RARE DISEASE
Benign non-familial infantile seizures
Benign non-familial infantile seizures
Benign non-familial infantile seizures
Drug discovery
12
papers
On emerging therapies
Overview
Benign non-familial infantile seizures (BNFIS) are self-limited focal epilepsy syndromes occurring in neurodevelopmentally normal infants aged 3-20 months (peak 5-6 months). Characterized by brief clustered focal seizures (motor arrest, head/eye deviation, clonic jerks), they typically resolve spontaneously by age 2-3 years without neurological sequelae. Diagnosis requires normal EEG between seizures and exclusion of metabolic/structural causes [1][8][14][19].
Therapies
Categories: rare neurological diseases
Research Papers
12 drug discovery papers about Benign non-familial infantile seizures. Recent publications:
12 drug discovery papers about Benign non-familial infantile seizures. Recent publications:
categories:
Small molecules
small molecules
2026-02-09 | A Case of Atypical Presentation of Paroxysmal Movement Disorder, Contributed to PRRT2 Gene Variant
The PRRT2 gene located at 16p11 encodes proline-rich transmembrane protein with the heterozygous PRRT2 mutation being commonly reported. The most common variant found was the c.649dup.(Arg217Profs*8). Various case reviews documenting pathogenic PRRT2 variants reported an association with paroxysmal movement disorders, including paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy, paroxysmal kinesigenic dyskinesia associated with infantile convulsions (PKD/IC), also known as infantile convulsions with choreoathetosis syndrome paroxysmal non-kinesigenic dyskinesia (PNKD), hemiplegic migraine, and exercise-induced dyskinesia. However, more recent reports have also documented mutation associated with a broader clinical picture presenting with congenital microcephaly, severe learning difficulties, and pharmacoresistant encephalopathy. We hereby report a patient who presented with paroxysmal dyskinesia, harbouring the mutation variant on PRRT2 gene. At 5 months of age, our proband presented to emergency because of jerking movements while in a moving car. This was followed by generalized tonic-clonic seizures and kinesigenic posturing. The latter would occur tens of times per day and a specific trigger did not always prevail. The movements responded well to low-dose carbamazepine and genetic studies confirmed a mutated variant of c.649dup.(Arg217Profs*8).
2023-09-23 | Mapping Structural Distribution and Gating-Property Impacts of Disease-Associated Missense Mutations in Voltage-Gated Sodium Channels
Abstract Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms. Our results show a high biophysical agreement (86%) between homologous disease-associated variants in different Na v genes, significantly surpassing the 60% phenotype (GoF o /LoF o ) agreement among homologous mutants, suggesting the need for more nuanced disease categorization and treatment based on specific gating-property changes. Using UniProt data, we mapped over 2,400 disease-associated missense variants across nine human Nav channels and identified three clusters of mutation hotspots. Our findings indicate that mutations near the selectivity filter generally diminish the maximal current amplitude, while those in the fast inactivation region lean towards a depolarizing shift in half-inactivation voltage in steady-state activation, and mutations in the activation gate commonly enhance persistent current. In contrast to mutations in the PD, those within the VSD exhibit diverse impacts and subtle preferences on channel activity. This study shows great potential to enhance prediction accuracy for variant effects based on the structural context, laying the groundwork for targeted drug design in precision medicine.
2020-09-04 | A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate
Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early‐onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from Benign Familial Neonatal Epilepsy (BFNE) to early‐onset developmental and epileptic encephalopathy. KCNQ2 variants account for the majority of pedigrees with BFNE and KCNQ3 variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel KCNQ3 variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S4 transmembrane segment. Whole cell patch-clamp recordings in Chinese Hamster Ovary cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilize the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to beta-hydroxybutyrate, a ketone body generated during the ketogenic diet, reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function pathogenic variant within the S4 segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed Kv7.3 variants that reduce current density. Our pharmacological results provide a rational for the use of ketogenic diet in patients carrying loss-of-function variants in Kv7.2 or Kv7.3 subunits.
2020-08-06 | Case Report: Benign Infantile Seizures Temporally Associated With COVID-19
Background: Nonfebrile illness seizures may present in previously healthy children as afebrile seizures associated with minor infections, such as mild gastroenteritis or respiratory tract infections, with a genetic predisposition. For the novel human coronavirus SARS-CoV-2 causing COVID-19, fever, cough and gastrointestinal complaints are the most common symptoms in children and a hyperimmune response may be present. No detailed temporally associated neurological complications have been documented in pediatric case series so far. Case description: We present the case of a 3-month-old girl with nonfebrile repeated seizures in a COVID-19 family setting. The infant started with mild fever and cough that lasted two days. At day 6 from onset, the girl presented two focal motor seizures with impaired consciousness and awareness. All investigations ruled out signs of meningo-encephalitis or active epilepsy, including normal electroencephalogram and cerebral magnetic resonance imaging. PCR from nasal and throat swabs was positive for SARS-CoV-2. Remarkably, blood ferritin and D-dimer levels were increased. At day 9, the infant presented another afebrile motor seizure and levetiracetam was started, with favourable response in 3 months of follow up. Much interest has raised on host genetic determinants to disease severity and susceptibility to COVID-19. We thus performed whole exome sequencing, revealing a pathogenic frameshift mutation in PRRT2 gene, in both the mother and the infant. The mother had presented two late infantile febrile convulsions with normal outcome afterwards. Discussion: The hyperimmune response described in adult cases with COVID-19 can be displayed by infants, even in absence of respiratory symptoms. Moreover, COVID-19 disease may present in infants as nonfebrile seizures, triggering early onset seizures in infants with a genetic predisposition. In this pandemic situation, precision medicine using massive sequencing can shed light to reveal underlying molecular mechanisms driving the host response to COVID-19.
2019-03-28 | Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity
Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Conventional heterozygous Scn2a knockout mice (Scn2aKO/+) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2aKO/+ mice with CX516. Additionally, Scn2aKO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2aKO/+ mice, with an increase in the gamma band. Scn2aKO/+ mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes.
small molecules
2026-02-09 | A Case of Atypical Presentation of Paroxysmal Movement Disorder, Contributed to PRRT2 Gene Variant
The PRRT2 gene located at 16p11 encodes proline-rich transmembrane protein with the heterozygous PRRT2 mutation being commonly reported. The most common variant found was the c.649dup.(Arg217Profs*8). Various case reviews documenting pathogenic PRRT2 variants reported an association with paroxysmal movement disorders, including paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy, paroxysmal kinesigenic dyskinesia associated with infantile convulsions (PKD/IC), also known as infantile convulsions with choreoathetosis syndrome paroxysmal non-kinesigenic dyskinesia (PNKD), hemiplegic migraine, and exercise-induced dyskinesia. However, more recent reports have also documented mutation associated with a broader clinical picture presenting with congenital microcephaly, severe learning difficulties, and pharmacoresistant encephalopathy. We hereby report a patient who presented with paroxysmal dyskinesia, harbouring the mutation variant on PRRT2 gene. At 5 months of age, our proband presented to emergency because of jerking movements while in a moving car. This was followed by generalized tonic-clonic seizures and kinesigenic posturing. The latter would occur tens of times per day and a specific trigger did not always prevail. The movements responded well to low-dose carbamazepine and genetic studies confirmed a mutated variant of c.649dup.(Arg217Profs*8).
2023-09-23 | Mapping Structural Distribution and Gating-Property Impacts of Disease-Associated Missense Mutations in Voltage-Gated Sodium Channels
Abstract Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms. Our results show a high biophysical agreement (86%) between homologous disease-associated variants in different Na v genes, significantly surpassing the 60% phenotype (GoF o /LoF o ) agreement among homologous mutants, suggesting the need for more nuanced disease categorization and treatment based on specific gating-property changes. Using UniProt data, we mapped over 2,400 disease-associated missense variants across nine human Nav channels and identified three clusters of mutation hotspots. Our findings indicate that mutations near the selectivity filter generally diminish the maximal current amplitude, while those in the fast inactivation region lean towards a depolarizing shift in half-inactivation voltage in steady-state activation, and mutations in the activation gate commonly enhance persistent current. In contrast to mutations in the PD, those within the VSD exhibit diverse impacts and subtle preferences on channel activity. This study shows great potential to enhance prediction accuracy for variant effects based on the structural context, laying the groundwork for targeted drug design in precision medicine.
2020-09-04 | A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate
Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early‐onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from Benign Familial Neonatal Epilepsy (BFNE) to early‐onset developmental and epileptic encephalopathy. KCNQ2 variants account for the majority of pedigrees with BFNE and KCNQ3 variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel KCNQ3 variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S4 transmembrane segment. Whole cell patch-clamp recordings in Chinese Hamster Ovary cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilize the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to beta-hydroxybutyrate, a ketone body generated during the ketogenic diet, reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function pathogenic variant within the S4 segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed Kv7.3 variants that reduce current density. Our pharmacological results provide a rational for the use of ketogenic diet in patients carrying loss-of-function variants in Kv7.2 or Kv7.3 subunits.
2020-08-06 | Case Report: Benign Infantile Seizures Temporally Associated With COVID-19
Background: Nonfebrile illness seizures may present in previously healthy children as afebrile seizures associated with minor infections, such as mild gastroenteritis or respiratory tract infections, with a genetic predisposition. For the novel human coronavirus SARS-CoV-2 causing COVID-19, fever, cough and gastrointestinal complaints are the most common symptoms in children and a hyperimmune response may be present. No detailed temporally associated neurological complications have been documented in pediatric case series so far. Case description: We present the case of a 3-month-old girl with nonfebrile repeated seizures in a COVID-19 family setting. The infant started with mild fever and cough that lasted two days. At day 6 from onset, the girl presented two focal motor seizures with impaired consciousness and awareness. All investigations ruled out signs of meningo-encephalitis or active epilepsy, including normal electroencephalogram and cerebral magnetic resonance imaging. PCR from nasal and throat swabs was positive for SARS-CoV-2. Remarkably, blood ferritin and D-dimer levels were increased. At day 9, the infant presented another afebrile motor seizure and levetiracetam was started, with favourable response in 3 months of follow up. Much interest has raised on host genetic determinants to disease severity and susceptibility to COVID-19. We thus performed whole exome sequencing, revealing a pathogenic frameshift mutation in PRRT2 gene, in both the mother and the infant. The mother had presented two late infantile febrile convulsions with normal outcome afterwards. Discussion: The hyperimmune response described in adult cases with COVID-19 can be displayed by infants, even in absence of respiratory symptoms. Moreover, COVID-19 disease may present in infants as nonfebrile seizures, triggering early onset seizures in infants with a genetic predisposition. In this pandemic situation, precision medicine using massive sequencing can shed light to reveal underlying molecular mechanisms driving the host response to COVID-19.
2019-03-28 | Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity
Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated. We investigated the behavior of mice with a conventional or conditional deletion of Scn2a in a comprehensive test battery including open field, elevated plus maze, light-dark box, three chambers, social dominance tube, resident-intruder, ultrasonic vocalization, and fear conditioning tests. We further monitored the effects of the positive allosteric modulator of AMPA receptors CX516 on these model mice. Conventional heterozygous Scn2a knockout mice (Scn2aKO/+) displayed novelty-induced exploratory hyperactivity and increased rearing. The increased vertical activity was reproduced by heterozygous inactivation of Scn2a in dorsal-telencephalic excitatory neurons but not in inhibitory neurons. Moreover, these phenotypes were rescued by treating Scn2aKO/+ mice with CX516. Additionally, Scn2aKO/+ mice displayed mild social behavior impairment, enhanced fear conditioning, and deficient fear extinction. Neuronal activity was intensified in the medial prefrontal cortex of Scn2aKO/+ mice, with an increase in the gamma band. Scn2aKO/+ mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes.
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