Genetics of the Partial Epilepsies: A Review

The research literature is consistent in reporting somewhat less familial aggregation in partial than in generalized epilepsy. However, relatives of patients with partial seizures do appear to have higher seizure risks than relatives of controls, suggesting that genetic factors are important in at least some partial epilepsies. Complex partial epilepsy appears to be only slightly less familial than other types of epilepsy. Relatives of patients with focal EEG abnormalities generally have been found to have lower risk of both EEG abnormalities and epilepsy than relatives of patients with generalized abnormalities. For focal temporocentral abnormalities, however, there is evidence of an important influence of genetic factors.     

Genetics of the Epilepsies

Summary: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene–gene–environmental interactions producing specific epilepsy syndromes can be explored.     

Analysis of Genetically Complex Epilepsies

Summary:  During the last decade, great progress has been made in the discovery of genes that influence risk for epilepsy. However, these gene discoveries have been in epilepsies with Mendelian modes of inheritance, which comprise only a tiny fraction of all epilepsy. Most people with epilepsy have no affected relatives, suggesting that the great majority of all epilepsies are genetically complex: multiple genes contribute to their etiology, none of which has a major effect on disease risk. Gene discovery in the genetically complex epilepsies is a formidable task. It is unclear which epilepsy phenotypes are most advantageous to study, and chromosomal localization and mutation detection are much more difficult than in Mendelian epilepsies. Association studies are very promising for the identification of complex epilepsy genes, but we are still in the earliest stages of their application in the epilepsies. Future studies should employ very large sample sizes to ensure adequate statistical power, clinical phenotyping methods of the highest quality, designs and analytic techniques that control for population stratification, and state-of-the-art molecular methods. Collaborative studies are essential to achieve these goals.     

Prevalence of the Epilepsies in Children and Adolescents

The prevalence of epilepsy in children and adolescents from birth through age 19 years was determined for residents of two counties in central Oklahoma. Cases, identified from hospitals, clinics, private physicians' offices, and EEG laboratory and emergency room records, numbered 1,159, yielding a prevalence rate of 4.71 per 1,000. The prevalence was highest in children aged 1-4 years. Overall, males had a slightly higher prevalence rate than females (M:F = 1.1). However, the male/female ratio varied by age, with the group aged less than 1 year having the highest ratio (M:F = 1.5), and by type of epilepsy, with males having higher rates of simple partial epilepsy (M:F = 1.8) and infantile spasms (M:F = 1.5). The prevalence of epilepsy was higher in blacks than in whites. Differences in prevalence by race were confined primarily to generalized epilepsies (B:W = 1.8). The most common types of epilepsy were tonic, clonic, and tonic-clonic (1.14 per 1,000), complex partial (0.39 per 1,000), and partial seizures secondarily generalized (0.33 per 1,000). Approximately 70% of cases were considered idiopathic. Among the presumed causes were perinatal factors (7%), trauma (4%), central nervous system (CNS) infection (3%), and congenital/developmental factors (3). Sixty-five percent of cases had at least one additional medical problem. The most common types of comorbidity were motor handicap (13%) and developmental delay (24%).     

Seizure Risk in Offspring of Parents with Generalized Versus Partial Epilepsy

Genetic factors are commonly assumed to play a more important role in generalized than in partial epilepsy. This study tested this hypothesis by comparing risks of unprovoked seizures in offspring of individuals with generalized versus partial epilepsy. Overall, seizure incidence was no higher in offspring of persons with generalized epilepsy than in offspring of those with partial epilepsy. The number of affected offspring was about three times that expected from population incidence rates, regardless of whether the parent had partial or generalized epilepsy. For the subgroup of generalized cases with absence seizures, however, seizure incidence in offspring was about three times as high as for partial cases. The higher incidence in offspring of absence cases was only partly explained by a higher proportion of absence than partial cases with two factors associated with high risk in relatives, namely early age at onset and idiopathic epilepsy. Offspring of absence cases had higher risk than offspring of other cases not only for absence seizures, but for other seizure types as well, suggesting that absence epilepsy is not genetically distinct from other seizure types of epilepsy. These results suggest that the higher incidence sometimes observed in relatives of patients with generalized epilepsy is due to a small proportion of generalized cases with extremely high familial risks--most generalized epilepsies are no more likely than partial epilepsies to have a genetic basis.     

Photosensitive Epilepsies and Photoconvulsive Responses in Arabs

The occurrence of photosensitivity (PS) was examined in 327 Arabs greater than or equal to 15 years of age with epilepsy by intermittent photic stimulation (IPS). A control group of 192 nonepileptic Arabs greater than or equal to 15 years of age were also examined by IPS. Of the epileptic patients, 24 (7.3%) were photosensitive, an incidence comparable to that in whites in contradistinction to the reported rarity among African blacks. This finding indicates that environmental factors, particularly excessive sunshine, does not appear to influence the occurrence of PS among epileptic patients. The occurrence of PS among epileptic patients may depend more strongly on the presence of an epileptic syndrome known to have association with PS.     

Classification of the Myoclonic Epilepsies

Summary:   The myoclonic epilepsies are a collection of syndromes in which myoclonic seizures are a prominent feature. Proper classification of a patient's syndrome is critical for appropriate treatment and prognosis. However, classification of such syndromes is often difficult because the terminology used to describe seizures can be confusing and inconsistent. Myoclonic epilepsy syndromes can be epileptic or nonepileptic and can also be divided into inherited and acquired forms. Progressive myoclonic epilepsy (PME) syndromes are the most severe of the myoclonic epilepsies. Diagnosis of PME syndromes on clinical grounds can be difficult, but advances in genetic testing have made diagnoses more accurate. Some other benign myoclonic epilepsy syndromes also have identified gene markers, which can aid in diagnosis. To accurately classify a patient's epilepsy syndrome, clinicians should use all available clinical laboratory tools appropriately. Improved accuracy of diagnosis for patients with myoclonic epilepsies should lead to more dependable prognoses and more effective treatment.     

Familial Aggregation and Severity of Epilepsy

Genetic models for complex diseases frequently assume that genetic factors play a greater role in severe forms than in mild forms of disease. This study examined familial aggregation of epilepsy in relation to two measures of severity: duration and remission. The study population comprised 358 offspring born in Rochester, MN, U.S.A., to parents with epilepsy who were diagnosed in Rochester between 1935 and 1979 and followed for greater than or equal to 5 years after the first seizure. Cox proportional hazards analysis was used to examine the effects of duration of the parent's epilepsy (less than 5 vs. greater than or equal to 5 years) and remission of the parent's epilepsy (greater than or equal to 5 years seizure-free) on risk of unprovoked seizures in offspring. The univariate rate ratio (RR) for parent's duration (long vs. short) was 1.1 (95% confidence interval 0.32-3.57). The RR for parent's remission was 2.5 (0.55-11.41), reflecting a higher risk for offspring of remitting parents, which was not statistically significant. Multivariate analysis was used to control for three other parental attributes associated with offspring seizure risk: sex, age at onset of seizures (less than 20 vs. greater than or equal to 20 years), and seizure type (absence vs. other). The RR for duration was not substantially changed in this analysis (1.2; 0.37-4.16). However, the RR for remission dropped to 1.2 (0.25-5.97), suggesting that the higher risk in offspring of remitting parents was largely explained by confounding with other factors that influence offspring seizure risk.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic testing in the epilepsies—Report of the ILAE Genetics Commission

In this report, the International League Against Epilepsy (ILAE) Genetics Commission discusses essential issues to be considered with regard to clinical genetic testing in the epilepsies. Genetic research on the epilepsies has led to the identification of more than 20 genes with a major effect on susceptibility to idiopathic epilepsies. The most important potential clinical application of these discoveries is genetic testing: the use of genetic information, either to clarify the diagnosis in people already known or suspected to have epilepsy (diagnostic testing), or to predict onset of epilepsy in people at risk because of a family history (predictive testing). Although genetic testing has many potential benefits, it also has potential harms, and assessment of these potential benefits and harms in particular situations is complex. Moreover, many treating clinicians are unfamiliar with the types of tests available, how to access them, how to decide whether they should be offered, and what measures should be used to maximize benefit and minimize harm to their patients. Because the field is moving rapidly, with new information emerging practically every day, we present a framework for considering the clinical utility of genetic testing that can be applied to many different syndromes and clinical contexts. Given the current state of knowledge, genetic testing has high clinical utility in few clinical contexts, but in some of these it carries implications for daily clinical practice.     

Status Epilepticus of Benign Partial Epilepsies in Children: Report of Two Cases

Benign partial epilepsies of childhood (BPEC) are one of the most frequent types of epilepsy in school-age children. Status epilepticus (SE) of these conditions have not yet been reported. Two children with clinical and EEG features consistent with the diagnosis of BPEC-SE are presented. In neither case did SE respond to current antiepileptic medications and stopped only after administration of steroids. At follow-up 1 and 2 years post SE, neurologic and intellectual development have been normal. Differential diagnoses included an atypical benign partial epilepsy, epilepsy with electrical status epilepticus during slow sleep, acquired epileptic aphasia, Lennox-Gastaut syndrome and epilepsia partialis continua.     

Genetics of Idiopathic Generalized Epilepsies

Summary:  The idiopathic generalized epilepsies (IGEs) are considered to be primarily genetic in origin. They encompass a number of rare mendelian or monogenic epilepsies and more common forms which are familial but manifest as complex, non-mendelian traits. Recent advances have demonstrated that many monogenic IGEs are ion channelopathies. These include benign familial neonatal convulsions due to mutations in KCNQ2 or KCNQ3 , generalized epilepsy with febrile seizures plus due to mutations in SCN1A , SCN2A , SCN1B , and GABRG2 , autosomal-dominant juvenile myoclonic epilepsy (JME) due to a mutation in GABRA1 and mutations in CLCN2 associated with several IGE sub-types. There has also been progress in understanding the non-mendelian IGEs. A haplotype in the Malic Enzyme 2 gene, ME2 , increases the risk for IGE in the homozygous state. Five missense mutations have been identified in EFHC1 in 6 of 44 families with JME. Rare sequence variants have been identified in CACNA1H in sporadic patients with childhood absence epilepsy in the Chinese Han population. These advances should lead to new approaches to diagnosis and treatment.     

Aggravation of Generalized Epilepsies

Summary: Generalized epilepsies are treatable with a number of antiepileptic drugs (AEDs) that are effective in different seizure types and epilepsy syndromes. The mechanisms of action of these AEDs are incompletely understood but include inhibition of low-threshold calcium currents and of voltage-gated sodium channels and facilitation of GABA_A receptor currents. The mechanisms of aggravation are also unknown but could include elevation of brain GABA, blockade of voltage-gated sodium channels, and idiosyncratic toxicity reactions. Anecdotal reports suggest that aggravation of generalized epilepsy can occur with virtually all AEDs. The best-documented examples are aggravation of absences by carbamazepine and aggravation of symptomatic generalized epilepsies by vigaba-trin. Therefore, the physician must be constantly aware of the problem of aggravation of seizures by AEDs. With careful diagnosis of the epileptic syndrome and an awareness of the problem, aggravation of seizures can be minimized.     

Seizures of Idiopathic Generalized Epilepsies

Summary:  Idiopathic generalized epilepsies (IGEs) comprise at least 40% of epilepsies in the United States, 20% in Mexico, and 8% in Central America. Here, we review seizure phenotypes across IGE syndromes, their response to treatment and advances in molecular genetics that influence nosology. Our review included the Medline database from 1945 to 2005 and our prospectively collected Genetic Epilepsy Studies (GENESS) Consortium database. Generalized seizures occur with different and similar semiologies, frequencies, and patterns, ages at onset, and outcomes in different IGEs, suggesting common neuroanatomical pathways for seizure phenotypes. However, the same seizure phenotypes respond differently to the same treatments in different IGEs, suggesting different molecular defects across syndromes. De novo mutations in SCN1A in sporadic Dravet syndrome and germline mutations in SCN1A, SCN1B, and SCN2A in generalized epilepsies with febrile seizures plus have unraveled the heterogenous myoclonic epilepsies of infancy and early childhood. Mutations in GABRA1, GABRG2, and GABRB3 are associated with absence seizures, while mutations in CLCN2 and myoclonin/EFHC1 substantiate juvenile myoclonic epilepsy as a clinical entity. Refined understanding of seizure phenotypes, their semiology, frequencies, and patterns together with the identification of molecular lesions in IGEs continue to accelerate the development of molecular epileptology.     

Reproduction Among Individuals with Idiopathic/Cryptogenic Epilepsy: Risk Factors for Spontaneous Abortion

Summary: Purpose: We wished to determine the effects of seizure type, age at onset, and family history of epilepsy on risk of spontaneous abortion in the pregnancies of adults with id-iopathichyptogenic epilepsy.
Methods : We examined pregnancy outcomes in 812 adults with idiopathic/cryptogenic epilepsy who had ever had or fathered a pregnancy and 250 of their same sex siblings who had ever had or fathered a pregnancy. We compared the likelihood of spontaneous abortion before and after onset of epilepsy with the likelihood of spontaneous abortion among same sex siblings.
Results : Risk of spontaneous abortion was not increased before onset of epilepsy. After onset of epilepsy, risk of spontaneous abortion was significantly increased in the pregnancies of wives of men who had localization-related epilepsy with age at onset <10 years or who did not have a family history of epilepsy. In women after onset of epilepsy, risk of spontaneous abortion was significantly increased for pregnancies of women with localization-related epilepsy with age at onset G20 years and for those of women with or without a family history of epilepsy. Risk of spontaneous abortion was greatest in the pregnancies of women with a positive family history of epilepsy odds ratio, (OR = 2.12, p < 0.05).
Conclusions : Risk of spontaneous abortion in the pregnancies of men and women with idiopathic/cryptogenic epilepsy varied with the clinical characteristics of their epilepsy. The increased risk of spontaneous abortion in women with a family history of epilepsy may influence the observed risk of epilepsy in their live-born offspring.     

The Epilepsies: Clinical Implications of the International Classification

Summary: From the earliest days of neurology, the classification of epileptic seizures into those generalized from the beginning and those with a definable localization in the cortex from the onset has added to knowledge about the function of the nervous system. Further elaboration of the classification of seizures into those localized to the six-layered isocortex and those whose elaboration involves regions of the brain involved with consciousness and memory has provided the basic focus for the burgeoning subspecialty of epilepsy surgery. It is increasingly apparent that the etiology of a seizure disorder is of at least equal or of greater significance than the nature of the seizures it spawns and is the product not only of localization in the nervous system but also of causative factors with implications reaching into areas of genetics, higher cortical function, and intelligence. The prognosis concerning the outcome of the epilepsy under consideration is based on all of these facets. This pathophysiological substratum, of which the seizure is only the presenting symptom, constitutes the epilepsy or epileptic syndrome on which the formulation of a rational treatment plan is based.     

Birth Order, Sibship Size, and Risk of Epilepsy

Summary: We examined the relation between epilepsy and birth order, using data on 1,950 probands with epilepsy and 4,636 of their full siblings without epilepsy from the Epilepsy Family Study of Columbia University. The proportion of first-born individuals appeared to be higher among probands with epilepsy than among their unaffected siblings, but this relation disappeared after we controlled for the confounding effect of sibship size. With sibship size controlled, the proportion of first-born individuals was similar to that in unaffected siblings for probands with idiopathickryptogenic epilepsy, generalized and partial onset seizures, and all ages at onset of epilepsy. Probands with remote symptomatic epilepsy had higher birth orders than their unaffected siblings, even after we controlled for sibship size.     

Epilepsy Genes and the Genetics of Epilepsy Syndromes: The Promise of New Therapies Based on Genetic Knowledge

Summary: Treatment strategies based on the molecular biology of the epilepsies may soon become a reality. Critical steps in this process are identifying molecular genetic defects in specific epilepsies, understanding of the neurobiologic consequences of those defects, and developing methods to correct the molecular defects or their downstream consequences. Identification of molecular defects is easier in single-gene epilepsies than in those with complex inheritance, although the latter are more common. A number of epilepsies have been mapped and, in two cases, specific genes have been identified. Unverricht-Lundborg disease is caused by defects in the cystatin B gene, with absence of the gene product. Autosomal dominant nocturnal frontal lobe epilepsy in some families is caused by mutations in the a4-subunit of the nicotinic acetylcholine receptor gene. In vitro studies suggest that the mutations lead to impaired function of the acetylcholine receptor, raising the possibility of cholinergic therapy for this condition. Advances in the molecular biology of the epilepsies are likely to change our understanding radically and to allow opportunities to develop innovative new treatments for epilepsy.