The CSMD genes, including CSMD1, CSMD2, and CSMD3, encoding synaptic transmembrane proteins, play important roles in neuronal maturation, growth of dendrites, and processes of synapses. Our recent study showed that CSMD1 was associated with developmental epileptic encephalopathy (DEE) and generalized epilepsy. The significance of CSMD2 and CSMD3 in human disease is unknown. Trio-based whole-exome sequencing was performed in patients with focal epilepsy without acquired etiologies. The gene-disease association was validated by excess and damaging effect of variants, genotype-phenotype correlation, and studies on spatial-temporal and single-cell expression. CSMD2 variants were identified in six and CSMD3 variants were identified in four cases with focal epilepsy. Additional CSMD3 variants were identified in three cases with febrile seizures plus and one case with infantile spasms. The variants included 1 de novo, 1 homozygous, and 12 pairs of compound heterozygous variants. All variants were missense except one and presented no or extremely low minor allele frequencies, which were significantly lower than that of benign variants and higher in excess by multiple statistical analyses. The gene-disease association was further supported by correlation between damage scoring of variants and phenotype severity. The three CSMD genes are expressed predominantly at early development stages, correlated with the neurodevelopment abnormalities/DEE. CSMD1 expression increases significantly starting with later childhood, consistent with the poor prognosis of DEE. CSMD2 presented the highest expression in the developing brain, with predominance in inhibitory neurons, explaining the focal epilepsy and focal cortical dysplasia (FCD). CSMD3 expressed in relatively low levels with less neuron-specificity explained the heterogeneous phenotypes. The CSMD genes are associated with epilepsies, CSMD2 with focal epilepsy/FCD, and CSMD3 with a phenotype spectrum that includes focal epilepsy, febrile seizures, and DEE. The distinct phenotypes of CSMD genes are explained by their features of genetic dependent stage and the development-dependent expression pattern of neuron specificity. The definition of a seizure is an abnormal, hypersynchronous discharge of cortical neurons causing transient signs and symptoms. Epilepsy is brain disorder "characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure." A diagnosis of epilepsy is considered in the following circumstances: Two unprovoked seizures more than 24 hours apart. One unprovoked seizure but with a high recurrence risk (such as abnormal baseline EEG). A diagnosis of an epilepsy syndrome. The terminology and classification of epilepsy have undergone significant change in recent years with the revised International League Against Epilepsy (ILAE) classification of epilepsies in 2017, replacing the 1989 classification. This update encompasses scientific advancement and establishes a viable clinical tool for the practicing clinician while remaining applicable for research and development of anti-epileptic therapies.  Focal Seizures have origins  “within networks limited to one hemisphere. They may be discretely localized or more widely distributed. Focal seizures may originate in subcortical structures.” Focal seizures can be further subclassified according to the following: 1. Motor onset or non-motor onset: Motor:(with subgroups of automatism, atonic, clonic, myoclonic, epileptic spasms, hyperkinetic, tonic) : automatism: coordinated, purposeful, repetitive motor activity, such as lip-smacking or swallowing  ; atonic: focal loss of tone; clonic: focal rhythmic jerking; myoclonic: irregular, brief focal jerking; epileptic spasms: focal flexion or extension of arms with flexion of the trunk ; hyperkinetic: activities such as pedaling or thrashing; tonic: sustained focal stiffening. Non-motor (with subgroups autonomic, behavior arrest, cognitive, emotional, sensory): autonomic: a sense of heat or cold, flushing, gastrointestinal sensations, a sense of heat or cold, piloerection (goosebumps), palpitations, sexual arousal, respiratory changes, or other autonomic effects   ; behavior arrest: behavioral arrest as the predominant aspect of the entire seizure; cognitive: deficits in language, thinking, or associated higher cortical functions, including feelings of déjà vu or jamais vu, hallucinations, or illusions. emotional: emotional changes, such as fear, anxiety, agitation, anger, paranoia, pleasure, joy, laughing (gelastic seizure), or crying (dacrystic seizure). These are often subjective. sensory: somatosensory sensations, such as olfactory, visual, auditory, hot or cold feeling, taste, or vestibular sensations. 2. Intact or non-intact awareness (a surrogate marker for consciousness). Awareness means consciousness during the seizure, not being aware that a seizure has occurred. Impairment of awareness at any point constitutes non-intact awareness. Responsiveness is not a classification criterion by ILAE as focal impaired consciousness seizures can be associated with alertness and responsiveness to basic commands. 3. Focal to bilateral tonic-clonic. This replaces the term "secondarily generalized tonic-clonic." "Bilateral" describes how the seizure propagates as opposed to "generalized" which describes generalized onset of the seizure location. Generalized onset seizures have origins “originating at some point within, and rapidly engaging, bilaterally distributed networks." Most generalized seizures are associated with impaired consciousness, so this is not a descriptive criterion. They are classified as motor or non-motor. As many seizures evolve into tonic-clonic, it is important to characterize the beginning of a seizure in detail. If a certain type of seizure only occurs when generalized (such as absence seizures), the "generalized" may be omitted. 1. Motor (tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms). See above for a description of terms, and the following are identifying characteristics of specific types of generalized onset motor seizures: Tonic-clonic seizure replaces the previous term "grand mal seizure" and is the most recognizable type. If initiated by myoclonic activity, it is classified as myotonic-tonic-clonic. The clonic phase usually decreases over the seizure course. They may be preceded by an "aura" or feeling of impending doom or other autonomic activity, but this does not contribute to focality of the seizure. Generalized clonic seizures begin and end with sustained jerking of the head, neck, face, and trunk. This type is most commonly seen in infants. Tonic seizures involve sustained extension, less commonly flexion, of a muscle group. It should be distinguished from dystonia and athetoid movement caused by antipsychotic medications. Atonic seizures often cause a patient to fall forward or onto the buttocks. In contrast, generalized tonic-clonic seizures generally cause a patient to fall backward. . Epileptic spasms cause flexion or extension of proximal muscles and the trunk. They occur most often in clusters and in infants, where they are called "infantile spasms.". 2. Non-motor or absence (typical, atypical, myoclonic, eyelid myoclonia). The ILAE classification systems retain the distinction between typical and atypical generalized seizures because of different EEG patterns, therapy, and prognosis. Typical generalized seizures with non-motor manifestations are commonly referred to as absence seizures. They present with sudden onset of cessation of activity, blank stare, and unresponsiveness. They usually last several seconds and are usually less than 10 seconds long. If performed during the event, EEG would show generalized epileptiform discharges. Clinically, absence seizures have some similarities to focal onset seizures with impaired consciousness (previously called complex partial seizures). Both present with staring, but they differ clinically as focal onset seizures with impaired consciousness are significantly longer lasting 30 seconds to 2 minutes; in addition to staring other associated signs are as repeated words, screaming, crying, or hallucinations. Absence seizures last only a few seconds and usually are characterized only by momentary inattention. Atypical absence seizures are associated with increased muscle tonic behavior and less abrupt beginning and ending of the event. EEG during the event would show slow, irregular spike-and-wave activity at a rate of <3 per second. Myoclonic seizures are characterized by 3-per-second myoclonic jerks ratcheting the arm upwards and correspond to 3-per-second generalized spike-and-wave readings on EEG. Eyelid myoclonia are eyelid myoclonic jerks accompanied by upward eye deviation. If accompanied by EEG abnormalities with eye closure and photosensitivity, this triad is called Jeavons syndrome. Seizures of unknown onset. If seizures are unwitnessed or unable to be accurately described, they are given this designation. They can be motor, non-motor, or unclassified.  Unclassified refers to seizures without enough descriptive information to classify or those that do not fit into other categories. Often, this includes tonic-clonic seizures for which the start is unwitnessed. There can be significant overlap between the different classifications and differing bystander opinions about the clinical presentations; therefore, the above classifications are only a framework to define seizure origin and type. The recommended classification system first classifies seizures by location (local, generalized, or unknown); then by type of epilepsy disease (focal, generalized, combined, or unknown); and finally, if the seizure and epilepsy type are part of an overall epilepsy syndrome (eg, JME, CAE, JAE). The 2017 ILAE terminology introduces new terminology, such as developmental and epileptic encephalopathy. Furthermore, the 2017 Classification also includes the following changes: 1. "Partial" becomes "focal.". 2. Awareness is used as a classifier of focal seizures. 3. The terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated. 4. New focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional. 5. Atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset. . 6. Focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure. 7. New generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic. 8. Seizures of unknown onset may have features that can still be classified. 9. Benign is replaced by the terms self-limited or pharmacoresponsive. This activity will focus on idiopathic (genetic) generalized epilepsy (IGE), one of the most well-recognized subgroups of generalized epilepsies. Idiopathic generalized epilepsy specifically refers to epilepsy syndromes such as juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), childhood absence epilepsy (CAE), and generalized tonic-clonic seizures alone.

To study seizure manifestations and outcomes in children with cortical versus white matter injury, differences potentially explaining variability of epilepsy in children with cerebral palsy. In this population-based retrospective cohort study, MRIs of children with cerebral palsy due to ischemia or haemorrhage were classified according to presence or absence of cortical injury. MRI findings were then correlated with history of neonatal seizures, seizures during childhood, epilepsy syndromes, and seizure outcomes. Of 256 children studied, neonatal seizures occurred in 57 and seizures during childhood occurred in 93. Children with neonatal seizures were more likely to develop seizures during childhood, mostly those with cortical injury. Cortical injury was more strongly associated with (1) developing seizures during childhood, (2) more severe epilepsy syndromes (infantile spasms syndrome, focal epilepsy, Lennox-Gastaut syndrome), and (3) less likelihood of reaching > 2 years without seizures at last follow-up, compared to children without cortical injury. Children without cortical injury, mainly those with white matter injury, were less likely to develop neonatal seizures and seizures during childhood, and when they did, epilepsy syndromes were more commonly febrile seizures and self-limited focal epilepsies of childhood, with most achieving > 2 years without seizures at last follow-up. The presence of cortical injury also influenced seizure occurrence, severity, and outcome within the different predominant injury patterns of the MRI Classification System in cerebral palsy, most notably white matter injury. Epileptogenesis is understood with cortical injury but not well with white matter injury, the latter potentially related to altered postnatal white matter development or myelination leading to apoptosis, abnormal synaptogenesis or altered thalamic connectivity of cortical neurons. These findings, and the potential mechanisms discussed, likely explain the variability of epilepsy in children with cerebral palsy and epilepsy following early-life brain injury in general.

Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA-associated pathogenesis which provides evidence for RNA dysfunction. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

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.

Self-limited infantile epilepsy (SeLIE) has distinctive clinical features, and the PRRT2 gene is known to be a considerable genetic cause. There have been a few studies on PRRT2-positive SeLIE only, and anti-seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients with PRRT2-positive SeLIE and to propose effective anti-seizure medications for seizure control. We retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants of PRRT2. In addition, six atypical cases with neonatal-onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum of PRRT2-related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti-seizure medications. Patients with PRRT2-related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short-duration (n = 33, 91.7%), and bilateral tonic-clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing the PRRT2 gene. One-third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti-seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control. Our results delineated the clinical characteristics of PRRT2-positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti-seizure medications for initial clustered seizure control. If afebrile bilateral tonic-clonic seizures develop in a normally developed infant as a clustered pattern, PRRT2-positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.