To provide new insights into the pathological mechanisms of epilepsy associated with variants in the calcium channel voltage-dependent L-type alpha1C subunit gene (CACNA1C, NM_001129837) and to expand the phenotype of CACNA1C-associated neurological disorders: familial mesial temporal lobe epilepsy (FMTLE). We conducted a comprehensive analysis of clinical data from a family affected by FMTLE and carried out genetic screening of CACNA1C variants through whole-exome sequencing combined with Sanger sequencing for validation. The clinical characteristics of FMTLE were systematically reviewed, and the pathogenic potential of the identified variant was assessed following the guidelines established by the American College of Medical Genetics and Genomics (ACMG). To explore the underlying pathogenic mechanisms, we utilized bioinformatics tools alongside molecular dynamics simulation methods. A novel CACNA1C variant (c.5480G > A, p.R1827Q) was identified in a large family with FMTLE. Unlike previous reports, the clinical phenotype of this genotype differs from previous reports, being mild, with focal to bilateral tonic-clonic seizures being more common. Bioinformatics analysis and molecular dynamics simulations indicated that this variant induces local structural changes in the protein. The findings of this study provide new insights into the complex molecular mechanisms underlying CACNA1C variants and their correlations with patient phenotypes. This research is the first to identify CACNA1C as a potentially new pathogenic gene in FMTLE.

To expand the clinical phenotype and mutation spectrum of familial mesial temporal lobe epilepsy (FMTLE) and provide a new perspective for exploring the pathological mechanisms of epilepsy caused by leucine-rich glioma inactivated 1 (LGI1) variants. We reported clinical data from two families with FMTLE and screened patients for variants in the LGI1 gene using Whole-exome sequencing and Sanger sequencing. The clinical features of FMTLE were analysed. The pathogenicity of the causative loci was assessed according to the American College of Medical Genetics and Genomics guidelines, and potential pathogenic mechanisms were predicted through multiple bioinformatics and molecular dynamics software. We identified two novel LGI1 truncating variants within two large families with FMTLE: LGI1 (c.1174C>T, p.Q392X) and LGI1 (c.703C>T, p.Q235X). Compared to previous reports, we found that focal to bilateral tonic-clonic seizures are a common type of seizure in FMTLE. The clinical phenotypes of patients with FMTLE caused by LGI1 variants were relatively mild, and all patients responded well to valproic acid. Bioinformatics analyses and molecular dynamics simulations showed that protein structure and interactions were considerably weakened or damaged as a result of both variants. This study presents the first report identifying LGI1 as a potential novel pathogenic gene within FMTLE families, thereby broadening the mutation spectrum associated with FMTLE. The findings of this study offer novel insights and avenues for understanding the intricate molecular mechanisms underlying LGI1 variants and their correlations with patient phenotypes. This study proposes the possibility of familial focal epilepsy syndromes overlapping.

Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835. DEPDC5-related epilepsy encompasses a range of epilepsy syndromes, almost all of which are characterized by focal seizures, with seizure onset in a discrete area of the brain. While most individuals with DEPDC5-related epilepsy have a normal brain MRI, some have epilepsy associated with a cortical malformation, usually focal cortical dysplasia or hemimegalencephaly. Seizure syndromes include familial focal epilepsy with variable foci (FFEVF), autosomal dominant sleep-related hypermotor epilepsy (ADSHE), familial mesial temporal lobe epilepsies (FMTLE), autosomal dominant epilepsy with auditory features (ADEAF), infantile spasms, and severe developmental encephalopathy. Although psychomotor development is usually normal, developmental delays, intellectual disability, or autism spectrum disorder have been reported in some individuals. The diagnosis of DEPDC5-related epilepsy is established in a proband with suggestive findings and at least one heterozygous pathogenic variant in DEPDC5 identified by molecular genetic testing. Some affected individuals have biallelic variants in DEPDC5, and some have a second mosaic (or postzygotic) DEPDC5 variant within the brain. Treatment of manifestations: The response to anti-seizure medication (ASM) is variable. While some individuals respond well to first-line ASMs, others are more refractory to treatment. There is currently no evidence that seizures respond better to one specific ASM. In individuals with hemimegalencephaly or focal cortical dysplasia and refractory epilepsy, resective epilepsy surgery should be explored early in the disease course. Standard treatment for developmental delay / intellectual disability and autism spectrum disorders. Surveillance: Assess for new or ongoing neurologic manifestations (such as new-onset seizures or changes in seizure symptoms), predictive factors for sudden unexpected death in epilepsy, and developmental progress at each visit. Repeat EEG as appropriate when seizure frequency increases or when seizures of new symptomatology occur. Repeat brain MRI with a higher-resolution technique in individuals with treatment-resistant seizures whose first brain MRI was normal to rule out subtle cortical dysplasia. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for developing seizures as early as possible. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family. Pregnancy management: Pregnant women should receive counseling regarding the risks and benefits of using ASM during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily; the effects of pregnancy on ASM metabolism; and the effect of pregnancy on maternal seizure control. DEPDC5-related epilepsy is an autosomal dominant disorder; however, affected individuals with germline biallelic missense variants have been rarely reported. All probands reported to date with biallelic DEPDC5 variants inherited variants from their heterozygous parents. In these families, heterozygous parents may or may not have manifestations of DEPDC5-related epilepsy. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If one parent of the proband has a DEPDC5 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. If both parents of a proband have a DEPDC5 pathogenic variant, sibs have a 75% chance of inheriting one or two pathogenic variants and a 25% chance of inheriting neither pathogenic variant and not being affected. Once the DEPDC5 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Most patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) have hippocampal sclerosis on the postoperative histopathological examination. Although most patients with MTLE do not refer to a family history of the disease, familial forms of MTLE have been reported. We studied surgical specimens from patients with MTLE who had epilepsy surgery for medically intractable seizures. We assessed and compared gene expression profiles of the tissue lesion found in patients with familial MTLE (n = 3) and sporadic MTLE (n = 5). In addition, we used data from control hippocampi obtained from a public database (n = 7). We obtained expression profiles using the Human Genome U133 Plus 2.0 (Affymetrix) microarray platform. Overall, the molecular profile identified in familial MTLE differed from that in sporadic MTLE. In the tissue of patients with familial MTLE, we found an over-representation of the biological pathways related to protein response, mRNA processing, and synaptic plasticity and function. In sporadic MTLE, the gene expression profile suggests that the inflammatory response is highly activated. In addition, we found enrichment of gene sets involved in inflammatory cytokines and mediators and chemokine receptor pathways in both groups. However, in sporadic MTLE, we also found enrichment of epidermal growth factor signaling, prostaglandin synthesis and regulation, and microglia pathogen phagocytosis pathways. Furthermore, based on the gene expression signatures, we identified different potential compounds to treat patients with familial and sporadic MTLE. To our knowledge, this is the first study assessing the mRNA profile in surgical tissue obtained from patients with familial MTLE and comparing it with sporadic MTLE. Our results clearly show that, despite phenotypic similarities, both forms of MTLE present distinct molecular signatures, thus suggesting different underlying molecular mechanisms that may require distinct therapeutic approaches.

The objectives of this study were to determine the inheritance pattern by which familial mesial temporal lobe epilepsy (FMTLE) is segregated in Mexican families, and to identify if there was an association between the clinical characteristics and the inheritance pattern. We included a total of 25 families with two or more members affected with MTLE during two years and elaborated a family pedigree for each family. The inheritance pattern was classified as autosomal dominant (AD) or autosomal recessive (AR), considering the affected members. We used statistical analysis association and differences between clinical characteristics and inheritance patterns. The affected families with the AD pattern were 15.7 fold times more likely to start seizures at 5 years of age or earlier than families with AR pattern, OR = 15.7 (IC 95% = 1.9-128.9). We observed a predominance and greater déjà vu association (64.4% vs 31.3%; p = 0.021), OR = 3.9 (CI 95% = 1.1-13.5) in patients with AD versus AR pattern. Finally, we identified that patients with AD pattern had a likelihood of presenting emotional alterations 5.6 times higher than AR (OR = 5.6, IC = 1.1-27.5). FMTLE is a heterogeneous syndrome, both phenotypically and genotypically; thus, our findings may be helpful for clinical use to perform an early diagnosis, to provide timely treatment, and to prevent comorbidities associated to this disease. However, in order to identify the possible genetic causes underlying these inheritance patterns, the use of molecular studies is necessary.