RARE DISEASE
Benign partial infantile seizures
Benign partial infantile seizures
Benign partial infantile seizures
Drug discovery
26
papers
On emerging therapies
Overview
Benign partial infantile seizures (BPIS), also termed self-limited infantile epilepsy (SeLIE) or benign familial infantile epilepsy (BFIE), are focal-onset seizures occurring in neurologically normal infants aged 3–20 months (peak 3–8 months). Seizures typically present as clusters of brief episodes with motor arrest, eye deviation, clonic jerks, and autonomic features, often resolving within 1–2 years. Most cases are linked to PRRT2 or SCN2A mutations. Prognosis is excellent with normal development and pharmacoresponsiveness [1][2][16].
Burden
Low morbidity: No cognitive deficits in 95% of cases, though rare association with paroxysmal dyskinesias (e.g., ICCA syndrome) [1][2].
Familial impact: Genetic counseling recommended for families with PRRT2 mutations [17].
Diagnostic costs: EEG/MRI often normal, reducing long-term monitoring needs [9][16].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
26 drug discovery papers about Benign partial infantile seizures. Recent publications:
26 drug discovery papers about Benign partial infantile seizures. Recent publications:
categories:
Small molecules
small molecules
2021-12-25 | Phenotypic and genetic spectrum in Chinese children with SCN8A-related disorders
BackgroundPathogenic variants in SCN8A have been demonstrated with a wide spectrum of epilepsy phenotypes, ranging from benign infantile epilepsy (BIE), to early onset developmental and epileptic encephalopathy (DEE) with moderate to severe developmental delay. In order to provide further insight on the spectrum of SCN8A-related epilepsy, we aimed to explore the clinical and genetic phenotype in Chinese children.MethodsA cohort of fifty Chinese patients with SCN8A-related disorders was included in the retrospective study. Genetic and clinical features and treatment effect of patients were further assessed based on phenotype parameters. The pathogenicity of variants was classified using the next-generation sequencing variation study.ResultsWe found 50 patients who presented with severe developmental and epileptic encephalopathy (DEE, 70%), benign infantile epilepsy (BIE, 12%), developmental encephalopathy with epilepsy (16%), and severe developmental delay without epilepsy (2%). The seizure onset age ranged from 1 day to 1 year and 11 months. After anti-seizure treatment, 28% of patients obtained seizure control. Sodium channel blockers showed good prognosis in 26% of patients with severe DEE. Oxcarbazepine (OXC) monotherapy was obviously effective in patients with BIE and developmental encephalopathy with epilepsy, most importantly, 87.5% received the anti-seizure therapy with sodium channel blockers in combination. All the variants were de novo missense with exception of one splice site variant. We reported three new variants, Asn1887Ser, Ile1605Thr, and Met1869Thr, which were associated with SCN8A-BIE.ConclusionThe phenotypic spectrum of SCN8A-related disorders in Chinese children ranged from severe developmental delay without epilepsy to severe DEE. Three new variants were associated with SCN8A-BIE. Sodium channel blockers were effective in treating seizures for some SCN8A-related disorders however may not be relevant to the mutant location.
2019-04-10 | The spectrum of intermediate SCN8A‐related epilepsy
Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies.A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study.We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser.With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.
2017-07-28 | Effects of various antiepileptic drugs in benign infantile seizures with mild gastroenteritis
Purpose: This study sought to deter mine the appr opr iate choice of antiepileptic dr ugs (AEDs) for seizures during the acute phase in patients with benign infantile seizures with mild gastroenteritis (BISMG).Methods: We retrospectively investigated the efficacy and dose of AEDs for BISMG by reviewing the medical records of 42 patients diagnosed with BISMG.In this study, AEDs were regarded as effective when seizures ceased for >24 h after administration.Results: AEDs were administered to 39 of 42 patients (92.9%).Carbamazepine was effective in 21 of 21 patients (100.0%),phenytoin/fos-phenytoin in three of four patients (75.0%), midazolam in one of two patients (50.0%), lidocaine in one of two patients (50.0%), and diazepam in 13 of 36 patients (36.1%).Intravenous diazepam was effective in seven of 11 patients (63.6%) and suppository diazepam in 10 of 25 patients (40.0%).The median dose of carbamazepine was 5.0 mg/kg/day (range, 3.0-5.0mg/kg/day) and the median duration of medication was 1 day (range, 1-5 days).Conclusion: Tr eatment for 1 day with low-dose carbamazepine was effective for BISMG.Phenytoin/fosphenytoin and intravenous diazepam, not but suppository diazepam, were also effective.We recommend 1 day of treatment with low-dose carbamazepine as the first-line treatment for BISMG.The unnecessary use of AEDs for BISMG should be avoided after the acute phase because seizures in BISMG rarely recur.
2016-07-01 | Clinical Potential of Neurosteroids for CNS Disorders
Neurosteroids are key endogenous molecules in the brain that affect many neural functions. We describe here recent advances in US National Institutes of Health (NIH)-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus (SE), traumatic brain injury (TBI), fragile X syndrome (FXS), and chemical neurotoxicity. The neurosteroid field has entered a new era, and many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends.
2014-01-06 | Sodium Channels, Inherited Epilepsy, and Antiepileptic Drugs
Voltage-gated sodium channels initiate action potentials in brain neurons, mutations in sodium channels cause inherited forms of epilepsy, and sodium channel blockers—along with other classes of drugs—are used in therapy of epilepsy. A mammalian voltage-gated sodium channel is a complex containing a large, pore-forming α subunit and one or two smaller β subunits. Extensive structure-function studies have revealed many aspects of the molecular basis for sodium channel structure, and X-ray crystallography of ancestral bacterial sodium channels has given insight into their three-dimensional structure. Mutations in sodium channel α and β subunits are responsible for genetic epilepsy syndromes with a wide range of severity, including generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome, and benign familial neonatal-infantile seizures. These seizure syndromes are treated with antiepileptic drugs that offer differing degrees of success. The recent advances in understanding of disease mechanisms and sodium channel structure promise to yield improved therapeutic approaches.
proteins
2023-06-19 | Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype.
The Phospholipid Phosphatase Related 4 gene (PLPPR4, *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus, we screened 18 patients with infantile epileptic spasms syndrome (IESS) and 98 patients with benign familial neonatal/infantile seizures (BFNS/BFIS) for the presence of PLPPR4 variants. A girl with IESS had inherited a PLPPR4-mutation (c.896C > G, NM_014839; p.T299S) from her father and an SCN1A-mutation from her mother (c.1622A > G, NM_006920; p.N541S). The PLPPR4-mutation was located in the third extracellular lysophosphatidic acid-interacting domain and in-utero electroporation (IUE) of the Prg-1p.T300S construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1Ap.N541S channel revealed partial loss-of-function. Another PLPPR4 variant (c.1034C > G, NM_014839; p.R345T) that was shown to result in a loss-of-function aggravated a BFNS/BFIS phenotype and also failed to suppress glutamatergic neurotransmission after IUE. The aggravating effect of Plppr4-haploinsufficiency on epileptogenesis was further verified using the kainate-model of epilepsy: double heterozygous Plppr4-/+|Scn1awt|p.R1648H mice exhibited higher seizure susceptibility than either wild-type, Plppr4-/+, or Scn1awt|p.R1648H littermates. Our study shows that a heterozygous PLPPR4 loss-of-function mutation may have a modifying effect on BFNS/BFIS and on SCN1A-related epilepsy in mice and humans.
2020-10-14 | Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis
Abstract Mutations in proline-rich transmembrane protein 2 ( PRRT2 ) have been recently identified as the leading cause of a clinically heterogeneous group of neurological disorders sharing a paroxysmal nature, including paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. To date, studies aimed at understanding its physiological functions in neurons have mainly focused on its ability to regulate neurotransmitter release and neuronal excitability. Here, we show that PRRT2 expression in non-neuronal cell lines inhibits cell motility and focal adhesion turnover, increases cell aggregation propensity, and promotes the protrusion of filopodia, all processes impinging on the actin cytoskeleton. In primary hippocampal neurons, PRRT2 silencing affects the synaptic content of filamentous actin and perturbs actin dynamics. This is accompanied by defects in the density and maturation of dendritic spines. We identified cofilin, an actin-binding protein abundantly expressed at the synaptic level, as the ultimate effector of PRRT2. Indeed, PRRT2 silencing unbalances cofilin activity leading to the formation of cofilin-actin rods along neurites. The expression of a cofilin phospho-mimetic mutant (cof-S3E) is able to rescue PRRT2-dependent defects in synapse density, spine number and morphology, but not the alterations observed in neurotransmitter release. Our data support a novel function of PRRT2 in the regulation of the synaptic actin cytoskeleton and in the formation of synaptic contacts.
small molecules
2021-12-25 | Phenotypic and genetic spectrum in Chinese children with SCN8A-related disorders
BackgroundPathogenic variants in SCN8A have been demonstrated with a wide spectrum of epilepsy phenotypes, ranging from benign infantile epilepsy (BIE), to early onset developmental and epileptic encephalopathy (DEE) with moderate to severe developmental delay. In order to provide further insight on the spectrum of SCN8A-related epilepsy, we aimed to explore the clinical and genetic phenotype in Chinese children.MethodsA cohort of fifty Chinese patients with SCN8A-related disorders was included in the retrospective study. Genetic and clinical features and treatment effect of patients were further assessed based on phenotype parameters. The pathogenicity of variants was classified using the next-generation sequencing variation study.ResultsWe found 50 patients who presented with severe developmental and epileptic encephalopathy (DEE, 70%), benign infantile epilepsy (BIE, 12%), developmental encephalopathy with epilepsy (16%), and severe developmental delay without epilepsy (2%). The seizure onset age ranged from 1 day to 1 year and 11 months. After anti-seizure treatment, 28% of patients obtained seizure control. Sodium channel blockers showed good prognosis in 26% of patients with severe DEE. Oxcarbazepine (OXC) monotherapy was obviously effective in patients with BIE and developmental encephalopathy with epilepsy, most importantly, 87.5% received the anti-seizure therapy with sodium channel blockers in combination. All the variants were de novo missense with exception of one splice site variant. We reported three new variants, Asn1887Ser, Ile1605Thr, and Met1869Thr, which were associated with SCN8A-BIE.ConclusionThe phenotypic spectrum of SCN8A-related disorders in Chinese children ranged from severe developmental delay without epilepsy to severe DEE. Three new variants were associated with SCN8A-BIE. Sodium channel blockers were effective in treating seizures for some SCN8A-related disorders however may not be relevant to the mutant location.
2019-04-10 | The spectrum of intermediate SCN8A‐related epilepsy
Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies.A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study.We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser.With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.
2017-07-28 | Effects of various antiepileptic drugs in benign infantile seizures with mild gastroenteritis
Purpose: This study sought to deter mine the appr opr iate choice of antiepileptic dr ugs (AEDs) for seizures during the acute phase in patients with benign infantile seizures with mild gastroenteritis (BISMG).Methods: We retrospectively investigated the efficacy and dose of AEDs for BISMG by reviewing the medical records of 42 patients diagnosed with BISMG.In this study, AEDs were regarded as effective when seizures ceased for >24 h after administration.Results: AEDs were administered to 39 of 42 patients (92.9%).Carbamazepine was effective in 21 of 21 patients (100.0%),phenytoin/fos-phenytoin in three of four patients (75.0%), midazolam in one of two patients (50.0%), lidocaine in one of two patients (50.0%), and diazepam in 13 of 36 patients (36.1%).Intravenous diazepam was effective in seven of 11 patients (63.6%) and suppository diazepam in 10 of 25 patients (40.0%).The median dose of carbamazepine was 5.0 mg/kg/day (range, 3.0-5.0mg/kg/day) and the median duration of medication was 1 day (range, 1-5 days).Conclusion: Tr eatment for 1 day with low-dose carbamazepine was effective for BISMG.Phenytoin/fosphenytoin and intravenous diazepam, not but suppository diazepam, were also effective.We recommend 1 day of treatment with low-dose carbamazepine as the first-line treatment for BISMG.The unnecessary use of AEDs for BISMG should be avoided after the acute phase because seizures in BISMG rarely recur.
2016-07-01 | Clinical Potential of Neurosteroids for CNS Disorders
Neurosteroids are key endogenous molecules in the brain that affect many neural functions. We describe here recent advances in US National Institutes of Health (NIH)-sponsored and other clinical studies of neurosteroids for CNS disorders. The neuronal GABA-A receptor chloride channel is one of the prime molecular targets of neurosteroids. Allopregnanolone-like neurosteroids are potent allosteric agonists as well as direct activators of both synaptic and extrasynaptic GABA-A receptors. Hence, neurosteroids can maximally enhance synaptic phasic and extrasynaptic tonic inhibition. The resulting chloride current conductance generates a form of shunting inhibition that controls network excitability, seizures, and behavior. Such mechanisms of neurosteroids are providing innovative therapies for epilepsy, status epilepticus (SE), traumatic brain injury (TBI), fragile X syndrome (FXS), and chemical neurotoxicity. The neurosteroid field has entered a new era, and many compounds have reached advanced clinical trials. Synthetic analogs have several advantages over natural neurosteroids for clinical use because of their superior bioavailability and safety trends.
2014-01-06 | Sodium Channels, Inherited Epilepsy, and Antiepileptic Drugs
Voltage-gated sodium channels initiate action potentials in brain neurons, mutations in sodium channels cause inherited forms of epilepsy, and sodium channel blockers—along with other classes of drugs—are used in therapy of epilepsy. A mammalian voltage-gated sodium channel is a complex containing a large, pore-forming α subunit and one or two smaller β subunits. Extensive structure-function studies have revealed many aspects of the molecular basis for sodium channel structure, and X-ray crystallography of ancestral bacterial sodium channels has given insight into their three-dimensional structure. Mutations in sodium channel α and β subunits are responsible for genetic epilepsy syndromes with a wide range of severity, including generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome, and benign familial neonatal-infantile seizures. These seizure syndromes are treated with antiepileptic drugs that offer differing degrees of success. The recent advances in understanding of disease mechanisms and sodium channel structure promise to yield improved therapeutic approaches.
proteins
2023-06-19 | Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype.
The Phospholipid Phosphatase Related 4 gene (PLPPR4, *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus, we screened 18 patients with infantile epileptic spasms syndrome (IESS) and 98 patients with benign familial neonatal/infantile seizures (BFNS/BFIS) for the presence of PLPPR4 variants. A girl with IESS had inherited a PLPPR4-mutation (c.896C > G, NM_014839; p.T299S) from her father and an SCN1A-mutation from her mother (c.1622A > G, NM_006920; p.N541S). The PLPPR4-mutation was located in the third extracellular lysophosphatidic acid-interacting domain and in-utero electroporation (IUE) of the Prg-1p.T300S construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1Ap.N541S channel revealed partial loss-of-function. Another PLPPR4 variant (c.1034C > G, NM_014839; p.R345T) that was shown to result in a loss-of-function aggravated a BFNS/BFIS phenotype and also failed to suppress glutamatergic neurotransmission after IUE. The aggravating effect of Plppr4-haploinsufficiency on epileptogenesis was further verified using the kainate-model of epilepsy: double heterozygous Plppr4-/+|Scn1awt|p.R1648H mice exhibited higher seizure susceptibility than either wild-type, Plppr4-/+, or Scn1awt|p.R1648H littermates. Our study shows that a heterozygous PLPPR4 loss-of-function mutation may have a modifying effect on BFNS/BFIS and on SCN1A-related epilepsy in mice and humans.
2020-10-14 | Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis
Abstract Mutations in proline-rich transmembrane protein 2 ( PRRT2 ) have been recently identified as the leading cause of a clinically heterogeneous group of neurological disorders sharing a paroxysmal nature, including paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. To date, studies aimed at understanding its physiological functions in neurons have mainly focused on its ability to regulate neurotransmitter release and neuronal excitability. Here, we show that PRRT2 expression in non-neuronal cell lines inhibits cell motility and focal adhesion turnover, increases cell aggregation propensity, and promotes the protrusion of filopodia, all processes impinging on the actin cytoskeleton. In primary hippocampal neurons, PRRT2 silencing affects the synaptic content of filamentous actin and perturbs actin dynamics. This is accompanied by defects in the density and maturation of dendritic spines. We identified cofilin, an actin-binding protein abundantly expressed at the synaptic level, as the ultimate effector of PRRT2. Indeed, PRRT2 silencing unbalances cofilin activity leading to the formation of cofilin-actin rods along neurites. The expression of a cofilin phospho-mimetic mutant (cof-S3E) is able to rescue PRRT2-dependent defects in synapse density, spine number and morphology, but not the alterations observed in neurotransmitter release. Our data support a novel function of PRRT2 in the regulation of the synaptic actin cytoskeleton and in the formation of synaptic contacts.
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