Lateral temporal lobe epilepsy (LTLE) is characterized by auditory auras and is often associated with genetic factors. Previous studies have identified various genes linked to LTLE, including LGI1. However, there remains a need to explore other genetic variants that contribute to the LTLE phenotype, particularly in the absence of LGI1 mutations. A cohort followed in our epilepsy center and diagnosed as LTLE with auditory aura was recruited to the study. We have performed whole exome sequencing data analysis of 19 patients using a two-step approach. In the first step, we have focused on six LTLE associated genes, namely LGI1, RELN, MICAL1, CNTNAP2, DEPDC5 and SCN1A. In the second step, the data was filtered against a list of epilepsy related genes. Our analysis identified novel variants in LTLE-associated genes, including RELN, SCN1A, and CNTNAP2, which confirmed previous findings. Importantly, for the first time, we identified a loss-of-function variation in the CHRNB2 gene that may be associated with the LTLE phenotype. Our study underscores the genetic heterogeneity of lateral temporal lobe epilepsy (LTLE) by identifying new genetic variants linked to the disorder. Notably, we propose that CHRNB2 is a novel gene associated with LTLE, thereby broadening the spectrum of known genetic contributors. This finding highlights the complexity of LTLE's genetic landscape and suggests new pathways for future research and clinical application.

Monoallelic pathogenic variants in LGI1 cause autosomal dominant epilepsy with auditory features with onset in childhood/adolescence. LGI1 is a secreted neuronal protein, functions as a ligand for ADAM22/23, and regulates excitatory synaptic transmission and neuronal excitability in the brain. While biallelic ADAM22 variants cause developmental and epileptic encephalopathy (DEE), the whole picture of LGI1-ADAM22/23 pathway-related diseases remains incompletely understood. Through international genetic data sharing, we identified the first ultra-rare biallelic LGI1 variants in six individuals from four consanguineous families. Affected individuals presented DEE with neonatal/infantile-onset epilepsy (n = 6/6), global developmental delay/intellectual disability (n = 6/6) and infant/premature death (n = 5/6). Brain MRI showed mild cerebral atrophy in a subset of patients (n = 3/6). Functional analyses revealed that all LGI1 variants result in reduced secretion and ADAM22-binding. Residual LGI1 function levels correlated with clinical severity, ranging from infantile lethality to intermediate phenotypes. Further, we observed epileptic discharges from the isolated whole hippocampus of Lgi1-/- knockout mice, experimentally modelling the hippocampal origin of LGI1-related epilepsy. Automated behavioural analysis of a mouse model for ADAM22-related DEE revealed its impaired cognitive function. Furthermore, we report the first ADAM23 variant associated with lethal neonatal-onset epilepsy and myopathy. Collectively, this study defines the LGI1-ADAM22/23 pathway-related disease spectrum.

Pathogenic KCNQ2 variants are associated with neonatal epilepsies, ranging from self-limited neonatal epilepsy to KCNQ2-developmental and epileptic encephalopathy (DEE). In this study, next-generation sequencing was performed, applying a panel of 142 epilepsy genes on three unrelated individuals and affected family members, showing a wide variability in the epileptic spectrum. The genetic analysis revealed two likely pathogenic missense variants (c.1378G>A and c.2251T>G) and the already-reported pathogenic splice site (c.1631+1G>A) in KCNQ2 (HGNC:6296). The phenotypes observed in the affected members of family 1, which shared the c.2251T>G variant, were epilepsy with auditory features (EAFs), focal epilepsy, and generalized epilepsy, and none of them suffered from neonatal seizures. The gene panel contained further genes related to EAFs (LGI1, RELN, SCN1A, and DEPDC5), which were tested with negative results. The phenotypes observed in family 2 members, sharing the splice site variant, were neonatal seizures and focal epilepsy in childhood. The last unrelated proband, harboring the de novo missense c.1378G>A, presented a clinical phenotype consistent with DEE. In conclusion, we identified two unreported KCNQ2 variants, and report a proband with EAFs and individuals without typical KCNQ2 neonatal seizures. Our study underscores the extreme variability in the phenotypic spectrum of KCNQ2-related epilepsies and unveils the prospect of its inclusion in screening panels for EAFs. Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds including humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion. Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms. Age at onset is usually in adolescence or early adulthood (age 10-30 years). The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy. The clinical diagnosis of ADEAF can be established in a proband with characteristic clinical features, normal brain imaging by MRI, and family history consistent with autosomal dominant inheritance. The molecular diagnosis is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in LGI1, MICAL1, or RELN identified by molecular genetic testing. Treatment of manifestations: Seizure control is usually readily achieved with standard anti-seizure medications (ASM). Surveillance: Monitoring of epilepsy as clinically indicated; neurocognitive assessments in individuals suspected to have memory or attention deficits; evaluation by a psychiatrist for any psychiatric comorbidities. Evaluation of relatives at risk: Interviewing relatives at risk to identify those with suggestive findings may enable early treatment in those who develop seizures. Pregnancy management: Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible. By definition, ADEAF is inherited in an autosomal dominant manner. Most individuals diagnosed with ADEAF have an affected parent; the proportion of individuals with ADEAF caused by a de novo pathogenic variant is believed to be low. Offspring of an individual with ADEAF who is heterozygous for a pathogenic variant have a 50% chance of inheriting the pathogenic variant; the chance that offspring who inherit the pathogenic variant will manifest ADEAF ranges from 54% to 85% depending on the assumed penetrance. Once the ADEAF-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Familial epilepsy with auditory features (FEAF), previously known as autosomal-dominant lateral temporal lobe epilepsy (ADLTE) is a genetically heterogeneous syndrome, clinically characterized by focal seizures with prominent auditory symptoms. It is inherited with autosomal-dominant pattern with reduced penetrance (about 70%). Sporadic epilepsy with auditory features cases are more frequent and clinically indistinguishable from familial cases. One causal gene, MICAL-1, encodes MICAL-1, an intracellular multi-domain enzyme that is an important regulator of filamentous actin (F-actin) structures. Pathogenic variants in MICAL-1 account for approximately 7% of FEAF families. Here, we describe a de novo MICAL-1 pathogenic variant, p.Arg915Cys, in a sporadic case, an affected 21-year-old Italian man with no family history of epilepsy. Genetic testing was performed in the patient and his parents, using a next-generation sequencing panel. In cell-based assay, this variant significantly increased MICAL-1 oxidoreductase activity, which likely resulted in dysregulation of F-actin organization. This finding provides further support for a gain-of-function effect underlying MICAL-1-mediated epilepsy pathogenesis, as previously seen with other pathogenic variants. Furthermore, the case study provides evidence that de novo MICAL-1 pathogenic variants can occur in sporadic cases with epilepsy with auditory feature (EAF). PLAIN LANGUAGE SUMMARY: In this study, we report a new MICAL-1 pathogenic variant in a patient without family history for epilepsy, not inherited from his parents. MICAL-1 is a protein with enzymatic activity that reorganizes the structure of the cell. We proved the pathological effect of this variant by testing its enzymatic activity and found an increase of this activity. This result suggests that non-familial cases should be tested to find novel pathogenic variants in this gene. 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.

Autosomal dominant epilepsy with auditory features (OMIM 600512) is characterised by focal seizures with distinctive auditory auras and/or ictal aphasia. We describe a 17-year-old girl with recurrent attacks of ictal aphasia and rare nocturnal convulsions. She had a four-generation paternal family history of epilepsy. Her father and aunt perceived bells ringing at the onset of seizures. Sequence analysis of the leucine-rich glioma-inactivated 1 (LGI1) gene identified a novel heterozygous variant in the proband and her father. LGI1-related genetic epilepsy has a benign clinical course with a favourable response to anti-seizure medications. Auditory or vertiginous seizures may be mistaken for peripheral audio-vestibular symptoms, while complex auditory ictal symptoms may be misattributed to primary psychiatric disorders. Recognising this distinctive inherited syndrome should prompt targeted analysis of the LGI1 gene.