Alternative titles; symbols
SNOMEDCT: 764522009; ORPHA: 98820; DO: 0081421;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q12.2-q12.3 | Epilepsy, familial focal, with variable foci 1 | 604364 | Autosomal dominant | 3 | DEPDC5 | 614191 |
A number sign (#) is used with this entry because of evidence that familial focal epilepsy with variable foci-1 (FFEVF1) is caused by heterozygous mutation in the DEPDC5 gene (614191) on chromosome 22q12.
Familial focal epilepsy with variable foci-1 (FFEVF1) 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 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 at about 70%. The phenotypic spectrum of FFEVF1 is wide, and may include nocturnal epilepsy, febrile seizures, and focal epilepsy with febrile seizures-plus (FEFS+) (summary by Klein et al., 2012; Liu et al., 2020). Detailed electrophysiologic, brain imaging, and/or histologic studies have indicated that some patients have subtle or clear evidence of focal cortical dysplasia (FCD), which may be associated with additional somatic mosaic loss-of-function DEPDC5 mutations in affected brain tissue (Baulac et al., 2015).
Reviews
Samanta (2022) provided a review of DEPDC5-related epilepsy, noting that there is a phenotypic spectrum, including autosomal dominant sleep-related hypermotor epilepsy (ADSHE), familial mesial temporal lobe epilepsy (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), febrile seizures and febrile seizures-plus (FEFS+), rolandic epilepsy, infantile spasms, and sudden unexpected death in epilepsy (SUDEP). The disorder results from enhanced activation of the mTOR (601231) signaling pathway.
Genetic Heterogeneity of Familial Focal Epilepsy with Variable Foci
See also FFEVF2 (617116), caused by mutation in the NPRL2 gene (607072) on chromosome 3p21; FFEVF3 (617118), caused by mutation in the NPRL3 gene (600928) on chromosome 16p13; and FFEVF4 (617935), caused by mutation in the SCN3A gene (182391) on chromosome 2q24.
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 50% 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.
Picard et al. (2014) reported 9 patients from 4 unrelated families of European descent with FFEVF presenting as autosomal dominant nocturnal frontal lobe epilepsy. The patients had onset of predominantly nocturnal seizures in the first 2 decades of life. Six patients also had rare diurnal seizures, and 3 had intellectual disability. There was a high rate of drug resistance (78%) in these patients. The features were similar to those observed in classic autosomal dominant nocturnal frontal lobe epilepsy, suggesting that these types of seizures are part of the spectrum of FFEVF.
Scheffer et al. (2014) reported a large Australian family in which 6 individuals had FFEVF. The patients presented between 1 and 12 years with frontal lobe epilepsy, often with secondary tonic-clonic seizures. Three patients had remission of seizures between 14 and 22 years. Brain imaging of 2 patients showed cortical thickening and loss of gray-white differentiation at the bottom of the sulcus, suggesting mild cortical dysplasia. One of the patients with cortical dysplasia had a more severe phenotype, with intellectual disability, autistic spectrum disorder, psychosis, and seizures that were refractory to medication. MRI studies in affected members of 2 previously reported families with genetically confirmed FFEVF, including 1 reported by Scheffer et al. (1998), showed that 1 patient from each family had cortical dysplasia: 1 had bottom-of-the-sulcus dysplasia and the other had subtle band heterotopia adjacent to a dysplastic cortex. The findings indicated that some patients, even within a family carrying the same mutation, may have clear or subtle brain malformations. Scheffer et al. (2014) suggested that activation of the mTOR (601231) pathway in patients with DEPDC5 mutations may result in cellular proliferation, reminiscent of the lesions observed in tuberous sclerosis (TSC; 191100).
Lal et al. (2014) reported 4 unrelated families in which a proband with epilepsy was found to carry either a heterozygous truncating or splice site variant in the DEPDC5 gene identified by whole-exome sequencing. Three of the probands had family members with various seizure disorders, mostly unclassifiable. The phenotype of the probands was variable, ranging from childhood-onset benign rolandic epilepsy with subsequent normal psychomotor development and rolandic epilepsy with persistence after adolescence, to severe infantile-onset myoclonic, atonic, and generalized tonic-clonic seizures and subsequent delayed psychomotor development. EEG performed in 3 patients showed characteristic centrotemporal spikes. The report expanded the epilepsy types associated with DEPDC5 mutations to include rolandic epilepsy, which is a form of focal epilepsy.
Baulac et al. (2015) reported 7 patients from 4 families with focal epilepsy and focal cortical dysplasia associated with heterozygous truncating mutations in the DEPDC5 gene. One of the families had been reported by Picard et al. (2000) and Ishida et al. (2013). The patients presented with treatment-resistant seizures, mostly nocturnal, between 3 days and 4 years of age. EEG showed focal spike or sharp waves, and stereo EEG (SEEG) was suggestive of focal cortical dysplasia type II (FCD II), which is characterized histopathologically by disrupted cortical lamination and dysmorphic neurons (Blumcke et al., 2011). Five patients underwent surgery for seizures, and 1 had a brain biopsy. Two patients had histopathologically confirmed FCD IIa with balloon cells, 2 had FCD I, characterized by disrupted cortical lamination without dysmorphic neurons, and 2 had inconclusive histology. Brain MRI was normal in 3 patients despite histologic evidence of FCD; brain MRI in the other 4 patients was abnormal, showing thickened gyrus, poor gray-white matter differentiation, and thickened deep sulcus. Three patients were seizure-free after surgery, and 1 showed clinical improvement. The findings expanded the phenotypic spectrum of FFEVF to include focal cortical dysplasia.
Nascimento et al. (2015) reported 9 patients from a French-Canadian family with FFEVF1 confirmed by genetic analysis. The patients, most of whom were adults at the time of study, had onset of various types of seizures between 2 and 18 years of age. Seizure types included focal, absence, generalized tonic-clonic, and febrile. The seizures were often nocturnal. A few patients reported auras. Most patients became seizure-free with or without medication. None had cognitive impairment. Two affected individuals died of sudden unexplained death in epilepsy (SUDEP) at 58 and 50 years of age.
Liu et al. (2020) reported 10 patients from 7 unrelated families of Han Chinese origin with focal and/or febrile epilepsy associated with heterozygous mutations in the DEPDC5 gene. Six patients were classified as having focal epilepsy with febrile seizures-plus (FEFS+), 1 had temporal lobe epilepsy, 2 had unclassified epilepsy (1 focal), and 1 had only febrile seizures. The patients, who ranged from 6 to 58 years of age, had onset of seizures between 2 and 16 years of age. EEGs showed focal or multifocal spike-wave discharges. The phenotype was generally mild, and all became seizure-free or showed improvement with medication. Focal cortical dysplasia was not observed in the patients who underwent brain MRI. There were 4 unaffected parents who also carried the mutation, indicating incomplete penetrance.
The transmission pattern of FFEVF is consistent with autosomal dominant inheritance with incomplete penetrance (Berkovic et al., 2004; Dibbens et al., 2013).
Baulac et al. (2015) reported 2 sisters with FFEVF who inherited a heterozygous DEPDC5 mutation from their unaffected father, who was found to be somatic mosaic for the mutation with a 5% allelic mutation load.
In 2 French Canadian families with partial epilepsy with variable foci, Xiong et al. (1999) mapped the disease locus to a 3.8-cM interval on chromosome 22q11-q12. Xiong et al. (1999) noted that the disorder reported by Scheffer et al. (1998) did not initially show linkage to chromosome 22.
By analysis of several candidate epilepsy loci in a Dutch family with FFEVF, Callenbach et al. (2003) found linkage to chromosome 22q12 (maximum multipoint lod score of 4.04 at D22S310, D22S1167, and D22S1176). The disease haplotype spanned 7.93 cM between D22S310 and D22S280, which showed complete overlap on the centromeric side with the locus identified by Xiong et al. (1999).
In a Spanish family with FFEVF, Berkovic et al. (2004) found linkage to chromosome 22q12 between D22S1154 and D22S283 (multipoint lod score of 3.4). A French Canadian family with the disorder was also linked to 22q12 and was found to carry the same haplotype as the families reported by Xiong et al. (1999). The combined multipoint lod score of 6.3 for the 2 families, together with the data from the original French Canadian pedigrees, mapped the locus to a 3.6-cM region between D22S1163 and D22S280.
By linkage analysis of a 5-generation Australian family with FFEVF, Klein et al. (2012) found linkage to chromosome 22q12 (maximum lod score of 2.38 at D22S1154). Linkage analysis of the Australian family reported by Scheffer et al. (1998) also showed linkage to chromosome 22q12 (maximum lod score of 2.94 at D22S278). Linkage to chromosome 2q, as originally reported by Scheffer et al. (1998), was excluded in that family. The findings indicated that there is a single locus for FFEVF.
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.
In affected members of 4 (13%) of 30 families of European descent with a clinical diagnosis of autosomal dominant nocturnal frontal lobe epilepsy, Picard et al. (2014) identified 4 different heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0004; 614191.0008-614191.0009). Two unaffected family members also carried the mutations, indicating incomplete penetrance. The findings broadened the seizure phenotype associated with DEPDC5 mutations. Functional studies of the variants were not performed, but Picard et al. (2014) postulated haploinsufficiency as a disease mechanism.
In 6 affected members of an Australian family with FFEVF, 2 of whom had evidence of focal cortical dysplasia, Scheffer et al. (2014) identified a heterozygous truncating mutation in the DEPDC5 gene (Q140X; 614191.0012).
By whole-exome sequencing of 207 unrelated patients with rolandic epilepsy and atypical rolandic epilepsy, Lal et al. (2014) identified 5 heterozygous variants in the DEPDC5 gene, including 1 truncating mutation, a splice site variant, and 3 missense variants of uncertain significance. However, the unaffected father of 1 of the patients with a missense variant was homozygous for the variant, suggesting it was not pathogenic. In a second cohort of 82 unrelated patients with focal or cryptogenic epilepsy, 2 were found to carry heterozygous truncating mutations in the DEPDC5 gene. Overall, 4 of the variants, 3 truncating and 1 splice site variants, were predicted to be damaging. The report strengthened the association between DEPDC5 and focal epilepsies, including rolandic epilepsy, although functional studies of the variants were not performed and segregation analyses within the families were incomplete.
Ricos et al. (2016) identified heterozygous mutations in the DEPDC5 gene in 18 of 322 probands with focal epilepsy. There was significant incomplete penetrance. Functional studies of the variants and studies of patient cells were not performed.
Weckhuysen et al. (2016) identified 4 heterozygous truncating mutations in the DEPDC5 gene in 4 (8%) of 50 probands with focal epilepsy with or without focal cortical dysplasia. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function and haploinsufficiency.
In 6 affected members of a French-Canadian family with FFEVF1, Nascimento et al. (2015) identified a heterozygous nonsense mutation in the DEPDC5 gene (Q216X; 614191.0015). The mutation segregated with the disorder in the family, although there was 1 asymptomatic carrier. Functional studies of the variant and studies of patient cells were not performed.
In a 6-year-old child with FFEVF1 and focal cortical dysplasia type IIa, Ribierre et al. (2018) identified a heterozygous germline nonsense mutation in the DEPDC5 gene (R286X; 614191.0013). The mutation, which was found by sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous nonsense mutation (Q289X) in the DEPDC5 that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (180460), consistent with increased mTOR (601231) activity.
In 10 individuals from 7 unrelated Han Chinese families with FFEVF1, Liu et al. (2020) identified heterozygous mutations in the DEPDC5 gene (see, e.g., 614191.0006 and 614191.0014). The mutations were found by sequencing of a targeted gene panel and confirmed by Sanger sequencing. Three families (families A-C) carried truncating mutations (2 nonsense and 1 frameshift), and family D carried a termination extension mutation, all of which were absent from gnomAD and predicted to result in functional haploinsufficiency. Studies of patient cells were not performed. Three families carried missense variants (Y7C, Y836C, and G1545S) that were present at low frequencies in public databases and were considered to be variants of uncertain significance (VUS). Of the whole cohort, 6 patients had focal epilepsy with febrile seizures-plus (FEFS+), 1 had febrile seizures, and 3 had focal or unclassified epilepsy. Four unaffected parents carried the variants, indicating incomplete penetrance. In addition, 8 individuals from 4 families (families G-J) with FEFS+, febrile seizures, or rolandic epilepsy, carried a heterozygous P1031H missense variant, and 1 patient (family K) with frontal lobe epilepsy with focal cortical dysplasia carried a homozygous P1031H variant. However, the authors noted that the pathogenicity of the P1031H variant is unclear, and has been classified as a VUS or likely benign. The 12 probands were ascertained from a cohort of 305 patients with focal epilepsy, with DEPDC5 variants accounting for 3.9%. The findings expanded the phenotype of FFEVF1 to include febrile seizures and FEFS+.
Baulac et al. (2015) found that 1 of the patients in the family reported by Ishida et al. (2013) who had a germline R239X mutation in the DEPDC5 gene (614191.0006) also carried a somatic heterozygous truncating mutation (R422X) in the DEPDC5 gene; the mutation was detected in a brain specimen examined after the patient underwent surgery for seizures. Histology of this brain sample was poor, but showed FCD I with a disturbance of cortical lamination. Baulac et al. (2015) suggested that this second mutation in the DEPDC5 gene resulted in biallelic inactivation in this tissue, consistent with a 2-hit hypothesis. However, brain tissue from an unrelated FFEVF patient with a heterozygous germline DEPDC5 mutation and similar brain pathology did not show a somatic DEPDC5 mutation.
Similar to the findings of Baulac et al. (2015), Ribierre et al. (2018) identified a somatic mosaic heterozygous nonsense mutation in the DEPDC5 gene (Q289X) in resected brain tissue from a 6-year-old patient with FFEVF1 and focal cortical dysplasia type IIa who had a germline heterozygous nonsense DEPDC5 mutation (R286X; 614191.0013). The somatic mosaic Q289X mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient and the Knudson 2-hit hypothesis in the developmental of focal cortical dysplasia. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (180460), consistent with increased mTOR activity.
Martin et al. (2014) identified 2 different heterozygous mutations in the DEPDC5 gene (R843X, 614191.0010 and T864M, 614191.0011) in 4 (5%) of 79 French Canadian probands with focal epilepsy. Haplotype analysis indicated that R843X was a founder mutation. Functional studies were not performed. Martin et al. (2014) noted that Dibbens et al. (2013) had previously identified the R843X mutation in a French Canadian family with the disorder.
Ribierre et al. (2018) found that mouse embryos with focal mosaic knockdown of the Depdc5 gene in postmitotic neurons, generated by in utero electrocorporation and CRISPR/Cas9 gene editing, demonstrated impaired neuronal radial migration to the cortical plate. The mutant neurons were round and balloon-like, similar to dysmorphic neurons found in focal cortical dysplasia IIa. These abnormalities were associated with increased mTOR (601231) activity, and the neuronal migration defects could be prevented by treatment with the mTOR inhibitor rapamycin. Focal mosaic mutant mice showed increased susceptibility to focal seizures, and some showed seizure-related death, reminiscent of sudden expected death in epilepsy (SUDEP). Pyramidal cells from mutant mice showed increased complexity of dendritic branching, hypertrophy of dendritic spins, and enhanced excitatory synaptic activity compared to controls. These findings indicated that complete inactivation of Depdc5 during brain development causes epilepsy with focal cortical malformations, and that biallelic DEPDC5 mutations, germline and brain somatic mosaic (representing Knudson's 2-hit hypothesis of disease mechanism), underlie the focal cortical dysplasia that is sometimes observed in this disorder.
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