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Keywords:

  • Idiopathic generalized epilepsies;
  • Genetic heterogeneity;
  • Ion channel mutations;
  • Channelopathy;
  • GABA receptor mutations

Abstract

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

Summary: Most epilepsies are categorized under the umbrella term “idiopathic;” these seizure disorders lack a known cause. New genetic technologies are rapidly identifying specific genes responsible for idiopathic generalized epilepsies (IGEs) and are gradually taking the “I” out of “IGE.” Ion channel (both voltage- and receptor-mediated) mutations have been linked to a variety of epilepsies considered idiopathic. Gene errors alter excitability in various ways, depending on the mutation, the regional network, and the stage of brain development. The majority of mutations prolong depolarization, favor repetitive firing, and alter neurotransmitter release or postsynaptic sensitivity at central synapses, but the reason for specific seizure types is unclear. Further analyses of these gene mutations and their effects on the developing brain are providing critical clues in the search to explain the origin of “idiopathic” epilepsy.

Although epilepsy has multiple causes, the exact etiology in a majority of cases remains unexplained (1). These cases are currently classified as idiopathic, meaning that the physician, having exhausted all available testing, still lacks sufficiently informative historical, clinical, laboratory, or familial evidence to suggest an inciting cause. In the last several years, advances in genetic analysis of nervous system disorders have pinpointed more than several dozen errors in 11 human genes individually linked to various patterns of nonlesional partial and generalized seizure disorder, dramatically changing the way the neuroscience community must view the biological origins of epilepsy (Table 1)(2). These discoveries not only reinforce the need to continue expanding the search to describe the genetic basis of idiopathic epilepsy, but also suggest that in the future, clinical evaluation of these genes may be required before the term can be correctly applied.

Table 1.  Genes identified for monogenic human idiopathic generalized epilepsy
Seizure/syndromeChromosomeGene
Generalized  
 GEFS+19q13SCN1B
 2q24SCN1A
 2q24SCN2A
 5q34GABRG2
 Benign neonatal familial convulsions20q13KCNQ2
 8q24KCNQ3
 Juvenile myoclonic epilepsy5q34GABRA1
 Absence5q34GABRG2
 19pCACNA1A
Partial  
 Autosomal dominant nocturnal   frontal lobe epilepsy20q13CHRNA4
 1qCHRNB2
 Temporal lobe epilepsy12pKv1.1

GENE DISCOVERY IN EPILEPSY

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

There are two general approaches to linking errors of individual genes to all epileptic phenotypes, and taken together, these approaches have resulted in the identification of over 60 genes for epilepsy. The conventional forward approach, accounting for about one half of the total number of genes, begins with the finding of significant family pedigrees that are carefully studied from a clinical genetic standpoint. Linkage analysis using DNA markers distributed over the genome is performed, and the location of the affected gene is narrowed down to a chromosomal site small enough to allow detection of the mutated gene residing within this region (positional cloning). The recent completion of the full human and mouse genome sequence has greatly accelerated the latter step (3,4).

An alternative approach to identifying candidate genes for human epilepsy has so far revealed a roughly equal number of genes linked to spontaneous seizure disorders in mice. Instead of starting with a family with epilepsy and looking for the gene responsible, molecular biologists select genes of interest and, using experimental chromosomal engineering, delete or alter them in some way (5). They then construct a mouse model bearing this mutation and evaluate the neurological phenotype. In nearly two dozen cases, novel genes linked to epileptogenesis have been so identified, and in two cases, a mutation in the related human gene has subsequently been linked to epilepsy (6, 7). This reverse path not only creates an animal model that can provide insight into the biology of the gene, but also generates novel gene candidates for human gene mapping.

Despite the general clinical resemblance of many seizure disorders within a given epilepsy syndrome, idiopathic epilepsies may arise from defects in entirely distinct biological pathways. The underlying pathological diversity of epilepsy is dramatically illustrated by the broad representation of epilepsy genes with regard to their molecular function. This is readily appreciated by considering an important analysis performed by the Human Genome Project, where the application of a computerized algorithm to evaluate all human gene sequences was used to compare them with sequence information from genes of known function. In more than half of the cases, it was possible to assign a cellular function to the gene product (3). When the known genes linked to epilepsy are similarly categorized according to function, at least 14 different groups are represented, comprising not only molecules that directly alter membrane excitability or synaptic release, such as ion channels, receptors, and transporters, but other proteins with less obvious roles in shaping the firing patterns of brain circuits, including transcription factors, intracellular signaling molecules, and other regulators of gene expression, cell proliferation, migration, or cell death (Fig. 1). Thus, genes underlying epilepsy do not belong to either a single or a few functional categories but to a broad group of molecular pathways controlling nervous system physiology and brain development. This genetic heterogeneity distinguishes epilepsy from many oligogenic, if not genetically unitary, disorders, such as Huntington disease.

image

Figure 1. The functional diversity of epilepsy genes. Adapted and reprinted with permission from Science(3). Copyright 2001, American Association for the Advancement of Science.

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The emerging evidence for genetic heterogeneity reinforces the view that human idiopathic epilepsies represent a phenotype of many, often individually rare, gene defects. This conclusion is further strengthened by the fact that when a novel gene defect for even a clinically well-characterized IGE syndrome is identified, it may only account for a small fraction of the diagnosed cases. For example, in the mutated γ-aminobutyric acid A3 receptor (GABRA3) that has been reported in a family with autosomal dominant juvenile myoclonic epilepsy (JME), not a single mutation in this subunit could be detected in 31 other individuals with diagnosed JME (8). An additional reason that the search for additional genes underlying IGE may be prolonged is the belief that, along with the monogenic syndromes, many cases of idiopathic epilepsy are likely to be inherited as a multigenic trait, with possible environmental influences. A discussion of the uncertainties regarding the identification of genes for complex epileptic traits has been published in a recent International League Against Epilepsy Genetics Commission conference report (2).

FROM CHANNELOPATHY TO MECHANISM

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

The majority of genes discovered to date for human IGE are inherited disorders of ion channels. There are three important questions to ask for each new gene mutation following its discovery:

  • (a) 
    What does the mutation do to the gene? Mutations in ion channel genes may affect not only the selectivity of the channel pore for specific ions, along with its kinetics and voltage dependence, but may also control how many, where, and when the channel subunits are expressed in specific locations in the neuron. Mutations also modify their ability to interact with related subunits and to be modulated by various intracellular signals.
  • (b) 
    What does the mutant channel do to the neuron? Depending on the behavior of the mutant channel, the neuron may be more or less excitable or may fire in novel patterns. Tetanic firing may synchronize some synapses while inhibiting others.
  • (c) 
    What does the mutant neuron do to the brain? As a result of the altered activation patterns in the neurons expressing the mutation, novel expression of other ion channel genes or other receptor molecules or growth factors may result, further distinguishing the epileptic circuit from the normal neural circuit. Depending on the time and location of these altered neurons, circuit behavior may be more or less influenced, and it is no longer difficult to imagine that the mutant protein may have multiple roles within the central nervous system.

Therefore, answers to the first three questions can be followed by another set of questions:

  • (a) 
    Where in the brain does this occur?
  • (b) 
    When does this circuit excitability defect begin, and does it propagate to involve neurons that do not express the mutation?
  • (c) 
    Why does the particular seizure phenotype emerge?

SODIUM CHANNEL MUTATIONS AND IGE

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

Ion channels are protein complexes comprising several subunits, and the distribution of each varies in different cell types throughout the brain. Over the past few years, several mutations have been reported in the genes encoding the Nav 1.1 and Nav 1.2 sodium channel (9–13). The mutations are found in patients with the syndrome of generalized epilepsy with febrile seizures plus (GEFS+) at sites distributed across the membrane-spanning regions of the pore-forming α1 and α2 subunit proteins, as well as in an extracellular portion of the β1 subunit, an auxiliary transmembrane subunit associated with both channel subtypes. In a study by Gong et al. (14), these channels are localized to largely nonoverlapping regions of neurons; the type-1 sodium channel is found to cluster in the cell bodies of neurons, while channels arising from the type-2 sodium channel gene preferentially reside in dendritic and axonal regions. It is notable that both genes are linked to GEFS+, as is the β1 subunit, which interacts with both subtypes of sodium channels and thus controls excitability throughout the neuron. It appears that sodium channel mutations do not give rise to a single neuronal or cerebral excitability phenotype because these mutations have been associated with the presence of multiple seizure types, including tonic-clonic, myoclonic absence, febrile, and astatic. While the firing patterns of neurons and neural circuits expressing these mutated channels have not yet been examined, their expression in model cells shows that the channel inactivates more slowly than usual in response to a controlled depolarizing pulse of the membrane, giving rise to a high probability of late channel openings and a persistent inward current (Fig. 2)(15). This behavior has been long associated with hyperexcitability in networks.

image

Figure 2. Generalized epilepsy with febrile seizures plus sodium channel mutations prolong inactivation and result in persistent inward current. Adapted and reprinted from Neuron(15). Copyright 2002, with permission from Elsevier.

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Not all sodium channelopathies are so well behaved. Unexpectedly, several laboratories have reported the existence of mutations linked to epilepsy occurring in the type-1 sodium channel that truncate the protein (16–18). These mutations stop translation of the full-length protein and are predicted to only produce a small truncated peptide that is typically degraded and would be unlikely to form a functional membrane sodium channel. The sodium channel truncation mutations have been found in a clinically unrelated syndrome termed severe myoclonic epilepsy of infancy (SMEI). These mutations, which affect a single allele and thereby halve the normal number of sodium channels, pose a fundamental puzzle regarding the mechanism whereby a decrease in voltage-gated membrane sodium channels could lead to a phenotype of neuronal hyperexcitability and seizures. If there were preferential expression of type-1 channels in inhibitory interneurons, an imbalance with excitatory circuits might be hypothesized; however, there is no evidence to support this possibility. It is also well established that hypoexcitability impairs the normal maturation and sculpting of synaptic connections early in brain development, allowing the potential emergence of a relatively disinhibited neural network with excessive excitatory glutamatergic connections, despite the reduction in overall sodium channel expression. Another possibility might be a defect in the normal switch of GABAergic neurotransmission from depolarizing to hyperpolarizing in the developing brain (19). If the expression of the KCC2 chloride transporter mediating the inhibitory chloride gradient is activity dependent, the appearance of GABAergic inhibition might be delayed in the sodium channel–deficient brain (20).

Owing to the high lethality of this syndrome, these truncation mutations are rarely inherited, nor are all cases of SMEI accounted for by mutation of the sodium channel. Nevertheless, the high frequency of sporadic channelopathies found in this subgroup has important implications for the way physicians may assess patients with idiopathic epilepsy in the future; if the founder mutation is identified in the proband rather than the parental genome, identification permits genetic counseling that could be reassuring to the parents, as well as providing an indication for early neuroprotective strategies in the patient, although the mechanism for such an intervention has yet to be discovered.

POTASSIUM CHANNEL MUTATIONS AND IGE

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

The phenotype of benign neonatal convulsions provides an interesting contrast and an equally compelling argument for clinical genotyping. The KCNQ2 and KCNQ3 channel subunits dimerize to form a potassium channel with essentially identical biophysical properties and pharmacological sensitivities as the M-current, a slowly activating outward potassium conductance that plays a critical role in determining the subthreshold electrical excitability of neurons (21). This is a well-behaved channelopathy in the sense that if these channels are blocked, repetitive firing is likely. Over 25 mutations in these channels have been identified (N. A. Singh, unpublished observations) (22–24). In contrast to SMEI, seizures occurring in the neonatal and infantile period are typically outgrown by early childhood. Genotyping after the first seizure could therefore have major implications in the correct counseling and clinical management of these two human channelopathies.

Partial epilepsy of temporal lobe origin has been reported in an individual bearing a loss of function mutation in the Kv1.1 channel gene (25). Inherited errors in this gene have previously been solely associated with myokymia and episodic ataxia. Because the channel is widely expressed in brain and the neuronal phenotype is predicted to feature abnormal repetitive firing, it is unclear why seizures are not a more common manifestation of this lesion within the extended pedigree and why epilepsy in this patient remains confined to the temporal lobe.

CALCIUM CHANNEL MUTATIONS AND IGE

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

To date, only one report has linked a generalized absence epilepsy in humans with a calcium channel pore mutation. The mutation lies in Cav2.1, the α1A subunit of the brain P/Q-type calcium channel, a gene previously related to familial hemiplegic migraine and episodic ataxia. Analysis of the mutation delineated by Jouvenceau et al. (C5733T), which occurs near the origin of the intracellular carboxy terminus, showed that the defect decreased calcium ion flux through the channel when expressed in a model cell system (6). A similar result was obtained in prior studies of the spontaneous tottering and leaner mouse mutations (26,27).

Recent work in the mouse models suggests a mechanism whereby decreases in calcium currents through the P/Q-type channel may alter thalamocortical oscillations associated with spike-wave absence epilepsy. Qian et al. applied selective calcium channel toxins to dissect the contribution of N- and P/Q-type calcium channels to presynaptic calcium entry and neurotransmitter release at a model hippocampal synapse (28). At many synapses, the ratio between N- and P/Q-type currents contributing to release is 50:50, and blockade of either calcium channel will halve the amount of neurotransmitter release at that synapse. In the tottering mouse, the mutated P/Q channel is noncontributory, and N-type toxins abolished postsynaptic responses, demonstrating that all release depends on the unaffected N-type channel (Fig. 3). This means that synaptic transmission solely depends on the N-type channel and its modulators. Interestingly, inhibitory thalamic synapses have been shown to undergo a developmental switch from combined N + P/Q-type transmission at postnatal day 10 to an exclusive reliance on P/Q-type channels alone at postnatal day 20 (29). Because tottering mice lack P/Q currents, the thalamic synapses would be functionally silenced by this switch, precisely corresponding with the age of onset of the thalamocortical seizure disorder (30). Thus, one potential mechanism for the developmental appearance of the absence epilepsy phenotype may be explained by an ontogenic switch in the presynaptic release machinery to reliance on a nonfunctional mutated (P/Q tg/la) channel.

image

Figure 3. Neurotransmitter release at synapses bearing a P/Q-type calcium channel mutation depends on the presence of functional N-type channels. Adapted and reprinted with permission from J Neurosci(28). Copyright 2000, the Society for Neuroscience.

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Seizures have been reported in two individuals with mutation of the calcium channel auxiliary subunit β4 (7), and in this case, analysis of the lethargic mutant mouse reveals that the failure of the cytoplasmic mutant subunit to interact with the pore-forming channel protein is replaced by alternative β1-3 subunit interactions (31, 32). The resulting pattern of abnormal calcium currents in a brain with this channelopathy is complex because the altered neuronal circuit (and the resulting clinical phenotype) critically depends on the availability of compensatory subunits rather than on the site of the mutant subunit itself.

GABA RECEPTOR MUTATIONS AND IGE

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

The expression of pentameric (α, β, and γ subunits) GABA-gated chloride channels is diffuse, and their location provides little insight into the seizure phenotypes that emerge at distinct ages following mutations of these subunits. For example, Cossette et al. found an Ala322Asp mutation in the GABA receptor α1 subunit in a single pedigree with recognized JME (8). The effect of this mutation was to lower GABA sensitivity more than tenfold; however, JME does not appear until adolescence. How can the late onset of epilepsy be explained by an impaired GABA receptor present since birth? Mutations of the γ2 GABA receptor subunit in families with GEFS+ offer a similar contradiction because either point or truncation mutations may also greatly impair the response of applied GABA, yet present with generalized absence epilepsy and febrile seizures rather than myoclonic seizures at young ages (33–37).

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

Genes for idiopathic epilepsies identify the molecular point of departure of the seizure disorder but raise other, still unanswered questions about epileptogenesis. In each case, significant research remains to define the mechanisms that explain where and when individual circuits in the brain become selectively vulnerable to the altered gene product.

In one instance, such as the newly described protein epitempin, the (nonchannel) product of the LGi1 gene linked to partial epilepsy with auditory features (38, 39), the disorder seems to neatly coincide with the regional expression of the mutated gene. However, in many channelopathies, including the nicotinic receptor subunit mutations of ADFLNE (40), the expression of the mutant channel appears to be far more widespread than the neurological phenotype might predict.

Idiopathic epilepsy syndromes can be clinically defined in many cases by the appearance and disappearance of seizures at different ages. What are the mechanisms mediating this plasticity? Are these direct effects, such as developmental substitutions of mutant subunits, or indirect ones, including the developmental changes in other molecular functions superimposed on the maturation of specific excitable networks? The final question remains the most enigmatic of all: What triggers the actual seizure itself? In all the genetic examples provided, it is understood why the person is predisposed to developing epilepsy; however, the factors that start and stop an individual seizure in each of these disorders remain a mystery.

ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES

Two organizations, the American Epilepsy Society and the Epilepsy Foundation, have created database tools to assist in the search for genes underlying epilepsy. One for physicians is called “I Know a Family,” and it allows clinicians to share their experience with potentially informative patients with other researchers. A site for patients is entitled “The Gene Discovery Project,” and it allows patients to learn more about the genetics of epilepsy and to initiate a research partnership with geneticists interested in epilepsy research.

The American Epilepsy Society Web site, “I Know a Family” (www.aesnet.org/research/i_know_info.cfm), is a free-form database where physicians can record clinical findings in families that may be of particular interest to epilepsy geneticists. Physicians enter a description of the seizures or syndromes they have encountered. Research groups interested in those phenotypes may then contact the clinician to collaborate on their study.

The Epilepsy Foundation Web site, “The Gene Discovery Project” (www.epilepsygene.org), serves a dual role. Typically, families would like to know more about genetics and epilepsy, and time restraints often limit full explanations of all the new information. This site serves as a starting point for patient education and also permits patients to learn how to build their own pedigree on the Web site. The data they provide are then encrypted, allowing participating scientists to review the anonymous pedigrees for possible study. If a significant pedigree is identified, researchers inform the Epilepsy Foundation, which contacts the family to inform them about a research center interested in the study of their family and provides them with information to directly contact the interested research center. This is a confidential, institutional review board–approved method of establishing a research connection between families and research centers. The Web site achieves two main objectives: to enable patients to form research partnerships with investigators who may be able to study the epilepsy in their family and to encourage all persons with epilepsy by demonstrating that physicians are continually learning more about the causes of these disorders.

Acknowledgment: I thank the members of the Blue Bird Circle Developmental Neurogenetic Laboratory and other collaborators for their help over the past few years. I also thank the Blue Bird Circle Foundation, American Epilepsy Society, the Epilepsy Foundation, and the National Institute of Neurological Disorders and Stroke for laboratory research support.

REFERENCES

  1. Top of page
  2. Abstract
  3. GENE DISCOVERY IN EPILEPSY
  4. FROM CHANNELOPATHY TO MECHANISM
  5. SODIUM CHANNEL MUTATIONS AND IGE
  6. POTASSIUM CHANNEL MUTATIONS AND IGE
  7. CALCIUM CHANNEL MUTATIONS AND IGE
  8. GABA RECEPTOR MUTATIONS AND IGE
  9. CONCLUSIONS
  10. ADDENDUM: ACCELERATING HUMAN GENETIC RESEARCH
  11. REFERENCES
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