMA and different familial patterns in EMA compared to CAE provide support for EMA as a distinct epilepsy syndrome from CAE.
It has been suggested that EMA should be considered a myoclonic epilepsy with overlap between JME and EMA (Panayiotopoulos, 2005; Yalcin et al., 2006). Although seven family members had myoclonic seizures, only 4% of relatives had JME, compared with 32% of relatives in families with JME probands. This absence of JME in relatives of EMA probands and difference in familial patterns between JME and EMA probands provides a similar argument for JME as CAE, suggesting that EMA is a separate entity from JME.
In conclusion, relatives of EMA probands have heterogeneous epilepsy phenotypes that are almost exclusively generalized. EMA appears to have shared genetic determinants with both cGGE and GEFS+. The clinical genetics of EMA as defined in this cohort would add support to the contention that EMA is a distinct syndrome from CAE, JAE, or JME.