FFEVF is an autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions in different family members. Many patients have an aura and show automatisms during the seizures, whereas others may have nocturnal seizures. ... FFEVF is an autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions in different family members. Many patients have an aura and show automatisms during the seizures, whereas others may have nocturnal seizures. There is often secondary generalization. Some patients show abnormal interictal EEG, and some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. Penetrance of the disorder is incomplete (summary by Klein et al., 2012).
Xiong et al. (1999) identified 2 large French Canadian families segregating a familial partial epilepsy syndrome with variable foci characterized by mostly nocturnal seizures arising from frontal, temporal, and occasionally occipital epileptic foci. There was no evidence for ... Xiong et al. (1999) identified 2 large French Canadian families segregating a familial partial epilepsy syndrome with variable foci characterized by mostly nocturnal seizures arising from frontal, temporal, and occasionally occipital epileptic foci. There was no evidence for structural brain damage or permanent neurologic dysfunction. The syndrome was inherited as an autosomal dominant trait with incomplete penetrance. Xiong et al. (1999) noted that the Australian family reported by Scheffer et al. (1998) had a similar phenotype. Callenbach et al. (2003) reported a 4-generation Dutch family in which 12 individuals had epilepsy consistent with FFEVF. Age at seizure onset ranged from 3 months to 24 years. Eight patients had nocturnal seizures and 9 had diurnal seizures. The seizures were mostly tonic, tonic clonic, or hyperkinetic. Seven patients reported autonomic or sensory auras, and 5 showed automatisms during the seizures. None had auditory symptoms. The severity and frequency of seizures was variable and tended to decrease during adulthood, although they rarely disappeared completely. All patients had normal intelligence, but 2 had autistic behavior and 1 had obsessive-compulsive disorder. Some patients had an abnormal interictal EEG with focal activity. Four family members reportedly had nocturnal episodes and frightening dreams, but it was unclear whether they were epileptic in origin. Thus, some of the features in this family were also consistent with autosomal dominant nocturnal frontal lobe epilepsy (see, e.g., ENFL1, 600513). There were at least 4 obligate carriers, indicating incomplete penetrance. Berkovic et al. (2004) reported a 5-generation Spanish family in which 14 individuals had partial seizures. The 37-year-old proband was ascertained due to nocturnal seizures. She had seizure onset at age 11 years with a nocturnal convulsion. Between ages 11 and 15 years, seizures occurred while asleep or awake. She would have loss of consciousness and fall, sometimes followed by tonic clonic convulsions. She was seizure free from age 15 to 21 years. From age 21 years, apart from some daytime seizures during pregnancy, all other seizures occurred at night. Ictal EEG was nonlocalizing, and interictal EEG was normal. Nine additional living family members had seizures, with a mean age at onset of 12 years (range 1 month to 25 years). A French Canadian family distantly related to the families reported by Xiong et al. (1999) was also reported. That family was initially classified as having autosomal dominant nocturnal frontal lobe epilepsy, and had been reported in several large studies ('family E' in Scheffer et al., 1995 and 'family Q' in Lopes-Cendes et al., 1995 and Phillips et al., 1998). There were 9 affected individuals with a mean age at onset of 17 years. Some had seizures only at night. The severity was variable. Klein et al. (2012) reported a 5-generation Australian family in which 5 individuals had features consistent with FFEVF. The median age at seizure onset was 7 months (range, 3 weeks to 10 years). The most severely affected individual had mild intellectual disability, with normal development prior to seizure onset at age 3 years. Klein et al. (2012) also restudied the Australian family reported by Scheffer et al. (1998) in which 11 individuals spanning 4 generations had a phenotype consistent with FFEVF. The mean age at onset was 13.5 years (range, 10 months to 40 years). Three individuals had autism spectrum disorder, including a 12-year-old boy who had not yet developed seizures. Affected individuals from both families had the characteristic variable epileptic foci: 6 patients with temporal, 3 frontal, 3 parietal, 1 parietooccipital, and 1 multifocal epilepsy. The seizures tended to be diurnal, and 10 patients had abnormal interictal EEG. Penetrance was incomplete, between 505 and 80%. Ishida et al. (2013) reported 6 unrelated families with autosomal dominant focal epilepsy. Two of the families had previously been reported by Picard et al. (2000) (families 'N' and 'S'). In family 'N,' 3 individuals had typical temporal lobe seizures whereas 2 others had hyperkinetic motor symptoms. One patient reported aura. Interictal EEG in the 2 patients with motor symptoms showed focal abnormalities. The family was initially characterized by Picard et al. (2000) as having familial temporal lobe epilepsy, but partial epilepsy with variable foci could not be excluded. Family 'S' showed clear partial epilepsy with variable foci. EEG of several patients showed different abnormalities in different patients, including seizures in the parietal, temporal, central, and frontal regions.
In affected members of 7 of 8 families with autosomal dominant familial focal epilepsy with variable foci, Dibbens et al. (2013) identified heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0001-614191.0004). The first 2 mutations were found by ... In affected members of 7 of 8 families with autosomal dominant familial focal epilepsy with variable foci, Dibbens et al. (2013) identified heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0001-614191.0004). The first 2 mutations were found by exome sequencing, and mutations occurred throughout the gene. All of the families had previously been reported (see, e.g., Xiong et al., 1999; Scheffer et al., 1998; Callenbach et al., 2003; Berkovic et al., 2004). No mutation was found in Australian 'family A' reported by Klein et al. (2012). Screening of this gene in 82 probands with focal epilepsy and no detectable structural lesions identified pathogenic DEPDC5 mutation in 10 (12.2%), indicating that mutations in this gene are an important cause of the disorder. Most mutations caused premature termination of the protein, suggesting haploinsufficiency as the disease mechanism. In affected members of 6 (37%) of 16 families with autosomal dominant focal epilepsies, Ishida et al. (2013) identified 6 different heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0005-614191.0007). Five of the mutations resulted in a truncated protein, indicating that haploinsufficiency is the disease mechanism. Four families had FFEVF, 2 had features consistent with temporal lobe epilepsy, and 1 had features consistent with nocturnal frontal lobe epilepsy, all of which are types of focal seizures.