Benign Neonatal Convulsions Research Articles

Infantile spasm: an overview

Infantile spasm (IS) is the archetypal catastrophic childhood epilepsy syndrome. It is catastrophic for two reasons: first, it is difficult to control and second, it is strongly associated with mental retardation. In some cases, profound mental retardation is an inevitable consequence of the underlying disease; for example, lissencephaly. In other cases, the developmental outcome may be improved by controlling the seizures. Thus, early diagnosis and treatment is important. IS has a characteristic clinical presentation with flexor spasms beginning in the first year of life. The diagnosis of IS is confirmed by the electroencephalogram (EEG), which typically demonstrated hypsarrhythmia, modified hypsarrhythmia or multifocal spikewave discharges. A normal EEG should raise the possibility of one of the benign infantile seizure disorders such as benign neonatal convulsions, benign infantile familial convulsions or benign infantile myoclonus. Having identified IS clinically and confirmed

V25. Benign familial neonatal seizures and transient neonatal diabetes in a family with a mutation in ABCC8 encoding the SUR1 subunit of the ATP-sensitive potassium (K-ATP) channel

Introduction Benign familial neonatal seizures (BFNS) are a distinct epilepsy syndrome with selflimited seizures starting in the first days of life. The majority of cases is caused by mutations in the genes KCNQ2 and KCNQ3, encoding the voltage gated potassium channels Kv7.2 and Kv7.3. Methods and results We report on a family (index patient and his mother) with a phenotype, consisting of benign neonatal convulsions in association with transient neonatal diabetes mellitus. Sequencing of neonatal diabetes-related genes revealed the mutation p.R1379H (c.4139G>A) in ABCC8, encoding the regulating sulfonylurea receptor subunit of the ATP-sensitive potassium channel. Discussion The mutation in our family has been previously described in patients with transient neonatal diabetes mellitus (TNDM) and maturity onset diabetes of the young. While mutations in the K-ATP channel are known to cause a severe neurological disorder with developmental delay, epilepsy and neonatal diabetes (DEND syndrome), our family is the first report of associated benign familial neonatal seizures.

Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders

Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C > T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.

KCNQ2 abnormality in BECTS: Benign childhood epilepsy with centrotemporal spikes following benign neonatal seizures resulting from a mutation of KCNQ2

The molecular pathogenesis of benign childhood epilepsy with centrotemporal spikes (BECTS) remains unclear whereas mutations of the KCNQ2 and KCNQ3 genes have been identified as causes of benign familial neonatal convulsions. We report here a girl with benign neonatal convulsions followed by BECTS, for whom a mutation of KCNQ2 was identified. This case may provide the clue to the understanding of the molecular pathogenesis of BECTS.

Benign convulsions in newborns and infants: Occurrence, clinical course and prognosis

Background During early development severe epilepsies may appear, some with well established occurrence. Benign non-epileptic and epileptic paroxysmal syndromes with excellent prognosis occur in the same period. There are no exact data on their occurrence. Aim We have reviewed medical histories of children with benign non-epileptic or benign epileptic events: benign myoclonus of early infancy, benign neonatal sleep myoclonus, benign sleep myoclonus in infancy, benign partial epilepsy in infancy (BPEI) and benign infantile familial convulsions (BIFC) were established. The occurrence, clinical characteristics and prognosis of these syndromes were evaluated. Methods Inclusion criteria were met in 31 children. Research included retrospective analysis of clinical characteristics, laboratory values, neuroimaging and neurophysiological assessments, followed by evaluation of psychosocial development with the use of the Strengths and Difficulties Questionnaire (SDQ), fulfilled by parents. Results In our group the incidence of benign non-epileptic convulsions was 6.69 per 10 000 live births and the incidence of benign epileptic convulsions was 1.35 per 10 000. Male/female ratio in the group of children with non-epileptic events was 2.1:1. Among non-epileptic group 5 out of 23 children and among epileptic group 3 out of 8 children had minimal, mild or moderate abnormalities at neurological assessment at the time of the first clinical examination. Nonspecific changes in laboratory values were seen in 6 out of 23 in the non-epileptic and in 1 out of 8 children in the epileptic group. Neurophysiological assessments showed subtle changes in 4/23 in the non-epileptic and 6/8 in the epileptic group. Neuroimaging was not optimal in 5/23 with non-epileptic and 3/8 with epileptic events. Analysis of SDQ did not show significant deviations in psyhosocial development. Statistically significant deviation was observed only in relations with peers ( p = 0.009). Conclusions Benign neonatal and infantile convulsions are more frequent than severe epilepsies of the same age period. Results show higher proportion of males with benign non-epileptic conditions. No deviations in further development was found. Laboratory values, neuroimaging and neurophysiological assessments were normal or nonspecifically changed.

Drosophila KCNQ channel displays evolutionarily conserved electrophysiology and pharmacology with mammalian KCNQ channels.

Of the five human KCNQ (Kv7) channels, KCNQ1 with auxiliary subunit KCNE1 mediates the native cardiac IKs current with mutations causing short and long QT cardiac arrhythmias. KCNQ4 mutations cause deafness. KCNQ2/3 channels form the native M-current controlling excitability of most neurons, with mutations causing benign neonatal febrile convulsions. Drosophila contains a single KCNQ (dKCNQ) that appears to serve alone the functions of all the duplicated mammalian neuronal and cardiac KCNQ channels sharing roughly 50–60% amino acid identity therefore offering a route to investigate these channels. Current information about the functional properties of dKCNQ is lacking therefore we have investigated these properties here. Using whole cell patch clamp electrophysiology we compare the biophysical and pharmacological properties of dKCNQ with the mammalian neuronal and cardiac KCNQ channels expressed in HEK cells. We show that Drosophila KCNQ (dKCNQ) is a slowly activating and slowly-deactivating K+ current open at sub-threshold potentials that has similar properties to neuronal KCNQ2/3 with some features of the cardiac KCNQ1/KCNE1 accompanied by conserved sensitivity to a number of clinically relevant KCNQ blockers (chromanol 293B, XE991, linopirdine) and opener (zinc pyrithione). We also investigate the molecular basis of the differential selectivity of KCNQ channels to the opener retigabine and show a single amino acid substitution (M217W) can confer sensitivity to dKCNQ. We show dKCNQ has similar electrophysiological and pharmacological properties as the mammalian KCNQ channels, allowing future study of physiological and pathological roles of KCNQ in Drosophila and whole organism screening for new modulators of KCNQ channelopathies.

P01.8 Serum S100B levels in children with simple febrile seizures

Results: The incidence of benign convulsion is 8,046/10,000 live births. 65% of included children were male, 26% had minimal, mild or moderate abnormalities in neurological evaluation at the time of first clinical examination. For a similar percentage we found nonspecific changes in laboratory values (23%), neurophysiological assessments (32%) and neuroimaging (26%). Spontaneous remission of seizures were observed in 38% of children with BPEI/BIFC. Analysis of SDQ did not show significant deviations in psyhosocial development. Statistically significant deviation was observed only in relations with peers (p=0.009). Conclusions: Benign neonatal and infantile convulsions are more frequent than severe epilepsies. Results show higher proportion of males with these conditions and no deviations in further development. Laboratory values, neuroimaging and neurophysiological assessments are normal or nonspecifically changed. Antiepileptic treatment is justified in a portion of children diagnosed with BPEI/BIFC.

Calmodulin Activation Limits the Rate of KCNQ2 K+ Channel Exit from the Endoplasmic Reticulum

The potential regulation of protein trafficking by calmodulin (CaM) is a novel concept that remains to be substantiated. We proposed that KCNQ2 K+ channel trafficking is regulated by CaM binding to the C-terminal A and B helices. Here we show that the L339R mutation in helix A, which is linked to human benign neonatal convulsions, perturbs CaM binding to KCNQ2 channels and prevents their correct trafficking to the plasma membrane. We used glutathione S-transferase fused to helices A and B to examine the impact of this and other mutations in helix A (I340A, I340E, A343D, and R353G) on the interaction with CaM. The process appears to require at least two steps; the first involves the transient association of CaM with KCNQ2, and in the second, the complex adopts an "active" conformation that is more stable and is that which confers the capacity to exit the endoplasmic reticulum. Significantly, the mutations that we have analyzed mainly affect the stability of the active configuration of the complex, whereas Ca2+ alone appears to affect the initial binding step. The spectrum of responses from this collection of mutants revealed a strong correlation between adopting the active conformation and channel trafficking in mammalian cells. These data are entirely consistent with the concept that CaM bound to KCNQ2 acts as a Ca2+ sensor, conferring Ca2+ dependence to the trafficking of the channel to the plasma membrane and fully explaining the requirement of CaM binding for KCNQ2 function.

Benign neonatal convulsions and spontaneous network activity in the developing brain: is there a link?

A striking feature of the immature brain is that spontaneous patterned activity can occur in the absence of afferent activity. In the developing retina, hippocampus, somatosensory cortex and elsewhere, circumstantial evidence strongly suggests that precisely timed and co-ordinated firing of many neurons contributes to establishing the initial synaptic connections among populations of neurons, thereby building a scaffold for subsequent information processing and experience-dependent learning. Although it is well established that spontaneous network activity fades with development, precisely why these bursts of discharges cease is not known. In this issue of The Journal of PhysiologySafiulina et al. (2008) identify a new player in the developmental regulation of spontaneous hippocampal activity, which may fortuitously shed light on why certain neonatal seizure syndromes also resolve after a few weeks of life. Of the various neonatal seizure disorders, perhaps the best understood from a mechanistic viewpoint is benign familial neonatal convulsions (BFNC). This dominantly inherited syndrome is caused by loss-of-function mutations of either KCNQ2 or KCNQ3, which encode Kv7.2 and Kv7.3, respectively (Jentsch, 2000). These K+ channel subunits coassemble to give rise to hetero-tetrameric channels which exhibit slow activation upon modest degrees of depolarization, and which are inhibited by muscarinic receptors through an incompletely understood intracellular cascade (Delmas & Brown, 2005). The discovery of these channels, which followed the positional cloning of candidate genes at two chromosomal loci linked to BFNC, actually resolved a long-standing puzzle as to the identity of the so-called ‘M’ conductance known to be modulated by muscarinic agonists. Because this current normally helps to keep neurons at rest, loss-of-function KCNQ2 or KCNQ3 mutations can be expected to lead to excessive firing and thus explain the associated propensity to seizures. However, unlike many other epileptic channelopathies, seizures in BFNC tend to remit spontaneously. Why? Although Safiulina et al. do not address BFNC directly, their study raises the possibility that the spontaneous remission seen in this disorder is related to a developmental up-regulation of M current density. They examine giant depolarizing potentials (GDPs) in the CA3 hippocampal subfield, a form of spontaneous network activity that can be studied in acute rodent brain slices in vitro (Ben-Ari et al. 1989). GDPs require both glutamate and GABA receptors, and it is tempting to speculate that their disappearance after the first postnatal week is related to a gradual hyperpolarization of the GABAA receptor reversal potential, as the Cl− ion exporter KCC2 starts to be expressed (Rivera et al. 1999). Removal of a GABAergic depolarizing drive to pyramidal neurons could thus diminish circuit excitability. The results of Safiulina et al., however, invoke a second player in the developmental disappearance of GDPs. They show that Kv7.2 expression and M current density both increase over the first 3 weeks of life, and that this is accompanied by a shift in activation threshold to more negative potentials as well as an acceleration of kinetics. All these effects are predicted to decrease the intrinsic excitability of neurons, which may interact with synaptic and non-synaptic forms of communication to affect the occurrence of GDPs. Indeed, Safiulina et al. also show that, although the muscarinic agonist linopirdine has little effect on neonatal neurons, it enhances spontaneous burst firing of older neurons and facilitates the occurrence of GDPs. Conversely, GDPs in neonatal neurons are abolished by the M current activator retigabine. Overall, these results show that intrinsic bursting and GDPs are exquisitely sensitive to the M current, and suggest that the maturation of the M current may contribute to the disappearance of GDPs. In common with other emergent phenomena, GDPs reflect the interplay of many phenomena, and so the two hypotheses to explain their disappearance (an increase in M current and a hyperpolarization of the GABAA reversal potential) are not mutually exclusive. Nevertheless, by drawing attention to the role of Kv7 channels in regulating GDPs, Safiulina et al. also raise the possibility that seizures in BFNC resolve with development because of a similar increase in M current expression. The mutations associated with the disorder are predicted to give only a modest decrease in Kv7/M current density (Schroeder et al. 1998), again arguing for an exquisite sensitivity of the immature brain to this K+ conductance. Although BFNC rarely requires drug treatment, the availability of a relatively selective Kv7 channel opener (retigabine) offers an almost unique tool to reverse the genetic defect. A phase III trial of retigabine as an add-on drug in localization-related epilepsy has recently been completed, although the outcome is not yet known.

A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions

Background: The underlying genetic abnormalities of rare familial idiopathic epilepsy have been identified, such as mutation in KCNQ2, a K + channel gene. Yet, few genetic abnormalities have been reported for commoner epilepsy, i.e., sporadic idiopathic epilepsy, which share a phenotype similar to those of familial epilepsy. Objective: To search for the genetic cause of seizures in a girl with the diagnosis of non-familial benign neonatal convulsions, and define the consequence of the genetic abnormality identified. Methods: Genetic abnormality was explored within candidate genes for benign familial neonatal and infantile convulsions, such as KCNQ2, 3, 5, KCNE2, SCN1A and SCN2A. The electrophysiological properties of the channels harboring the identified mutation were examined. Western blotting and immunostaining were employed to characterize the expression and intracellular localization of the mutant channel molecules. Results: A novel heterozygous mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified in the patient. The mutation was de novo verified by parentage analysis. The mutation was associated with impaired functions of KCNQ K + channel. The mutant channels were expressed on the cell surface. Conclusion: The mutant Phe304del of KCNQ2 leads to null function of the KCNQ K + channel but the mutation does not alter proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy.

KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes

To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.

Decreased Subunit Stability as a Novel Mechanism for Potassium Current Impairment by a KCNQ2 C Terminus Mutation Causing Benign Familial Neonatal Convulsions

KCNQ2 and KCNQ3 K+ channel subunits underlie the muscarinic-regulated K+ current (I(KM)), a widespread regulator of neuronal excitability. Mutations in KCNQ2- or KCNQ3-encoding genes cause benign familiar neonatal convulsions (BFNCs), a rare autosomal-dominant idiopathic epilepsy of the newborn. In the present study, we have investigated, by means of electrophysiological, biochemical, and immunocytochemical techniques in transiently transfected cells, the consequences prompted by a BFNC-causing 1-bp deletion (2043deltaT) in the KCNQ2 gene; this frameshift mutation caused the substitution of the last 163 amino acids of the KCNQ2 C terminus and the extension of the subunit by additional 56 residues. The 2043deltaT mutation abolished voltage-gated K+ currents produced upon homomeric expression of KCNQ2 subunits, dramatically reduced the steady-state cellular levels of KCNQ2 subunits, and prevented their delivery to the plasma membrane. Metabolic labeling experiments revealed that mutant KCNQ2 subunits underwent faster degradation; 10-h treatment with the proteasomal inhibitor MG132 (20 microm) at least partially reversed such enhanced degradation. Co-expression with KCNQ3 subunits reduced the degradation rate of mutant KCNQ2 subunits and led to their expression on the plasma membrane. Finally, co-expression of KCNQ2 2043deltaT together with KCNQ3 subunits generated functional voltage-gated K+ currents having pharmacological and biophysical properties of heteromeric channels. Collectively, the present results suggest that mutation-induced reduced stability of KCNQ2 subunits may cause epilepsy in neonates.

Pharmacology Review

The first part of this series (May 2004 NeoReviews ) examined “first-line” antiepileptic drugs (AEDs) for neonatal seizures, including phenobarbital (Pb), phenytoin (PHT), and the benzodiazepines diazepam (DZP) and lorazepam (LZP). This part of the series examines the question of when therapy should be discontinued following control of neonatal seizures and the therapies employed, including metabolic treatments, when neonatal seizures do not respond to standard AEDs. If seizures do not respond to initial treatment with Pb, traditionally PHT is administered, followed by LZP. With ongoing seizures, should treatment continue with a “standard approach,” such as “second-line” AEDs (at usual doses) or should seizures be suppressed with high-dose agents, termed “high-dose suppressive therapy” (HDST)? (1) A specific cause requiring specific treatment should be excluded, if possible, such as basic metabolic disorders, the inborn errors of metabolism (IEM), (2) and certain dependency and deficiency states. Once seizures are controlled, how long should AEDs be continued or should they be discontinued? In older children, treatment duration generally is 1 to 2 years after seizure control is achieved. It is important to differentiate neonatal seizures from neonatal-onset epilepsy (3) because there are major implications for continuing maintenance AED therapy. Neonatal seizures have a higher incidence of symptomatic causes, in which seizures during the acute insult may be an epiphenomenon and may not necessarily persist after resolution of the acute insult. For example, seizures occurring with hypoxic-ischemic encephalopathy may not recur after AEDs are stopped. However, the acute insult may create a chronic epileptic state with ongoing seizures that requires AED treatment. In contrast, there are neonatal-onset epilepsies in which seizures are not caused by an acute insult and may have a genetic basis. These may occur even in the intrauterine period. (4)(5) Neonatal onset-epilepsies include benign neonatal convulsions, benign neonatal familial convulsions, neonatal …

Complete loss of the cytoplasmic carboxyl terminus of the KCNQ2 potassium channel: a novel mutation in a large Czech pedigree with benign neonatal convulsions or other epileptic phenotypes.

Benign neonatal familial convulsions (BNFCs) represent a rare epileptic disorder with autosomal dominant mode of inheritance. To date, two voltage-gated potassium (K+) channel genes, KCNQ2 and KCNQ3, have been identified in typical BNFC families. The study of new pedigrees may help detect new mutations and define genotype-phenotype correlations. A large Czech family was detected in which BNFC was inherited together with a broad range of various nonneonatal epileptic phenotypes. Genetic linkage study and direct mutation analysis were performed to find the disease-causing mutation. In seven patients with BNFCs and no recurrence of seizures, a novel two-base-pair deletion (1369del2) was identified within the coding sequence of the KCNQ2 gene. The mutation led to a putative protein that lacked nearly all its carboxyl terminus part, which plays a critical role for the accurate expression of the functional K+ channels. Three patients with generalized tonic-clonic seizures (GTCSs), all without any history of BNFCs, also displayed 1369del2. Three other patients with other idiopathic epileptic phenotypes did not have the mutation. A novel 2-bp deletion within the coding sequence of the potassium channel KCNQ2 gene was detected in patients from a large and heterogeneous family with BNFCs or non-BNFC seizures.

Canalopatías en neurología

The main function of ionic channels are the conduction, recognition and selection of specific ions. They open and close in respond answer to electrical, mechanical and chemical stimulus, acting in the excitation or transmission of diverse tissues. The clinical and molecular manifestations of channelophathies are varied and use to shown up in continuous or paroxystic ways. Alteration of Ca channels cause muscle dysfunction periodic paralysis with or without potassium changes, myasthenia or myasthenic disorders, like Lambert Eaton syndrome, amyotrophic lateral sclerosis, Central Core disease, malignant hyperthermia. Cl and Na channels alterations produce myotonic diseases: Thomsen, Becker and paramyothonies, potassium sensible paralysis, fluctuant congenital myotonic, Andersen s syndrome. Channelopathies also produce various episodic ataxia type 1, type 2, spinocerebellar 6 and familial hemiplegic migraine. Abnormal paroxystic movements are present as channelophaties: episodic nocturnal dystonia, paroxystic dyskinesia. In some families are associates abnormal episodic movements and epilepsy. Several epileptic syndromes are also related with channels dysfunction: frontal lobe nocturnal epilepsy, choreoatetosis epilepsy, benign neonatal convulsions, generalized epilepsy with febrile convulsions plus. Voltage gated channels dysfunction are related to diseases with episodic phenomena or permanent conditions on muscle or neuronal tissues, with clinical and genetic heterogenous manifestations.

Inherited ion channel disorders.

The inherited ion channel disorders (channelopathies) are a group of disorders caused by mutations in genes encoding ion channels. Ion channel disorders can affect any tissue, but the majority affect skeletal muscle or the central nervous system. These disorders include skeletal muscle sodium channelopathies causing hyperkalaemic periodic paralysis, paramyotonia congenita and potassium-aggravated myotonia. Skeletal muscle calcium channelopathies can cause hypokalaemic periodic paralysis, malignant hyperthermia and central core disease. Skeletal muscle chloride channelopathies can cause Thomsen and Becker myotonia. A neuronal sodium channelopathy causes the generalised epilepsy febrile seizures plus syndrome. Neuronal potassium channelopathies can cause familial benign neonatal convulsions and episodic ataxia type 1. Finally, neuronal calcium channelopathies can cause episodic ataxia type 2, familial hemiplegic migraine and spinocerebellar ataxia type 6. The clinical features, aetiology and pathogenesis of inherited voltage-gated ion channel disorders affecting muscle and the central nervous system are reviewed here.

The new voltage gated potassium channel KCNQ5 and neonatal convulsions.

In 1998, mutations in the voltage gated potassium channel gene KCNQ2 were found to be the main cause underlying the autosomal dominant inherited syndrome of benign familial neonatal convulsions (BFNC). In one BFNC family a mutation was found in an homologous gene, KCNQ3. We have now identified another brain-expressed member of this ion channel subfamily, KCNQ5, which maps to chromosome 6q14. On the genomic level KCNQ5 is composed of 14 exons, which are coding for 897 amino acid residues. Mutation analysis made KCNQ5 unlikely as a candidate gene for benign neonatal convulsions in patients with a positive family history for neonatal or early infantile seizures, but without mutations in the KCNQ2 or KCNQ3 genes.

Neonatal seizures: early-onset seizure syndromes and their consequences for development.

The determination of the developmental consequences of seizure syndromes in the neonate is based upon a number of factors which include: understanding of the clinical and electroencephalographic (EEG) features of neonatal seizures; current theories of the mechanisms by which neonatal seizures are generated; a current classification of neonatal seizures; potential etiologic and risk factors for seizures; and therapies. In addition, different seizure types, mechanisms of generation and etiologies of cerebral dysfunction may vary with conceptional age of the infant. There are a few distinct neonatal epileptic syndromes, which are rare, have been well described: benign neonatal convulsions; benign neonatal familial convulsions; early myoclonic encephalopathy and early infantile epileptic encephalopathy. The prognosis for the first two is relatively good while the outcome for the other two with encephalopathy is catastrophic. However, the majority of neonatal seizures occur as acute, reactive events in association with a wide range of etiologic factors. These etiologic factors, as well as those of the more traditionally defined syndromes, are the main determinants of eventual developmental outcome of neonates who experience seizures. Although experimental data suggests that some epileptic seizures eventually may have physiological, histological, metabolic, or behavioral consequences, there is yet direct evidence in humans to suggest that the occurrence of seizures themselves in the neonate is the main determinant of long-term outcome.

Voltage-gated ion channels and hereditary disease.

By the introduction of technological advancement in methods of structural analysis, electronics, and recombinant DNA techniques, research in physiology has become molecular. Additionally, focus of interest has been moving away from classical physiology to become increasingly centered on mechanisms of disease. A wonderful example for this development, as evident by this review, is the field of ion channel research which would not be nearly as advanced had it not been for human diseases to clarify. It is for this reason that structure-function relationships and ion channel electrophysiology cannot be separated from the genetic and clinical description of ion channelopathies. Unique among reviews of this topic is that all known human hereditary diseases of voltage-gated ion channels are described covering various fields of medicine such as neurology (nocturnal frontal lobe epilepsy, benign neonatal convulsions, episodic ataxia, hemiplegic migraine, deafness, stationary night blindness), nephrology (X-linked recessive nephrolithiasis, Bartter), myology (hypokalemic and hyperkalemic periodic paralysis, myotonia congenita, paramyotonia, malignant hyperthermia), cardiology (LQT syndrome), and interesting parallels in mechanisms of disease emphasized. Likewise, all types of voltage-gated ion channels for cations (sodium, calcium, and potassium channels) and anions (chloride channels) are described together with all knowledge about pharmacology, structure, expression, isoforms, and encoding genes.

Idiopathic generalized epilepsies with typical absences.

Idiopathic generalized epilepsy (IGE) comprises several subsyndromes. These are principally: benign neonatal familial convulsions, benign neonatal convulsions, benign myoclonic epilepsy in infancy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with generalised tonic-clonic seizures on awakening. In addition, there are less well-recognized syndromes, such as eyelid myoclonia with absences. The pathophysiology of the IGE syndromes is not fully understood; it is evident that typical absences are the result of abnormal oscillations between the thalamus and cerebral cortex. Genetic studies are in progress to elucidate the biochemical defects underlying the conditions. The clinical and electroencephalographic features of the individual subsyndromes are distinct, but some patients may be difficult to classify into a particular subgroup. A correct syndromic diagnosis is important, as treatment strategies differ for patients with the different forms of IGE, and it is necessary for genetic research.