SCN1A mutation analysis in myoclonic astatic epilepsy and severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures.

Severe myoclonic epilepsy in infancy (SMEI), severe idiopathic generalized epilepsy of infancy (SIGEI) with generalized tonic clonic seizures (GTCS), and myoclonic astatic epilepsy (MAE) may show semiological overlaps. In GEFS+ families, all three phenotypes were found associated with mutations in the SCN1A gene. We analyzed the SCN1A gene in 20 patients with non-familial myoclonic astatic epilepsy -- including 12 probands of the original cohort used by Doose et al. in 1970 to delineate MAE. In addition, 18 patients with sporadic SIGEI -- mostly without myoclonic-astatic seizures -- were analyzed. Novel SCN1A mutations were found in 3 individuals. A frame shift resulting in an early premature stop codon in a now 35-year-old woman with a borderline phenotype of MAE and SIGEI (L433fsX449) was identified. A splice site variant (IVS18 + 5 G --> C) and a missense mutation in the conserved pore region (40736 C --> A; R946 S) were detected each in a child with SIGEI. We conclude that, independent of precise syndromic delineation, myoclonic-astatic seizures are not predictive of SCN1A mutations in sporadic myoclonic epilepsies of infancy and early childhood.

Atypical "benign" partial epilepsy of childhood or pseudo-lennox syndrome. Part II: family study.

Atypical benign partial epilepsy of childhood (ABPE = Pseudo-Lennox syndrome) shows semiologic parallels to Lennox-Gastaut syndrome, however--besides the lack of tonic seizures--it has an entirely different etiology and prognosis. Recently Hahn et al [17] investigated the long-term evolution of 43 cases with ABPE. Symptomatology, EEG findings, and course were found to overlap with Rolandic epilepsy, Landau-Kleffner syndrome and ESES. The incidence of seizures in relatives was determined in the whole series investigated by Hahn et al [17]. Five of 56 siblings suffered from seizures (3 Rolandic seizures; one febrile convulsions; one unclassified). Three fathers reported grand mal. In 29 families of the series of Hahn et al EEG recordings were performed: 22 brothers, 19 sisters and 16 pairs of parents. In 29% of the siblings a sharp wave focus was demonstrable. The rate rose to 40% when only siblings investigated at the age of maximum expression (3 to 10 years) were considered. Sharp wave foci were mostly multifocal and indistinguishable from those observed in siblings of children with Rolandic epilepsy. Photoparoxysmal response and generalized spikes and waves during rest and hyperventilation were also found to be significantly elevated (26% and 13% respectively). We conclude that ABPE is a subgroup of idiopathic partial epilepsy of childhood (representing a less benign part of a spectrum) that has to be ranked in a continuum with Rolandic epilepsy. The different clinical phenotype might be caused by a higher expressivity of the identical genetic trait, possibly facilitated by other genetic or acquired factors. Genetic heterogeneity represents another possibility.

Preponderance of female sex in the transmission of seizure liability in idiopathic generalized epilepsy.

BACKGROUND: the predominance of the female sex in the transmission of seizure liability is a known phenomenon. However, all hitherto published genetic studies are based on reported seizure frequencies only. The aim of this investigation was to reexamine this problem by combining clinical and family EEG data. METHODS: families of 82 index cases fulfilling the following core criteria were ascertained; (1) definite clinical and EEG diagnosis of idiopathic generalized epilepsy with absences and/or myoclonic astatic seizures; (2) obtainable history and EEG recordings from both the parents and one or more siblings. EEG recordings were evaluated for different genetic traits of epileptiform EEG activity (EPA), as well as genetic characteristics of background activity. RESULTS: of the 164 parents 9% suffered from seizures. EPA was detected in 24% of probands' mothers versus 12% in fathers. Altogether 28% of probands' mothers were positive for seizures or EPA versus 16% of the fathers. Of parents with EPA in the EEG only about 50% showed seizures. Twenty one percent of all the parents and 60% of the mothers with EPA showed generalized alpha-activity (9% in controls). In contrast, in mothers without EPA a 'non alpha-EEG' was overrepresented. In probands' siblings, 14% showed seizures and 23% showed seizures or EPA. In probands' siblings with EPA seizure risk was 50 versus only 8% in siblings without EPA. The highest siblings risk was conferred by SW and an affected mother. If a father was affected, risk for the siblings of probands was almost equal to that in families with both the parents unaffected. Siblings of female probands were more often affected than those of male probands (19 vs. 8%; P<0.05). Generalized SW occurred in 17% of probands' siblings, in girls siblings significantly more often than in boys siblings (25 vs. 9%; P<0.01). CONCLUSION: clinical history and family EEG equally contribute information contents. Female preponderance in transmission of seizure liability is the result of a complex of genetic interactions that include the generalized alpha-EEG.

Multifactorial pathogenesis of neonatal seizures--relationships to the benign partial epilepsies.

Elevated incidence of neonatal seizures (NS) in children with idiopathic partial epilepsies, as well as reports on the transition of NS into benign partial epilepsy, point to pathogenetic relationships between these conditions. Further insight into the nature of these relationships can be expected only from NS patients with long-term follow-up, which includes the age range of maximum manifestation of subsequent seizures or epilepsies (SSE), and age-dependent genetic EEG traits. A sample of such cases will necessarily be selected and thus prohibit any quantitative inferences regarding the incidence of SSE and special EEG characteristics. Nevertheless, the data provide new aspects with regard to a possibly multifactorial pathogenesis of NS and SSE. Children in the present study were selected applying the following inclusion criteria: cerebral seizures during the first 14 days of life; follow up of more than two years with at least two EEG recordings beyond the age of two. Children with metabolic NS or subsequent West syndrome were not included. Seventy-six cases were confirmed, 42 with SSE, 34 without. The incidence of EEG symptoms of a generalized genetic seizure liability (theta rhythms, generalized spikes and waves, photoparoxysmal response) was significantly elevated, equally in children with and without SSE. Beyond the age of two years, 50% of the probands had focal sharp waves foci characteristic of idiopathic partial epilepsy (e.g. rolandic epilepsy). Among SSE, febrile convulsions and partial epilepsies with benign course dominated. Idiopathic generalized epilepsies were not observed. These findings indicate that in a certain proportion of cases, NS have genetic factors in common with idiopathic partial epilepsies. Quantitative representative data cannot be obtained to determine the incidence of such pathogenetic mechanisms in NS and SSE.

The concept of hereditary impairment of brain maturation.

The classification of benign partial epilepsies and related conditions includes (besides rolandic epilepsy) atypical benign partial epilepsy, bioelectrical status epilepticus (ESES) and a variety of other syndromes. The broad overlap of the clinical and bioelectrical symptomatology might reflect a pathogenetic background common to these epilepsies. In order to understand the great phenotypic variability, the clinical symptomatology in 56 sibships with focal sharp waves of genetic origin was analyzed. A genetic determination was assumed if, in addition to the index case, at least one sibling or offspring revealed typical focal sharp waves. The 56 index-cases and their 61 sib/offspring/parents showed a broad spectrum of epileptic and non-epileptic conditions ranging from mild selective performance deficits to severe complex mental retardation, from neonatal seizures, febrile convulsions, and simple rolandic epilepsy to severe epilepsies with minor seizures or ESES. The different conditions are not disease entities but sets of variably weighted symptoms of a complex pathogenetic background, in which a genetic disposition to focal anomalies of brain function is of decisive importance. As can be demonstrated by the data, this genetic liability coincides with other widespread genetic traits, expressed in certain EEG patterns, as well as with lesional pathogenetic factors. The biological background of the genetic focal anomaly is currently unknown. The marked age dependence of the symptoms justifies the assumption of an hereditary impairment of brain maturation.

Benign idiopathic partial epilepsy and brain lesion.

A 14-year-old girl had severe head trauma from a dog bite at the age of 9 days. This resulted in extensive brain damage, tetraplegia, mental retardation, and epilepsy. The seizures were of rolandic type, and the EEG showed multifocal sharp waves. The course was benign. The initial diagnosis of a pure symptomatic epilepsy was revised after demonstrating typical benign focal sharp waves in the EEG of the healthy sister. Thus a phenocopy of a benign partial epilepsy by the brain lesion could be excluded with sufficient certainty. This observation allows the conclusion that the genetic disposition underlying the sharp-wave trait characteristic of benign partial epilepsies can be involved also in the pathogenesis of seemingly pure symptomatic epilepsies. EEG studies on siblings of such patients are needed to exclude possible phenocopies.

Severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures.

PURPOSE: While the literature on infantile epilepsies with minor and major seizures is extensive, little consideration has been given to infantile epilepsy with generalized tonic-clonic seizures (GTCS) alone. The aim of the present study was to analyze the data of a large group of patients and their families to obtain further insight into the clinical picture and pathogenesis of this type of epilepsy. METHODS: The 101 children (58 boys, 43 girls) met the following inclusion criteria: onset of the epilepsy with febrile or afebrile GTCS in the first 5 years of life, absence of primary organic brain lesion or progressive brain disease, severe course with frequent febrile and/or afebrile GTCS, failure of conventional anticonvulsive therapy. RESULTS: The epilepsy predominantly afflicts normally developed infants, boys and girls being about equally affected. The epilepsy begins with frequent febrile or afebrile GTCS, characteristically of long duration and often with alternating lateralization. In half of the cases additional myoclonic or myoclonic astatic seizures and/or absences occur. The initial GTCS phase is the same in epilepsies with and without minor seizures. Erratic myoclonias are especially characteristic. With advancing age, the symptomatology becomes increasingly polymorphic due to the occurrence of additional simple and complex focal and tonic seizures. Severe impairment of mental development soon after onset is a leading symptom. The overall death rate was 9%. Only 11% of the patients had been seizure-free for at least two years at final examination. The EEG was initially normal and subsequently exhibited diffuse 4-7/s rhythms, and only later spikes and waves of irregular shape (87%). Focal sharp waves occurred transiently in 26%. The family history and EEG of probands and relatives showed the pathogenesis to be decisively determined by genetic factors. CONCLUSION: Early infantile GTCS epilepsy represents a genetically determined (idiopathic) epileptic encephalopathy. It overlaps with other forms of early childhood epilepsy such as severe myoclonic epilepsy, severe type of myoclonic astatic epilepsy, as well as early childhood absence epilepsy with GTCS.

Children with focal sharp waves: clinical and genetic aspects.

PURPOSE: To investigate the spectrum of clinical manifestations in children with benign focal sharp waves in the EEG to gain further insight into the genetic background of clinical and EEG symptomatology in a family study. METHODS: All 147 children (134 with seizures, 13 without) met the following inclusion criteria: (a) at least one EEG with focal sharp waves characteristic of benign partial epilepsies, and (b) at least 1 sibling investigated by EEG. The families were questioned orally or in writing regarding the occurrence of seizures. Patients' records were evaluated by a standardized scheme. RESULTS: The following types of seizures occurred: febrile convulsions (FC), afebrile generalized tonic-clonic seizures (GTCS), simple and (rarely) complex partial seizures; and rolandic seizures in the strict sense. Neonatal seizures were overrepresented (6%); there were no indications of lesional causes. FC occurred in 38 children (26%). As compared with unselected cases of FC, complex symptoms were overrepresented. Family data suggested a maternal preponderance in the transmission of FC liability. Affected relatives of FC probands manifested FC more often than did relatives of probands without FC. Families of 32 patients with typical rolandic seizures (24% of the 134 probands with seizures) showed no aggregation of rolandic epilepsy, but did show variable seizure types. In the entire sample, EEG investigations showed focal sharp waves in 11% of siblings aged 2-10 years. No relation existed between clinical symptomatology and sharp wave findings in siblings. In 66% of probands, the EEG disclosed generalized genetic patterns. Siblings with generalized spike-waves (sw) and/or theta rhythm had focal sharp waves more often than those without sw and/or theta rhythm. CONCLUSIONS: The phenotypic expression of the genetic anomaly underlying focal sharp waves shows considerable variability. The clinical and EEG findings are in agreement with a multifactorial pathogenesis of epilepsies with "benign" focal epileptiform sharp waves.

Seizure risk in offspring of individuals with a history of febrile convulsions.

UNLABELLED: One-hundred and seventy-nine offspring of 120 probands with a history of febrile convulsions (FC) were studied to determine the risk of seizures and possible factors influencing this risk. The conditions for this study were especially good since all of the probands had undergone clinical and EEG examinations as well as an assessment of family history of seizures during childhood. Hence, for the first time the seizure status of the probands' parents could be included in the calculation of risk in offspring. In sibs the risk was highest if the mother of the proband had experienced seizures (20% vs 9% in offspring of probands with nonaffected parents). Similarly, offspring of probands with affected mothers had a much higher risk (27%) than offspring of probands with affected fathers (7%). Our findings point to a maternal preponderance in the transmission of FC liability. No relationship was found between the presence of EEG traits of a genetic seizure liability (theta rhythms, spikes and waves, photoparoxysmal response, focal sharp waves) in probands during childhood and the seizure risk in their offspring. The present data provide no basis for forming an hypothesis regarding the possible mode of inheritance of FC. This is not surprising since FC as already shown in the EEG-are not a homogeneous disorder, but are caused by a variety of genetic factors occurring in variable constellations. Possibly, in a subgroup of probands with seizure affected mothers the susceptibility to FC follows a multifactorial polygenic mode of inheritance. CONCLUSION: The seizure incidence in offspring of individuals with a history of FC was 10% (only FC in 64% of the affected offspring). Offspring of females with affected parents were at an increased risk. Pathological childhood EEG findings of the probands were not related to an increased risk in offspring.

Children with benign focal sharp waves in the EEG--developmental disorders and epilepsy.

Focal sharp waves (shw) in the childhood EEG with predominantly centrotemporal localization are a diagnostic hallmark of idiopathic partial epilepsy and have been shown to be genetically determined. Absence of neurological and neuropsychological impairment was long considered to be a prerequisite for diagnosis. For years, this diagnostic paradigm obscured the large phenotypic variability of genetically determined focal shw. The purpose of the present review is to survey and critically evaluate the widely dispersed literature on this topic. Two main groups can be distinguished: Idiopathic partial epilepsies and specific developmental disorders such as dysphasia, dyslexia etc. These conditions, however, do not represent clear-cut nosologic entities, but exhibit large symptomatic overlaps. In non-epileptic children, developmental disabilities constitute the main symptoms, in epileptic children-at least in non-selected groups-they are an optional feature. Conversely, epileptic phenomena can dominate the clinical picture or be an optional symptom in developmentally disabled children. The wide spectrum of epileptic and non-epileptic disorders probably represents the multifarious clinical manifestations of a common widespread, genetically determined pathogenetic mechanism. The marked age-dependency of the EEG and clinical symptoms, and the almost regular disappearance of both at puberty appear to justify the hypothesis of a hereditary impairment of brain maturation. The large phenotypic variability can be explained by differences in location and extent of the maturational disturbance as well as by the effect of additional genetic and environmental factors. The nature and cause of the hypothetical maturational disturbance are still unknown.

Parental generalized EEG alpha activity predisposes to spike wave discharges in offspring.

Familial and twin studies have shown that the individual variability of the normal human electroencephalogram (EEG) is largely genetically determined. In epileptology, these genetic parameters of the EEG background activity are almost totally neglected. The aim of the present study has been to investigate whether a special genetic type of background activity might be related to the pathogenesis of epilepsy. EEG recordings of parents of 257 epileptic children were evaluated retrospectively. Some 156 healthy adults served as controls. Special attention was paid to alpha activity extending to the frontal region, both in bipolar and in referential recordings (Alpha I). Alpha I was found significantly more often in parents of children with primary generalized epilepsy (18%) compared with parents of children with focal epilepsy (8%) or controls (9%). In a second step, parental EEGs of children with different EEG patterns associated with epilepsy were studied. Alpha I was found significantly more often in parents of children with focal sharp waves and generalized spikes and waves (26%) than in parents of probands with focal sharp waves without additional generalized spikes and waves (8%) or in controls (9%). Parents of probands with theta rhythms and spikes and waves had alpha I significantly more often (18%) than parents of probands with theta rhythms without additional spikes and waves (8%) or controls (9%). The findings reveal a clear correlation between the type of EEG background activity in parents and the EEG characteristics in their children, thus pointing to common mechanisms.

Absence epilepsy of early childhood--genetic aspects.

Clinical and EEG family data of 140 cases with early childhood epilepsy with absences are presented. The aim of the study was to evaluate, whether the occurrence of generalized tonic clonic seizures (GTCS) as a presenting symptom might correlate with family data, i.e. whether there are indications of heterogeneity. One hundred and forty cases were selected from the epilepsy family data base of the Neuropaediatric Department. The selection parameter was epilepsy with absences manifesting between the 1st and 5th year of age. The incidence of seizures was evaluated in siblings, parents and parents' siblings. EEG records were available from 103 parents and 106 siblings. The analysis supports the assumption of heterogeneity within early childhood absence epilepsy. Parents and their sibs of cases manifesting with GTCS had seizures twice as often than parents and their sibs in the non-GTCS group. In the affected relatives of the GTCS group early onset GTCS prevailed, whereas in the relatives of the non-GTCS group absences were found more frequently. The EEG of relatives showed elevated incidences of spikes and waves and photosensitivity in both groups, indicating common genetic factors. In parents of the non-GTCS group, however, EEG pathology was significantly more frequent than in parents of the GTCS group. Comparing EEG pathology in parents with seizure risk in siblings, evidence for maternal preponderance in transmission of the seizure liability was found. Mothers' EEG seems to be the best predictor of the seizure risk in probands' siblings.(ABSTRACT TRUNCATED AT 250 WORDS)

Photosensitivity--genetics and clinical significance.

Photosensitivity is defined by the occurrence of spikes or spikes and waves in response to intermittent light stimulation (= photoparoxysmal response [PPR]). The EEG pattern can show a wide range of expression from solely occipital spikes to generalized irregular spikes and waves. The different types of responses represent different levels of expression of the same genetically determined trait. The photoconvulsive response of Bickford et al (7) is only a subtype of the PPR characterized by close relation to epilepsy. The average incidence of PPR is 7.6% in healthy children aged 1 to 16 years. Girls are more often affected than boys. The available data provide evidence for autosomal dominant inheritance of photosensitivity. Genetic heterogeneity must be considered. In studies starting from a neurobiological genetic point of view including the whole spectrum of PPR, the phenomenon could be shown to be a widespread condition being only loosely associated with epilepsy, but more often with symptoms of psychovegetative instability. Only about 3% of children with PPR of the given definition will manifest epilepsy up to age 20 years. According to family studies in epileptic and non-epileptic photosensitive probands, the phenotypical expression of the PPR and carriers' risk to manifest epileptic phenomena is decisively determined by other pathogenetic factors related to epilepsy. Possible interactions of photosensitivity within the multifactorial pathogenetic background of the epilepsies are reviewed.

Exclusion of linkage of genetic focal sharp waves to the HLA region on chromosome 6p in families with benign partial epilepsy with centrotemporal sharp waves.

Benign partial epilepsy with centrotemporal sharp waves (benign rolandic epilepsy, BRE) is a common form of idiopathic, localisation-related epilepsy of childhood. The characteristic age-dependent focal sharp wave (fsw) found on the EEG in this disorder segregates as an autosomal dominant trait in families with probands with BRE and acts as a neurobiological marker for the increased risk of developing BRE, other benign partial epilepsies of childhood, and other developmental disorders in these families. One of the genes for idiopathic generalised epilepsy (IGE), designated EJM1, has been mapped in families with probands with juvenile myoclonic epilepsy, by linkage to the HLA region on chromosome 6. As BRE and IGE are benign, idiopathic, age-dependent epilepsies, EJM1 is a candidate locus for the fsw underlying BRE and related disorders. Genetic linkage analysis was undertaken in 11 families with probands with BRE and one or more first degree relatives with fsw, with or without BRE, using a polymorphic DNA marker within the HLA region. Apparently unaffected individuals were classed as affection status unknown. Assuming autosomal dominant inheritance with a penetrance of 0.9 gave a lod score of -2.3 at zero recombination, excluding the candidate gene region around HLA. These observations exclude an important candidate gene for this common disorder, and suggest a fundamental molecular and genetic distinction between the benign partial epilepsies of childhood and the idiopathic generalised epilepsies.

Benign childhood epilepsy with centrotemporal spikes and the focal sharp wave trait is not linked to the fragile X region.

Benign childhood epilepsy with centrotemporal spikes (BCECS, benign rolandic epilepsy) is a common form of genetically determined localisation-related epilepsy of childhood. The characteristic age-dependent focal sharp wave (fsw) found on the EEG in this disorder segregates as a dominant trait in families with probands with BCECS. Seizures occur in a significant proportion of individuals with the fragile X syndrome in association with EEG abnormalities comparable to those found in BCECS. The possibility of a common genetic basis for these disorders was investigated by linkage analysis. Six pedigrees with probands with BCECS were analysed using a marker locus DXS548, close to the fragile X site, fra (X). Obligate recombinants between DXS548 and the fsw trait were observed in all six families. Assuming X-linked dominant inheritance and penetrance values of 0.4 (male) and 0.1 (female) a negative lod score of -6.823 was obtained at zero recombination and lod scores of -2.0 at 10cM either side of the fra (X) locus. These results exclude an important candidate gene for this common childhood disorder.

The different patterns of the photoparoxysmal response--a genetic study.

In order to investigate the significance of different patterns of the photoparoxysmal response (PPR), an electroencephalographic family study on 135 probands and 371 relatives was carried out. The PPR was subclassified in 4 phenotypically different types. Considering all types of PPR, the incidence was equal in siblings of probands with epilepsy and in siblings of probands without epilepsy. Type 4 (generalized spikes and waves) occurred more often both in probands with epilepsy and their siblings than the respective controls. Thus, the coincidence of photosensitivity will appear as higher if only a PPR with generalized spikes and waves is considered to be indicative of photosensitivity. A striking age dependency of the phenotypical expression of the PPR was found. These findings suggest that the phenotypical expression of the PPR is age-related and modified by other factors predisposing to generalized epilepsy, the varied patterns of the PPR only representing different levels of expression of the same genetically determined trait. The importance of an adequate technique of intermittent light stimulation is discussed.

[Pathogenesis of epilepsy in childhood and adolescence]. / Pathogenese der Epilepsien im Kindes-und Jugendalter.

After a short discussion of the basic mechanisms of epileptic reactions, the conditions for epileptrogenesis are reviewed. As demonstrated by studies in animal models, distinctive structural and neurochemical characteristics of the brain tissue, probably genetically determined, build a main precondition for seizure manifestation. Starting from these basic concepts, the multifactorial pathogenesis of human epilepsy is discussed with special regard to genetic factors. The seizure liability results from the interaction of several independently transmitted genetic and lesional factors. None of these traits are epileptogenic by themselves, but effective only in interaction with other pathogenetic factors. Genetically determined "normal" structural and functional properties of the brain, e.g. expressed by generalized alpha rhythm, are involved in the complex pathogenesis of epilepsy. From a neurobiological point of view, epilepsy is always a multifactorially determined disease. The nowadays usual separation of idiopathic and symptomatic types of epilepsy may be helpful for communication in daily practice, but represents a simplification under pathogenetic aspects.

Myoclonic-astatic epilepsy.

Myoclonic-astatic epilepsy (MAE) belongs to the group of epilepsies with primarily generalized seizures as absence epilepsies, and juvenile myoclonic epilepsy, as well as infantile and juvenile idiopathic epilepsy with generalized tonic-clonic seizures. Like these types of epilepsy, MAE is polygenically determined with little non-genetic variability. The disease is characterized by the following criteria: genetic predisposition (high incidence of seizures and/or genetic EEG patterns in relatives); mostly normal development and no neurological deficits before onset; primarily generalized myoclonic, astatic or myoclonic-astatic seizures, short absences and mostly generalized tonic-clonic seizures; no tonic seizures or tonic drop attacks during daytime (except for some rare cases with a most unfavourable course); generalized EEG patterns (spikes and waves, photosensitivity, 4-7/sec rhythms), no multifocal EEG abnormalities (but often pseudofoci). There is a partial overlap with other 'syndromes', such as benign and severe myoclonic epilepsy in infants (Dravet et al., 1985a, b), myoclonic epilepsy of infancy and early childhood (Aicardi and others). In differential diagnosis the Lennox-Gastaut syndrome in its stricter sense has to be considered, and also atypical benign partial epilepsy or pseudo-Lennox syndrome. Discussion is presented of possible pitfalls in the classical syndromic approach to classifying epilepsies of early childhood, and of the advantages of a neurobiological view for understanding the immense variability of clinical manifestations of epilepsy.