Familial Focal Epilepsy with Variable Foci: A Novel DEPDC5 Gene Mutation

Field: Medicine (Health Sciences)

Dear Editor, The DEPDC5 gene, which includes Disheveled, Egl-10, and the Pleckstrin homology domain, plays a role in protein synthesis, cell growth, and metabolism. Loss of function in the DEPDC5 gene causes increased neuronal excitability due to increased mechanistic target of rapamycin (mTOR) signaling.[1]DEPDC5 gene mutations are the most common causes of familial focal epilepsies.[2] Familial focal epilepsy with variable foci (FFEVF) is in the group of genetic focal epilepsies, and the semiology of seizures varies within families. We aimed to demonstrate the clinical and molecular findings of three affected patients from the same family, including two brothers and their father, all of whom were shown to have the same DEPDC5 variant by trio-whole-exome sequencing (WES). Patient #1 was a 24-year-old right-handed male patient who was his mother's first pregnancy. Focal onset seizures started at the age of 12 years. According to his medical history, he was born by cesarean section due to intrauterine growth restriction and fetal distress. His walking and speech were delayed until the age of 3 years. Both the frequency and severity of seizures increased in the last 2 years. At admission, he was on sodium valproate, lamotrigine, and phenytoin. His neurologic examination was normal, and his cranial magnetic resonance imaging (MRI) was within normal limits. A neuropsychological assessment revealed no significant features. Seizure semiology was bilateral tonic-clonic with focal onset in video electroencephalography (EEG) monitoring (VEM). The seizures started from the left frontocentrotemporal region. Interictal EEG revealed independent epileptic foci in both frontocentrotemporal and bilateral temporal regions. Hypermetabolism was observed in the right frontal region on ictal single-photon emission computed tomography (SPECT). Likewise, hypometabolism was also observed in interictal SPECT and positron emission tomography (PET) on the right [Figure 1].Figure 1: (a) Ictal single-photon emission computed tomography (SPECT) indicating hypermetabolism in the right frontal region. (b) Hypometabolism on interictal SPECT in the same regionThe 21-year-old brother of patient #1 started to have seizures at the age of 6 years and has been resistant to drugs. Previously, his seizures displayed a focal onset with impaired awareness but without aura. The semiology of seizures altered at the age of 13 years, and he began to have hypermotor features, starting with a sensation that he could not be identified and continued as clusters throughout the night. He was on oxcarbazepine, lamotrigine, and clobazam at admission. No features were found in his cranial MRI and neuropsychological assessment. In VEM, multiple foci were observed interictally, but the onset of the seizures could not be lateralized or localized electrophysiologically due to hypermotor seizure semiology. The hypermetabolic activity was observed in the bilateral frontal, right posterior frontal, and right parietal regions in ictal SPECT, and the interictal SPECT and PET also showed hypometabolic activity in the same regions [Figure 2].Figure 2: Hypermetabolism on ictal single-photon emission computed tomography (a) Right frontal region, (b) Left frontal region, (c) Right posterior frontal region, (d) Right parietal regionThe 58-year-old father of the two affected brothers started to have seizures at the age of 36 years, sometimes only with dejavu as aura and sometimes focal seizures with impaired awareness and accompanied by oral automatisms. Neurologic examination and cranial MRI were normal. He was using valproic acid and topiramate at the admission of his sons without a notable response. The father did not accept any further investigation. In the father's family tree, no additional relatives with similar phenotypes were reported. Venous blood samples were taken into ethylenediamine tetraacetic acid tubes from each patient after obtaining informed consent for the molecular analysis. The genomic DNA of the patients was isolated from lymphocytes using an automated method (QIAcube instrument with QIAamp DNA Blood MiniQIAcube Kit, Qiagen, Germany). To our knowledge, the mutation in DEPDC5, including heterozygous c. 4085del p. (Asn1362Thrfs*19), was first detected using second-generation sequencing in all three patients [Figure 3]. This variant creates a shift in the reading frame starting at codon 1362. The new reading frame is predicted to end in a stop codon 18 positions downstream. The c. 4085del p. (Asn1362Thrfs*19) variant detected in our patients was located in the C-terminal domain (CTD) domain of the gene [Figure 4]. Loss-of-function variants further downstream have been described as disease-causing for DEPDC5-related epilepsy, familial focal with variable foci.[2] The identified variant is a novel variant that was neither reported in 1000 Genomes Project, GnomAD (including ExAC), CentoMD, HGMD nor ESP databases. Therefore, it is classified as likely pathogenic (class 2) according to ACMG classification criteria.Figure 3: Pedigree presentation of our familyFigure 4: The domains of the DEPDC5 gene, reported variants and their location in the gene. Different variant types are shown with different color bars. The red arrow shows the mutation detected in our casesThe familial cases in our study showed clinical variability. The siblings' seizures started in childhood, whereas their father's seizures started in adulthood. There was focal onset in the seizure semiology of the two patients who underwent VEM. Multiple epileptic foci originating from the frontal, temporal, and parietal regions were seen in the interictal EEGs of these patients. These EEG findings supported the diagnosis of FFEVF. The fathers' seizures were considered focal-onset seizures with impaired awareness. These clinical and electrophysiologic differences in the three cases from the same family are consistent with the DEPDC5-related epilepsy phenotypes reported in the literature.[2] As observed in our clinical practice, patients with focal epilepsy with DEPDC5 gene mutations are more resistant to treatment. It was decided to administer everolimus, an mTOR inhibitor, in the treatment because DEPDC5 mutations were detected in all three patients with drug-resistant seizures. If seizures could not be controlled with medical treatment, surgical treatment planning was considered. Exome sequencing is a useful method as a diagnostic tool for FFEVF. The diagnostic yield of WES in patients with epilepsy was reported to be between 33% and 45%, and the molecular diagnosis changed the clinical management of 39% of diagnosed patients.[3,4] Trio-WES (family WES) has higher diagnostic yields than solo-WES, allowing visualization of the familial segregation of the detected variant simultaneously. Its diagnostic yield was found to be 38% in a population in which solo-WES was undiagnostic.[5] Family WES (WES-trio) revealed the same novel DEPDC5 variant in all three patients and allowed for the diagnosis of each simultaneously. In conclusion, WES is highly recommended as a first-tier genetic test for disorders with prominent genetic heterogeneity and overlapping clinical features, such as epilepsy. In addition, family WES should be considered for familial cases or patients who cannot be diagnosed using solo-WES. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.