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We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected individuals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.
Herein we report a new family with FFEVF that maps to chromosome 22q12. We also rephenotyped the original family including new affected family members and show that it now maps to the chromosome 22q12 locus.
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FFEVF is an unusual but distinctive familial focal epilepsy syndrome. The original Australian FFEVF family (family B) introduced the concept that different focal epilepsies in different family members could result from a dominant gene defect. This was confirmed by the study of six further families with FFEVF (Table 1) and identification of the common chromosome 22q12 locus for which the gene remains unknown.
Our families show the characteristic variable foci of FFEVF with six patients with temporal, three frontal, three parietal, one parietooccipital, and one multifocal epilepsy. Penetrance was also typical between 50% and 80%.
We distinguished the phenotype of the original FFEVF family from subsequent families with FFEVF on the basis of seizures in wakefulness, frequent interictal epileptiform activity on EEG, and lack of the nocturnal frontal lobe epilepsy (NFLE) phenotype (Scheffer et al., 1998; Berkovic et al., 2004). Further phenotyping and linkage analysis of the original FFEVF family is now consistent with the same 22q12 region as the other families and excludes the previously reported suggestive linkage to chromosome 2q. Our data do not narrow the previously reported 22q12 region (3.6 cM, 5.2 Mb) between microsatellite markers D22S1163 and D22S280.
The question remains whether there are two familial patterns within the FFEVF syndrome or if they simply reflect a spectrum of phenotypes that can occur in FFEVF. Families A and B share features that differ from the remaining six families as they have more awake seizures and more active EEG studies (three of five in family A and seven of nine in family B, Table 1). In contrast with other FFEVF families who have individuals with nocturnal frontal lobe seizures (Xiong et al., 1999; Callenbach et al., 2003; Berkovic et al., 2004; Morales-Corraliza et al., 2010), our families can easily be distinguished from autosomal dominant NFLE due to their predominantly diurnal attacks and seizures emanating from regions other than the frontal lobe. However, the occurrence of brief nocturnal seizures in our families cannot be excluded without video-polygraphic recordings, which were not available. The concept of a broader phenotypic spectrum is supported by the Dutch family who had both interictal epileptiform discharges and nocturnal seizures (Callenbach et al., 2003; Table 1). Further clinical and molecular characterization of FFEVF will clarify this question.
For the success of the linkage analysis it is important to minimize the number of phenocopies, that is, individuals who have a phenotype within the FFEVF range not due to the same genetic cause. This is particularly difficult in a disorder with the high phenotypic variability characteristic of FFEVF. Here, and in previous work, challenges in phenotyping included whether children with common focal epilepsies of childhood (B-V-11, B-V-5) had FFEVF. Haplotype analysis has helped to distinguish phenocopies (B-V-11, Berkovic et al., 2004). In addition, the proband of family A (A-IV-19) was readily distinguished from FFEVF as he had focal cortical dysplasia consistent with a structural etiology. Febrile seizures occurred in two individuals in family A. Previous studies of FFEVF have not reported febrile seizures. Moreover, our haplotype analysis suggested that febrile seizures were not part of this familial syndrome.
As FFEVF is characterized by a wide phenotypic spectrum, it can be difficult to distinguish from other focal epilepsy syndromes. For example, a Gypsy family included affected family members with the majority having temporal lobe epilepsy and some family members with extratemporal seizure semiology such that the family could be consistent with FFEVF (Angelicheva et al., 2009). However, in the Gypsy family, clinical and EEG data were often not congruent, and linkage analysis excluded the FFEVF locus on chromosome 22q12, suggesting that chromosome 22q12 FFEVF in the Gypsy family was unlikely (Angelicheva et al., 2009).
Autism spectrum disorders have not previously been considered part of FFEVF. However, two of the three subjects in family B with ASD had seizures, and all three carried the chromosome 22q12 haplotype (B-V-9, B-V-10, B-IV-16). Callenbach et al. (2003) described autistic features in two affected individuals and obsessive compulsive features in another individual with FFEVF. Furthermore, intellectual disability was noted in two affected individuals in family B and in one in family A; in both adult cases, their epilepsy was severe. These observations suggest that ASD and intellectual disability are likely to be part of the phenotypic spectrum of FFEVF; modifying genes may explain these severe phenotypes.
Our findings clarify that chromosome 22q12 is the only known candidate region for FFEVF. Both families display phenotypes that expand the phenotypic spectrum at this locus. Next-generation sequencing may be an appropriate tool to identify the underlying gene mutation. This will enable detection of smaller families with FFEVF, and potentially sporadic cases that currently elude diagnosis because of insufficient family members to display phenotypes that produce a recognizable FFEVF pattern.