The relationship between genes affecting the development of epilepsy and approaches to epilepsy therapy.

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Review

The relationship between genes affecting the development of epilepsy and approaches to epilepsy therapy Expert Rev. Neurother. 14(3), 329–352 (2014)

Thomas N Ferraro Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA [email protected]

The epilepsies are a clinically heterogeneous group of common brain diseases which are refractory to pharmacotherapy in up to one-third of patients. The discovery of DNA variants that cause or predispose to epilepsy has the potential to lead to new treatments that are based on the protein products or functional pathways of implicated genes. Overlap of gene classes involved in several broad phenotypic categories of epilepsy provides a means to prioritize various genetic leads for therapy development. In cases of epilepsy that are influenced strongly by single genetic defects, treatments may be personalized based upon the structural nature of the DNA alteration rather than on the function of the defective gene(s) or pathway(s). However, since most cases of epilepsy may be polygenic, the extent to which this approach may be widely applicable is unclear, thus creating a need for development of new target-based medications as well as further refinement of currently effective therapies. KEYWORDS: anti-sense nucleotide pharmacotherapy • common variant • ion channel • monogenic epilepsies • multifactorial epilepsies • pleiotropy • polygenic epilepsies • rare variant • RNA import • SCN1A • stop-codon read-through

Genetics of the epilepsies

The promise of the genetic information explosion in modern medicine is that improved treatments and indeed, cures, for human disease will emerge from the analysis and understanding of the genome. The field of epilepsy research has long hoped to be a major beneficiary of genome science; however, major breakthroughs in developing new treatments have yet to transpire. Part of the explanation for this delay is that of the many illnesses afflicting mankind, none may have a biological determinism or genetic architecture more varied and complex than the epilepsies. The many genes and types of genetic influences that have been documented to be relevant to the epilepsies is not surprising given the high degree of clinical heterogeneity exhibited among epilepsy patients and variable patterns of inheritance that characterize this group of common brain diseases. The number of genes informahealthcare.com

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that affect the development of epilepsy in any individual may vary, and although epilepsy may be caused by a single defective gene, the majority of epilepsy cases are believed to result from the action (and interaction) of several or even many gene variants. Given this landscape, identifying and validating specific genetic factors is difficult, and advances in treatment based on genetic discoveries have been slow in coming. This article will address the use of genetic information in epilepsy to target therapy or develop new therapeutic approaches. It begins with a discussion of genetic variants, their general nature and their role in therapy development. The need to validate genetic information prior to its use for guiding treatments is addressed and methodologies that enable the discovery of disease-related variants and some of their limitations are briefly discussed. Three realms of epilepsy genes are then reviewed: risk factors, genes causative for pure

2014 Informa UK Ltd

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Table 1. Types of genetic variants discovered in epilepsy. Variant

Description

Missense

Exonic single nucleotide substitution; produces amino acid substitution

Nonsense

Exonic single nucleotide substitution; creates premature stop codon

Splice site

Intronic single nucleotide substitution; adds or removes splice site; alters transcript exon composition

Frameshift

Exonic insertion or deletion; changes protein amino acid sequence

Partial gene deletion

Loss of one or more exons or introns, in full or in part; loss of 5´ or 3´ regulatory sequences

Large chromosomal deletion

Loss of multiple linked genes; copy number variation

Chromosomal translocation

Inactivation of genes at chromosomal breakpoints; long-range gene expression effects

Gene duplication

Duplication of one or more linked genes; copy number variation

Tandem repeat alteration

Contraction or expansion of a dinucleotide or trinucleotide repeat sequence; adds or removes tandem amino acid residues

epilepsy syndromes and genes causative for syndromes with complex phenotypes that include epilepsy, with a focus on identifying potential leads for new therapies. The article concludes by presenting several examples of novel or emerging genetic approaches to treatment that are relevant to the epilepsies. Common versus rare variants: relevance to therapy

Although epilepsy is a common disease, the relative importance of common versus rare genetic variants with regard to etiology is unknown. Moreover, the relative potential for developing new epilepsy treatments based on targets defined by common genetic variants as opposed to those defined by rare genetic variants is also unknown. This may be a moot point since the distinction between common and rare variants with respect to their frequency is not always clear, such as when there are large differences between ethnicities or races. In general, rare variants are observed in less than 1% of individuals from a given population, with new mutations and those private to individual families having an even lower frequency. Gene variants that are common in the population at large appear to exert relatively small effects individually on the development of epilepsy. This conclusion comes from the many genetic association studies that have been conducted in epilepsy and more recently from genome-wide association studies [1]. However, there may be no direct relationship between the magnitude of the relative risk associated with common variants in a given gene and the value of that gene or its product as a target for treating epilepsy. This idea is supported by studies of the SCN1A gene in which only weak effects of common variants on the risk for developing epilepsy are reported [2–4]; this is in contrast to the very large number of epilepsy patients who benefit from treatment with drugs that block the ion channel formed by the SCN1A gene product, Nav1.1 [5]. Unlike common gene variants, rare gene variants, or mutations, often have strong influence on expression of disease. This is exemplified by studies in unique forms of epilepsy, such as Dravet syndrome, and by recent studies involving analysis of chromosomal microdeletions and other gene copy number variation, in 330

which a single gene or genetic locus is documented as the cause of disease [6,7]. Thus, with regard to the potential for developing treatment strategies that will have a large positive impact on clinical outcome, there is a strong rationale for identifying therapeutic targets based both on susceptibility genes identified from studies of common variants via association analyses as well as on rare variants in single epilepsy-causing genes identified via positional cloning and/or DNA sequencing. The types of DNA variation that have been documented to influence the development of epilepsy span a broad range of structural changes including missense, nonsense and frameshift alterations as well as changes in splice site sequences (TABLE 1). In addition, more extensive alterations have been documented including partial gene deletions and large chromosomal deletions that encompass entire genes. Elucidating the nature of the genetic alteration is equally as important as identifying specific dysfunctional genes with regard to implications for the development of new therapeutic strategies. On one hand, identifying an epilepsy-causing mutation immediately suggests a therapy based on the product of the gene or on the type of mutation. Such therapies would be of potential benefit to those patients harboring the given mutation. On the other hand, knowing the identity of a particular epilepsy-causing gene can reveal a biochemical pathway that may consist of multiple targets and that may be exploited for the development of therapies to benefit potentially a broader group of epilepsy patients, including those without defects in any of the genes in the pathway. Such a situation exists now in the realm of epilepsy therapy, where many patients are treated successfully with drugs that target sodium channels in the absence of any evidence that there are sodium channel subunit gene defects or defects in genes directly related to the function of sodium channels. Technology & methodology

The ability to discover DNA alterations that are involved in epilepsy is related directly to the development and application of biotechnology as well as to the availability of appropriate research subjects. Initial genetic studies of epilepsy in rare Expert Rev. Neurother. 14(3), (2014)


Relationship between genes affecting the development of epilepsy & approaches to epilepsy therapy

families segregating illness according to the laws of Mendel involved linkage analysis and subsequent positional cloning of defective genes. However, the relative paucity of epilepsy families suitable for linkage analysis emphasized the need to develop approaches to study sporadic cases. Thus, technological advances in single nucleotide polymorphism analysis [8] and the completion of the HapMap project [9] spawned an era of intensive association analysis that is now culminating in a series of genome-wide association studies [10–12]. Although linkage and association methods are effective in some research design settings, the introduction of newer molecular genetic tools is permitting discovery of rare disease-causing variants at a more rapid pace. One technique that has proven valuable for identifying structural DNA alterations is comparative genomic hybridization (CGH). Used in conjunction with high-density oligonucleotide arrays, CGH offers a means to measure variation in the number of copies of specific genetic loci, thus allowing identification of deletions and duplications essentially anywhere in the genome. Single nucleotide polymorphism arrays are also used for analysis of copy number variation, however, there is some evidence that array CGH is more comprehensive [13]. Currently, the most powerful methods for discovery of rare genetic variation involve ‘next-generation’ DNA sequencing. Next-generation DNA sequencing can be applied using several different strategies depending on the research question or study design. Targeted approaches may focus upon a single candidate gene or single genetic locus and perform the analysis at high coverage. Such ‘deep sequencing’ of targeted regions is often applied when screening populations of unrelated individuals under specific hypotheses. Application of this approach to epilepsy under the ion channelopathy hypothesis has so far failed to identify clearly causative gene effects [14]. More global or exploratory approaches involve sequencing the entire exome or genome. With these methods, depth of coverage is sacrificed to expand breadth, but the relative lack of bias aids to support subsequent validation of results. Whole exome sequencing (WES) focuses on the known coding regions of the genome and can be used to discover single base changes that alter the properties or expression profiles of protein products and result in manifestation of disease. WES is compatible with family-based study designs [15], although application to common forms of generalized epilepsy has failed to identify single rare variants of large effect [16]. On the other hand, application of WES in the epileptic encephalopathies has identified several interesting gene candidates for further study [17]. Similarly, whole genome sequencing can be applied in family settings to identify disease-causing single gene mutations [18]. By generating data on non-coding DNA sequence, whole genome sequencing expands the spectrum of causative mutations that may be discovered into regulatory regions of the genome as well as into regions of genome that are not well annotated. All of the currently known epilepsycausing genes and alleles have been identified with one or a combination of the above methods. informahealthcare.com

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Validation

Discovery of rare variants that are putative epilepsy-causing mutations requires validation in order to optimize the value of such information. This is also a critical step in the assessment of a putative susceptibility gene or allelic variant, especially in the case of single nucleotide changes, since their influence may be highly dependent upon genetic background [14]. Although a variety of methods are useful to help determine whether a newly discovered DNA sequence variation is causative, there is no criterion that by itself establishes causation. One important metric is whether the variant can be shown to exist in unaffected family members or in a control population of unaffected individuals. If so, appropriate statistical methods must be applied to determine whether any difference in frequency between cases and controls is significant. In addition to genetic validation, rare variants should be subject to functional analysis. The nature of such functional tests is dictated generally by the biological role of the encoded product of the gene or by the structural nature of the variation. Artificial expression of variants in relevant in vitro systems allows for many types of functional assessment and, specifically for ion channel gene variants, this is a routine method that is well suited to evaluating their potential for causing epilepsy [19]. Animal models offer another means of validating the effect of rare variants suspected of causing epilepsy, and in particular, ‘humanized’ mice have been created via genetic engineering and serve as important tools to evaluate the pathogenicity of specific gene defects [20]. However, while several such avatars have been developed, testing human gene variants in animal models is not widely pursued at the present time and the majority of putative pathogenic alleles for so-called ‘epilepsy genes’ have not been studied in this way. Currently, in vitro methods that are under development involve sampling readily accessible cells (e.g., fibroblasts) from individual patients, de-differentiating them to form pluripotent stem cells and then re-programming them with specific transcription factors to become neurons [21]. Such cells can be studied in various ways to characterize phenotypes associated with the genetic variant in question and have the major advantage of permitting analysis of variants in the context of their genetic background. Of relevance to epilepsy, ion channel gene variants are highly amenable to such approaches [22]. Monogenic epilepsies

Whereas the majority of epilepsy cases are considered to be multifactorial, there are a large number of syndromes in which a single genetic locus or gene defect has been documented to be sufficient to cause disease. Nonetheless, monogenic epilepsies are considered rare, representing 1% or less of all epilepsy cases. They exhibit variable modes of inheritance including autosomal dominant, recessive and X-linked. Some syndromes involve epilepsy alone and other syndromes comprise a broader clinical condition, some affecting only the central nervous system, and some affecting multiple organ systems. TABLE 2 lists genes that, when specifically altered, cause a syndrome in which epilepsy is the sole or predominant phenotype. 331

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Table 2. Genes causing pure epilepsy syndromes. Symbol

Gene name

Functional class

Syndrome

Mode of inheritance

CACNA1A

Calcium channel, voltage-dependent, P/Q type, a-1A subunit

Ion channel

CAE, JAE

Monogenic, complex

[83,84]

Ref.

CACNB4

calcium channel, voltage-dependent, b-4 subunit

Ion channel

JME

Monogenic

[85,86]

CASR

Calcium-sensing receptor

Signal transduction

Various

Monogenic

[87]

CHRNA4

Cholinergic receptor, nicotinic, a-4 (neuronal)

Membrane receptor, ligand-gated

ADNFLE

Monogenic

[88]

CHRNB2

Cholinergic receptor, nicotinic, b-2 (neuronal)


ADNFLE

Monogenic

[89]

CLCN2

Chloride channel, voltage-sensitive 2

Ion channel

JME, JAE

Monogenic, complex

[90]

CPA6

Carboxypeptidase A6

Peptide metabolism

TLE, FS

Monogenic

[91,92]

DEPDC5

DEP domain containing 5

Unknown

FFEVF

Monogenic

[93,94]

EFHC1

EF-hand domain (C-terminal) containing 1

Unknown

JME

Monogenic

[41]

GABRA1

GABA-A receptor, a-1


CAE, JME

Monogenic

[95,96]

GABRB3

GABA-A receptor, b-3


CAE

Monogenic, complex

[97,98]

GABRD

GABA-A receptor, d


GGE

Complex

GABRG2

GABA-A receptor, g-2

Membrane receptor

GEFS+, CAE, GGE

Monogenic, complex

GPR98

G protein-coupled receptor 98

Unknown

FS

Monogenic

KCNQ2

Potassium voltage-gated channel, KQT-like subfamily, member 2

Ion channel

BNFC, GGE

Monogenic, complex

[54,104]

KCNQ3

Potassium voltage-gated channel, kqt-like subfamily, member 3

Ion channel

BNFC, GGE

Monogenic, complex

[55,104]

LGI1

Leucine-rich, glioma inactivated 1

Unknown

TLE

Monogenic

[105]

NIPA2

Non-imprinted in Prader-Willi/ Angelman syndrome 2

Membrane transporter

CAE

Monogenic

[106]

PRRT2

Proline-rich transmembrane protein 2

Unknown

BFIE

Monogenic

[107]

SCN1A

Sodium channel, voltage-gated, type I, a-subunit

Ion channel

TLE, GEFS+

Monogenic, complex

[108,109]

SCN1B

Sodium channel, voltage-gated, type I, b-subunit

Ion channel

TLE, GEFS+

Monogenic

[110,111]

SCN2A

Sodium channel, voltage-gated, type 2, a-subunit

Ion channel

BFNIS

Monogenic

[112]

SCN3A


Ion channel

Focal epilepsy

Monogenic

[113]

SCN9A


Ion channel

FS

Monogenic

[114]

SLC2A1

Solute carrier family 2 (facilitated glucose transporter), member 1


CAE

Monogenic

[115]

UBR5

Ubiquitin protein ligase E3 component n-recognin 5

DNA repair

FAME

Monogenic

[116]

[99] [100–102] [103]

ADNFLE: Autosomal dominant nocturnal frontal lobe epilepsy; BFIE: Benign familial infantile epilepsy; BFNC: Benign neonatal familial convulsions; BFNIS: Benign familial neonatal-infantile seizures; CAE: Childhood absence epilepsy; FAME: Familial adult myoclonic epilepsy; FFEVF: Familial focal epilepsy with variable foci; FS: Febrile seizures; GEFS+: Generalized epilepsy with febrile seizures plus; GGE: Genetic generalized epilepsy; JAE: Juvenile absence epilepsy; JME: Juvenile myoclonic epilepsy; TLE; Temporal lobe epilepsy.

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Of all epilepsy-related genes, SCN1A may be considered a prototype with relevance to therapy from several perspectives. There are hundreds of SCN1A mutations cataloged that are considered causative for epilepsy and the range of phenotypes associated with these mutations includes the spectrum of Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) [23]. In addition, genetic association studies have found a relationship between SCN1A polymorphisms and common genetic generalized epilepsy [4]. Finally, a number of standard anti-epileptic drugs act on the NaV1.1 sodium channel, which contains SCN1A subunits, including phenytoin, carbamazepine and valproic acid [5]. Attempts to refine therapeutic approaches related to SCN1A pharmacology have revealed several obstacles, especially ubiquitous expression patterns and fundamental role of NaV1.1 channels in the brain. Moreover, variants characterized by both loss-of-function as well as gainof-function may be similarly detrimental to normal physiology [24] and result in seizure activity. Although these factors complicate the use of genetic information for the development of therapy, careful analysis of genotype–phenotype relationships may lead to new opportunities for therapeutic advance. In addition, systems approaches that model genetic effects may be able to identify key nodes for therapeutic intervention to restore network balance and prevent seizures [25]. Another ion channel that has been identified as being able to cause epilepsy when mutated is the chloride channel that contains subunits encoded by the CLCN2 gene. The evidence supporting a role for CLCN2 as an epilepsy gene is weakened by family studies that revealed unaffected members carrying presumed pathogenic mutations [26] and by discrepancies in datasets from original publications [27]. Although this has generated questions regarding the potential value of CLCN2 as a therapeutic target [28], it is possible that such findings signal incomplete penetrance or genetic heterogeneity since data suggesting a causal role for CLCN2 mutations have been reported by independent laboratories [29,30]. Further analysis of this molecule is warranted by virtue of the biological function of chloride channels and also the anti-epileptic efficacy of drugs that modulate ligand-gated chloride channels associated with GABA-A receptors. Mutations in SLC2A1, the gene encoding the glucose transporter 1 (GLUT1), lead to deficiency of glucose transport across the blood–brain barrier, alteration of intermediary metabolism in the brain and seizures. GLUT1 deficiency was first associated with an epileptic encephalopathy [31], and more recently found in rare families and individuals with epilepsy of various types [32]. SLC1A2 variants may either cause epilepsy per se, or act as susceptibility alleles, requiring other genetic factors for expression of disease as discussed below. SLC2A1 mutations contribute to approximately 1% of generalized epilepsies, both as a dominant gene and as a susceptibility allele in complex inheritance. Myoclonic-astatic epilepsy is also associated with GLUT1 deficiency and 5% of patients with myoclonic-astatic epilepsy were shown to harbor SLC2A1 mutations [33]. Diagnosis of GLUT1 deficiency requires either documentation of low spinal fluid glucose level followed by SLC2A1 sequencing or direct gene informahealthcare.com

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sequencing and it has important treatment implications. Specifically, GLUT1 deficiency is a strong indication for early implementation of the ketogenic diet, which may substantially improve outcome [34,35]. More flexible diets, like the modified ketogenic diet, can also be effective with regard to seizure control [36]. The treatment mechanism of restricted glucose delivery is novel in that it differs from the current focus on epilepsies as ion channel disorders. In addition, the potential for broader utility of metabolism-based treatments is supported by an association between seizures and blood glucose levels in diabetic patients [37] and documented abnormalities in the oral glucose tolerance test in drug-refractory epilepsy patients [38]. Thus, given the pre-clinical advances in manipulation of metabolic pathways as an anti-seizure therapy in animal models [39], this strategy should be further pursued and refined as a means to restore cellular energy balance and treat epilepsy in humans. Two epilepsy gene-encoding proteins that may have unique brain function are leucine-rich glioma-inactivated 1 (LGI1) and elongation factor-hand domain (C-terminal)-containing protein 1 (EFHC1). The LGI1 gene was brought to attention as a result of mutations that cause a rare familial form of autosomal dominant lateral temporal lobe epilepsy with auditory signs [40]. Although the precise role of the LGI1 protein in the brain is unclear, it appears to be involved in synaptic transmission directly via interaction with potassium channels and indirectly via interaction with certain types of glutamate receptors. EFHC1 was identified due to mutations that cause a familial form of juvenile myoclonic epilepsy [41]. Like LGI1, the function of its encoded protein is not perfectly clear, although it appears to play a role in cell signaling via modulation of calcium homeostasis. Although EFHC1 and LGI1 may have potential value for epilepsy therapies in the future, insufficient information is available regarding their role in normal physiology to make them currently useful targets from a drug development perspective. Epilepsies with complex genetics

The epilepsies with complex genetics, previously referred to as idiopathic, are very common, representing the vast majority of non-symptomatic forms of the disease. Complex genetic epilepsies may be either generalized, involving the entire brain, or focal, involving specific regions of the brain [42]. Genetic generalized epilepsies comprise one-third to one-half of all cases of epilepsy [43]. There are several more or less well-defined syndromes in the category of genetic generalized epilepsies including childhood and juvenile absence epilepsies, juvenile myoclonic epilepsy and generalized tonic-clonic epilepsy. On the other hand, many phenotypic variations are observed among patients with generalized epilepsy and the characteristics of seizures may change or evolve over time in the same individual. Focal or localization-related epilepsies, in particular temporal lobe epilepsies, are also very common and may represent half or more of all epilepsy cases [44]. Common forms of generalized and focal epilepsy are characterized by non-Mendelian modes of inheritance and are thought of primarily as having a polygenic determinism [45]. Often there is no known family history of 333


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epilepsy and cases arise sporadically. On the other hand, there are examples in the literature of common forms of epilepsy that segregate in families in relatively predictable ways and that lend themselves to traditional approaches of genetic analysis [46]. Thus, inheritance patterns overall are truly complex. Despite their name, genetic epilepsies are multifactorial. Thus, in addition to a specific burden of genetic risk variants, they are also influenced strongly by environmental factors including stress and sensory stimuli. Moreover, various combinations of alleles from multiple genes may provide the genetic substrate for susceptibility and this set of factors can interact with one another to produce synergistic effects on development of disease. As a result, the polygenic nature of the genetic epilepsies hinders the identification of individual contributing factors, even in families in which there is clear evidence of disease transmission. This problem is compounded by the relatively weak effects exerted by any single susceptibility allele, which may be lost in the phenotypic ‘noise’ associated with genetic studies. Such circumstances have precluded the use of traditional genetic approaches such as linkage analysis, and have led to an integration of approaches from studies of related and unrelated subjects. Thus, in many instances, candidate genes for genetic association analysis in sporadic cases of epilepsy come from genes identified in studies of families with either common or rare forms of disease [4]. Candidates also emerge from studies of animal models or are nominated simply by their known function and biological plausibility. Genetic association analysis has led to the identification of numerous putative gene variants that increase risk for epilepsy, and a compendium of genetic association data has been established as a useful resource to catalog variants along with basic genotypic and phenotypic details [47]. Susceptibility alleles discovered via genetic association explain only a small fraction of epilepsy heritability, each factor increasing risk for disease by no more than a few percent. However, despite such weak effects, the potential value in documenting susceptibility alleles for epilepsy stems from the fact that they mark genes whose products affect global excitability of the nervous system and they may reveal novel molecules and/or pathways that could stimulate discovery of new therapies. KCNJ10 is an example of a gene where common polymorphisms exert weak effects [48–50], but where nonsense or other more deleterious DNA alterations exert strong phenotypic effects [51,52]. Thus, the impact of therapies designed from clues provided by risk genes or genes of partial effect may be profound despite the fact that naturally occurring polymorphisms exert effects that are weak. A caveat related to the potential usefulness of genes discovered by association analysis, especially in candidate approaches, is that there are numerous variables that may result in false positive results, some of which are cryptic and difficult to control [53]. One criterion that helps to increase confidence in the true nature of a risk allele is confirmation in multiple studies by independent laboratories. The subset of genes that harbor common, independently confirmed risk alleles for epilepsy is shown in TABLE 3. 334

Confirmed epilepsy risk genes fall into several distinct functional categories, but a large majority are related to synaptic neurotransmission. Prominent among these are several encoding subunits of receptors for the neurotransmitter GABA. This is not surprising given that GABA receptors are targets of pharmacological agents that have long been known to have antiepileptic properties, particularly those from the benzodiazepine and barbiturate drug classes. Similarly, the sodium channel subunit encoded by SCN1A is part of a molecular complex that is the target of a number of conventional anti-epileptic drugs [5]. It is worth recalling that these drugs, along with benzodiazepines and barbiturates, were introduced into the clinic long before detailed knowledge about receptors and ion channels was available and represent proof of the principle that epilepsy risk genes are relevant to epilepsy treatment strategies. In contrast to genes for GABA receptors and sodium channels, other epilepsy risk genes are more directly linked to advances in therapy. KCNQ2 and KCNQ3 encode protein subunits that interact to form a potassium channel that mediates the so-called neuronal M-current, a slowly activating and deactivating potassium conductance that helps determine the electrical excitability of neurons as well as responsiveness of neurons to synaptic inputs. Elucidation of the M-current channel followed from discovery of epilepsy-causing mutations in KCNQ2 and KCNQ3 [54,55], findings that are consistent with the development of retigabine, an activator of the M-current, as an approved epilepsy treatment [56]. KCNQ2 and KCNQ3 are examples of genes that were first brought to light through discovery of deleterious mutations that cause benign neonatal familial convulsions, a rare monogenic form of epilepsy, and only more recently associated with common forms [57]. Interestingly, while retigabine acts upon the product of the gene that is defective in benign neonatal familial convulsions (BNFC), it is not a drug of choice in BNFC patients who require treatment. Indeed, it may be that the drug requires functional KCNQ2 and KCNQ3 channels in order to exert its anti-epileptic effect. Thus, although retigabine is not useful for treating BNFC, its potential utility in more common forms of epilepsy underscores the value of discovering epilepsy-causing gene mutations, namely that such genes point to molecules and pathways that may be exploited for larger therapeutic benefit. Drugs with action at various types of calcium channels, such as gabapentin and pregabalin, have also been established as anti-epilepsy treatments [5], but again these developments took place independent from studies of epilepsy risk genes and their use in patients with different types of epilepsy was determined through clinical trials. Another ion channel that has emerged more recently as a potential target for epilepsy therapy is the hyperpolarizationactivated cyclic nucleotide-gated potassium channel encoded by the HCN2 gene. A 9-bp deletion in the HCN2 gene that produces a protein variant lacking a stretch of 3 proline residues was found overrepresented in generalized epilepsy patients with febrile seizures and patients with GEFS+ compared with controls and with epilepsy patients who do not have febrile seizures [58]. In vitro functional expression studies revealed that Expert Rev. Neurother. 14(3), (2014)


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Table 3. Susceptibility genes for genetic generalized and focal epilepsies. Gene symbol

Gene name

Functional class

Epilepsy phenotype

Ref.

SLC6A4

Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4

Membrane transporter Serotonin re-uptake

TLE

[117,118]

apoE

Apolipoprotein E

Lipid metabolism

TLE (early onset)

[119,120]

BDNF

Brain-derived neurotrophic factor

Cell signaling Trophic factor

TLE, RS

[121,122]

BRD2

Bromodomain containing 2

Unknown

JME

[123,124]

CACNA1G

Calcium channel, voltage-dependent, T type, a-1G-subunit

Ion channel Calcium flux

JME, JAE

CACNA1H

Calcium channel, voltage-dependent, T type, a-1H-subunit

Ion channel Calcium flux

CAE, GGE

[126,127]

CACNG3

Calcium channel, voltage-dependent, g subunit 3

Ion channel Calcium flex

CAE

[128,129]

CHRNA4

Cholinergic receptor, nicotinic, a-4

Membrane receptor Sodium, Calcium flux

GGE, FS

[130,131]

Cx36

Connexin 36

Cell adhesion

JME

[132,133]

GABBR1

GABA-B receptor, 1

Membrane receptor G-protein-linked

TLE

[134,135]

GABRB3

GABA-A receptor, b-3

Membrane receptor Chloride flux

CAE

[136,137]

GABRG2

GABA-A receptor, g-2

Membrane receptor Chloride flux

GGE

[102,138]

HCN2

Hyperpolarization activated cyclic nucleotide-gated potassium channel 2

Ion channel

GGE

[54,139]

IL-1B

IL 1, b

Cytokine

TLE, FS

[140,141]

IL-1RA

IL 1 receptor, type I

Cytokine receptor

FS

[142,143]

KCNJ10

Potassium inwardly rectifying channel, subfamily J, member 10

Ion channel Potassium flux

GGE, TLE

KCNQ2



GGE

[104,144]

KCNQ3



GGE, JME

[104,145]

PDYN

Prodynorphin

Cell signaling Neurotransmitter

TLE, ADLTE

[146,147]

PRNP

Prion protein

Unknown

TLE

[148]

SCN1A

Sodium channel, voltage-gated, type I, a subunit

Ion channel Sodium flux

GGE, FS

[2,3]

SLC2A1



GGE

[125]

[48–50]

[115,149]

Genes listed are supported by at least two independent literature reports as having alleles associated with epilepsy or epilepsy-related phenotypes. ADLTE: Autosomal dominant lateral temporal epilepsy; CAE: Childhood absence epilepsy; FS: Febrile seizures; GGE: Genetic generalized epilepsy; JME: Juvenile myoclonic epilepsy; RS: Rett Syndrome; TLE: Temporal lobe epilepsy.

the variant enhances channel conductance, and it is thus hypothesized that it may increase neuronal excitability and cause epilepsy [58]. Lamotrigine, gabapentin and propofol are drugs that have been shown to interact with HCN channels and studies are underway to identify compounds with more informahealthcare.com

specific action [59]. Other epilepsy risk genes that encode proteins important for synaptic function include the gene for a serotonin re-uptake protein, a gene for a subunit of a nicotinic acetylcholingeric receptor and the gene that encodes the dynorphin family of neuropeptides (TABLE 3). None of these genes 335


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encode products that are known to be directly associated with any specific epilepsy treatments or that fall into pathways affected by such treatments, thus there is potential for antiepilepsy therapy development in these neurochemical areas. With one notable exception, that is, SLC2A1 (discussed above), non-neurotransmission-related risk genes listed in TABLE 3 similarly are not known to be targeted by current treatments for epilepsy and therefore also offer new areas for therapy development. One of these areas is inflammation [60], as represented by risk alleles for genes for the cytokine IL-1B and the cytokine receptor IL-1RA. Another area is ontological development and cellular plasticity, as represented by genes encoding the trophic factor BDNF and the cell adhesion molecule Cx36. A third area is cellular metabolism as represented by risk genes encoding SLC2A1, critical for glucose uptake into brain, and apoE, involved in lipid biosynthesis. Interestingly, the functional domains represented by risk genes for polygenic epilepsies overlap in large part with those for monogenic forms of epilepsy (TABLE 2) and other broader monogenic syndromes in which epilepsy is one component of larger constellation of clinical manifestations (TABLE 4). Given the large number of ion channel-related genes expressed in the brain, it is surprising that relatively few variants have been documented to be associated with epilepsy or have been found to be mutated in epilepsy patients. It is possible that many more genetic associations and influences of ion channel genes will be discovered in the future; however, current effort to refine therapy should focus on better understanding the biology of neurons and glia that express ion channel subunits already confirmed to harbor common risk variants or causative mutations. Priority may be afforded to subunits that have variants that are both confirmed susceptibility factors and that also have been documented to harbor pure epilepsy-causing mutations including CACNA1H, CHRNA4, GABRB3, GABRG2, KCNJ10, KCNQ2, KCNQ3, SCN1A and SLC2A1 (TABLES 2 & 3). Complex phenotypes that include epilepsy

Epilepsy co-occurs with complex phenotypes that result from defects in many other organ systems as well as from other nervous system defects. Numerous clinical syndromes such as those involving inborn errors of metabolism, neuronal migration defects and lipid storage disorders, include epilepsy as one part of a larger constellation of abnormal phenotypes. FIGURE 1 depicts the frequency of association between epilepsy and co-occurring conditions and phenotypes. The mutated genes involved in causing many of these syndromes have been deduced and are listed in TABLE 4, together with a summary of major co-morbidities and epilepsy subtype when known. As noted above, the same functional classes of genes that act as susceptibility factors for complex forms of epilepsy, or that are causative for rare monogenic epilepsy syndromes, are also found as causative among the broader syndromes with complex phenotypes; this includes genes encoding ion channel subunits and intracellular signaling molecules. Ion channel genes are from the chloride, potassium and sodium classes, 336

with a notable absence of calcium channel subunit genes. A novel potassium channel gene discussed earlier, is KCNJ10 which is documented to cause SESAME/EAST syndrome [51,52]. A major function of KCNJ10 protein in the brain, which is expressed primarily in glial cells, is as a component of the potassium ‘sink’, a buffering mechanism that is crucial for regulating extracellular levels of potassium. Deficiencies in potassium buffering result in alteration of extracellular potassium levels, which leads to neuronal hyperexcitability and seizures. KCNJ10 channels represent novel targets for the development of anti-epilepsy treatment strategies, which could take several different forms including channel-opening drugs, gene therapy approaches or stem cell-based treatments. In addition to ion channel genes, multiple examples of specific types of signaling molecules are also found as causes of syndromes with a complex phenotype that includes epilepsy such as protein kinases, scaffold proteins, membrane transporters and neurotransmitter receptor subunits. None of these molecules has led to the development of epilepsy therapies from a pharmacological perspective, although a number of potential targets have been identified such as those encoded by GPHN [61] and PLCB1 [62]. Another area of functional overlap between genes causing pure epilepsy syndromes and genes causing broader phenotypic syndromes is in the control of intermediary metabolism, as discussed above with use of the ketogenic diet in GLUT1 deficiency. In addition to GLUT1 deficiency, several syndromes have been described in which epilepsy co-occurs with non-specific metabolic disturbances, such as acidosis and alkalosis or with more specific clinical entities, such as diabetes. In particular, the syndrome called developmental delay, epilepsy and neonatal diabetes is caused by a mutation in the KCNJ11 potassium channel, which is functionally related to the sulfonylurea receptor on pancreatic islet cells. Control of blood glucose levels is key to controlling seizures in patients with the syndrome of developmental delay, epilepsy and neonatal diabetes patients, with effects of oral hypoglycemic drugs superior to those of anti-epilepsy drugs. As noted above for GLUT1 deficiency, this is consistent with reports describing a high incidence of epilepsy in patients with more common forms of diabetes and the relationship between control of blood glucose and control of seizures [37]. More studies of the relationship between seizures and variants in genes controlling cellular energy metabolism will allow development of epilepsy treatment strategies in this area that may be applicable to larger populations of patients. Although there is overlap in functional gene classes between complex epilepsies, monogenic epilepsy syndromes, and syndromes with complex phenotypes that include epilepsy, there are many additional types of genes found mutated in the broader clinical syndromes. Other functional classes that are well represented include genes controlling cell adhesion, cell migration and composition of the extracellular matrix as well as some encoding transcription factors. In addition, defects that lead to global dysfunction of specific cellular organelles are also associated with epilepsy, especially dysfunction of lysosomes Expert Rev. Neurother. 14(3), (2014)

DNA repair Extracellular matrix

Extracellular matrix Extracellular proteolysis Ganglioside GM3 synthesis

Leucyl-tRNA synthetase 2, mitochondrial

TRNS2 – mitochondrially encoded tRNA serine 2 (AGU/C)

Arginyl-tRNA synthetase 2, mitochondrial

Mitochondrially encoded tRNA isoleucine

Contactin associated protein-like 2

Neurexin 1

Protocadherin 19

Immediate early response 3 interacting protein 1

DnaJ (Hsp40) homolog, subfamily C, member 6

Ubiquitin protein ligase E3 component n-recognin 5

Polynucleotide kinase 3´-phosphatase

Collagen, type XVIII, a-1

Collagen, type VI, a-2

Sushi repeat protein upregulated in leukemia

ST3 b-galactoside a-2,3-sialyltransferase 5

Methyl-CpG binding domain protein 5

LARS2

MT-TS2

informahealthcare.com

RARS2

MTTI

CNTNAP2

NRXN1

PCDH19

IER3IP1

DNAJC6

UBR5

PNKP

COL18A1

COL6A2

SRPX2

ST3GAL5

MBD5

Gene expression

DNA repair

Chaperone

Cell differentiation apoptosis

Cell adhesion

Cell adhesion

Cell adhesion

Amino-acyl transferase





Lysyl-tRNA synthetase

KARS

Functional class

Gene name

Gene symbol

Generalized epilepsy, febrile seizures

Generalized epilepsy

Rolandic epilepsy

Progressive myoclonus epilepsy

Epilepsy

Generalized epilepsy (infantile onset)

Myoclonus epilepsy

Epilepsy

Generalized epilepsy, hypsarrhythmia

Generalized epilepsy (female-specific)


Focal epilepsy

Myoclonus epilepsy

Myoclonus epilepsy

Myoclonus epilepsy

Myoclonus epilepsy


Epilepsy phenotype

Table 4. Genes causing complex phenotypic syndromes including epilepsy.

Autism spectrum disorder

Developmental delay, intellectual disability

Speech dyspraxia, mental retardation

Muscle weakness

Myopia, vitreoretinal degeneration, retinal detachment, ataxia, macular abnormalities, occipital encephalocele

Microcephaly, development delay

Intellectual disability

Parkinsonism, obesity, mental retardation

Obesity, diabetes, microcephaly

Developmental regression, mental retardation

Autism spectrum

Autism spectrum

Neural deafness, ataxia, muscle weakness, intellectual disability, cardiomyopathy

Neural deafness, ataxia, muscle weakness, intellectual disability, cerebellar hypoplasia

Neural deafness, ataxia, muscle weakness, intellectual disability

Neural deafness, ataxia, muscle weakness, intellectual disability, stroke-like episodes

Peripheral neuropathy, developmental delay, self-abusive behavior, dysmorphic features

Additional phenotypes


156200

609056

300643

[151]

267750

613402

601068

[150]

614231

300088

614325

610042

590045

611523

540000

604544

613641

OMIM # [Ref.]


Review

337

338 Intracellular Signaling Intracellular signaling

Methyl CpG binding protein 2

SET domain, bifurcated 1, histone methyltransferase

Protein phosphatase 1, regulatory subunit 3C

Dolichyl-phosphate (UDP-Nacetylglucosamine) Nacetylglucosaminephosphotransferase 1

Dentin matrix protein 2

Phosphatidylinositol glycan anchor biosynthesis, class T

Phosphatidylinositol glycan anchor biosynthesis, class V

Coiled-coil and C2 domain containing 2A

DEP domain-containing protein 5

Fibroblast growth factor receptor 3

Phospholipase C, b-1

RAB3 GTPase activating protein subunit 1

Spastin

Chloride channel, voltage-sensitive 4

MECP2

SETDB1

PPP1R3C

DPAGT1

DPM2

PIGT

PIGV

CC2D2A

DEPDC5

FGFR3

PLCB1

RAB3GAP1

SPAST

CLCN4

Ion channel

Intracellular trafficking

Intracellular signaling



Glycoprotein biosynthesis

Glycoprotein biosynthesis

Generalized epilepsy, epileptic encephalopathy

Temporal lobe epilepsy with partial complex seizures

Epilepsy

Generalized epilepsy, tonic-clonic seizures, focal seizures

Temporal lobe epilepsy

Focal epilepsy

Epilepsy



Generalized epilepsy, focal epilepsy, myoclonic seizures

Epilepsy, infantile spasms, intractable seizures

Glycoprotein biosynthesis Glycoprotein biosynthesis

Myoclonic epilepsy, absence epilepsy

Epilepsy

Epilepsy

Epilepsy

Epilepsy phenotype

Glycogen biosynthesis

Gene expression

Gene expression

Gene expression

Methyl-CpG binding domain protein 6

MBD6

Functional class

Gene name

Gene symbol

Table 4. Genes causing complex phenotypic syndromes including epilepsy (cont.).

Developmental delay, autistic features, cognitive impairment, motor deficits

Spastic paraplegia

Microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, mental retardation, spastic diplegia, hypogonadism

Hypotonia, spastic quadriparesis, developmental regression

Hypochondroplasia

Intellectual disability, autism spectrum

Mental retardation, retinitis pigmentosa, nystagmus

Developmental delay, language and auditory defects, hypotonia, dysmorphologies

[153]

604277

602536

613722

134934

604364

612013

239300

615398

603564

Psychomotor delay, hypotonia, motor abnormalities, intellectual disability Facial dysmorphology, intellectual disability, hypotonia, abnormal skeletal, endocrine, and ophthalmologic findings

608093

254780

[152]

312750

[152]

OMIM # [Ref.]

Developmental delay, hypotonia, dysmorphologies

Developmental delay, hypotonia, dysmorphologies


Rett syndrome




Review Ferraro


Gene name

Potassium voltage-gated channel, subfamily H (eag-related), member 5



Potassium channel, subfamily T, member 1

Potassium channel tetrameriZation domain containing 7

Sodium channel, voltage-gated, type I, a-subunit

Sodium channel, voltage-gated, type II, a-subunit

Sodium channel, voltage-gated, type VIII, a-subunit

Lipoic acid synthetase

Palmitoyl-protein thioesterase 1

Ceroid-lipofuscinosis, neuronal 3




Gene symbol

KCNH5

KCNJ10


KCNJ11

KCNT1

KCTD7

SCN1A

SCN2A

SCN8A

LIAS

PPT1

CLN3

CLN5

CLN6

CLN8

Lysosome function

Lysosome function

Lysosome function

Lysosome function

Lipoprotein metabolism

Lipid metabolism

Ion channel

Ion channel

Ion channel

Ion channel

Ion channel

Ion channel

Ion channel

Ion channel

Functional class





Progressive myoclonus epilepsy, motor seizures

Epilepsy


Generalized epilepsy, focal seizures, intermittent myoclonic jerks, atonic seizures, febrile seizures

Generalized epilepsy, focal seizures, febrile seizures


Generalized epilepsy, early onset, malignant migrating partial seizures of infancy, focal seizures


Generalized epilepsy, generalized tonic-clonic seizures


Epilepsy phenotype


Mental regression, speech impairment, loss of vision, personality disorders

Cognitive decline, motor abnormality, visual defect

Mental retardation, ataxia

Progressive dementia, macular degeneration, progressive visual failure, parkinsonism

Mental retardation, loss of speech, ataxia, psychosis

Metabolic disorder, hypotonia, respiratory motor deficiency

610003, 600143

601780, 204300

256731

204200

256730

614462

614558

613721 Ataxia, slurred speech, headache, back pain, hypermotor activity, hyperventilation, vomiting, motor dyspraxia Developmental delay, intellectual disability, hypotonia, ataxia, psychiatric symptoms

614959

Intellectual disability

611726

614959, 615005

Developmental delay, microcephaly, cortical atrophy, hypotonia, language dysfunction

Intellectual disability, migraine

600937

612780

[153]

OMIM # [Ref.]

Developmental delay, neonatal diabetes

Delayed psychomotor development, ataxia, deafness, electrolyte imbalance

Developmental delay, epileptic encephalopathy, autistic features, cognitive impairment, motor deficits




Review

339

340 Generalized epilepsy

Generalized epilepsy, myoclonic seizures

Membrane transporter Membrane transporter Membrane transporter

Angiotensin II receptor, type 2

Calcium-sensing receptor

Glutamate receptor, ionotropic, AMPA 3

Glutamate receptor, metabotropic 1

Leptin receptor

ATP-binding cassette, sub-family C (CFTR/MRP), member 8

ATPase, Na+/K+ transporting, a-2 polypeptide

Solute carrier family 25 (mitochondrial carrier; ornithine transporter) member 15

Solute carrier family 25 (mitochondrial carrier: glutamate), member 22


CASR

GRIA3

GRM1

LEPR

ABCC8

ATP1A2

SLC25A15

SLC25A22

SLC2A1 (GLUT1)



Membrane receptor

Membrane receptor

Membrane receptor

Membrane receptor

Membrane receptor

Generalized epilepsy, early-onset absence epilepsy, myoclonic-astatic epilepsy, focal epilepsy

Myoclonic epilepsy

Epilepsy

Epilepsy

Epilepsy

Generalized epilepsy, tonic-clonic seizures, myoclonic jerks, status epilepticus

Generalized epilepsy, myoclonic seizures, absence seizures, febrile seizures, focal seizures, generalized tonic-clonic seizures

Epilepsy

300699

Mental retardation, macrocephaly, autistic behavior, muscle weakness, hyporeflexia, dysmorphologies, language delay

609304 612126, 606777

Mental retardation, ataxia, hemolytic anemia, dystonia

238970

104290

[154]

[150]

Hypotonia, intellectual disability

Mental retardation, spastic paraparesis

Hemiparesis or paresthesias, aphasia, headaches, behavioral changes, visual and language disturbance

Developmental delay, neonatal diabetes

Hyperphagia, obesity, alterations in immune function, hypogonadism

614831

601198

Hypoparathyroidism, hypocalciuric hypercalcemia, nephrolithiasis, peptic ulcer

Delayed psychomotor development, intellectual disability, ophthalmologic defects, ataxia

300852

610951

254900

OMIM # [Ref.]

Mental retardation, pervasive developmental disorder

Mental retardation, pervasive developmental disorder, motor and visual impairment;

AGTR2

Lysosome membrane transporter

Generalized and partial epilepsy, myoclonus

Major facilitator superfamily domain containing 8

Tremor, gait ataxia, dysarthria, renal failure, cognitive decline



MFSD8 (CLN7)

Lysosome function

Lysosome membrane protein 2

Epilepsy phenotype

SCARB2

Functional class

Gene name

Gene symbol



Review Ferraro


Gene name

Solute carrier family 9, subfamily A (NHE6, cation proton antiporter 6), member 6

Acyl-CoA dehydrogenase, C-2 to C-3 short chain

Adenylosuccinate lyase

Aldehyde dehydrogenase 7 family, member A1

Asparagine-linked glycosylation 1, b-1,4-mannosyltransferase homolog

Cdc42 GEF-9

N-acylsphingosine amidohydrolase (acid ceramidase) 1

Branched chain ketoacid dehydrogenase kinase

Isocitrate dehydrogenase 1 (NADP+)

L-2-hydroxyglutarate dehydrogenase

Methylenetetrahydrofolate reductase (NAD(P)H)

Spermine synthase

Rho GEF-15

Gene symbol

SLC9A6

ACADS


ADSL

ALDH7A1

ALG1

ARHGEF9

ASAH1

BCKDK

IDH1

L2HGDH

MTHFR

SMS

ARHGEF15

Metabolic enzyme/ exchanger

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme

Metabolic enzyme


Epilepsy, myoclonus

Epilepsy

Epilepsy, nocturnal myoclonus

Epilepsy

Generalized epilepsy, febrile seizures, temporal lobe epilepsy


Generalized epilepsy, focal seizures, tonic seizures

Focal epilepsy

Generalized epilepsy, in utero seizures (prenatal Dx), clonic seizures, generalized tonic seizures, myoclonic jerks


Epilepsy

Generalized epilepsy, early-onset

Membrane transporter Metabolic enzyme

Epilepsy phenotype

Functional class


Developmental delay, autistic features, cognitive impairment, motor deficits

Mental retardation, hypotonia, unsteady gait, osteoporosis, dysmorphology, face, hands, feet

Developmental delay, psychosis, coronary artery disease, neural tube defects, cleft lip/palate

Developmental delay, brain tumor

[153]

309583

236250

236792

[155]

614923

Autism, intellectual disability

Developmental delay, hypotonia, cardiomyopathy, dysmorphic features

159950

300607 Tremor, muscle weakness

Hyperekplexia, mental retardation, developmental delay, ataxia

608540

266100

Developmental delay

Psychomotor and mental retardation, hypogonadism, contractures, areflexia, cardiomyopathy

103050

201470

300243

OMIM # [Ref.]

Psychomotor delay, growth retardation, autism

Myopathy, metabolic acidosis, developmental delay

Microcephaly, impaired ocular movement, developmental delay, developmental regression, hypotonia, abnormal movements




Review

341

342

Peroxisome biogenesis factor 19

Tripeptidyl peptidase I

Synaptic Ras GTPase activating protein 1

Cystatin B

PEX19

TPP1 (CLN2)

SYNGAP1

CSTB

Cyclin-dependent kinase-like 5

Syntaxin binding protein 1

STXBP1

CDKL5

TBC1 domain family, member 24

TBC1D24

Calcium/calmodulin-dependent serine protein kinase

Hydroxysteroid (17-b) dehydrogenase 10

HSD17B10

CASK

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit a

PIK3CA

v-akt murine thymoma viral oncogene homolog 3 (protein kinase B, g)

nudE nuclear distribution E homolog 1

NDE1

AKT3

Mitochondrial DNA polymerase

Polymerase (DNA directed), g

POLG

Protein kinase

Protein kinase

Protein kinase

Protease inhibitor

Postsynaptic density protein

Peptide metabolism

Peroxisome activity

Neurotransmitter release

Neuronal plasticity

Mitochondrial protein fatty acid oxidation

Mitosis, migration, signaling

Mitosis, migration, signaling

Functional class

Gene name

Gene symbol

Generalized epilepsy, epileptic encephalopathy, late multifocal and myoclonic epilepsy


Epilepsy

Epilepsy, myoclonus

Epilepsy

Epilepsy, myoclonus

Epilepsy

300749 300672 Mental retardation, developmental delay, dysmorphic features, dysmorphic facial features, sleep disturbances, gastrointestinal problems, respiratory defects, stereotypic hand movements

[156]

603387

254800

612621

204500

Mental retardation, developmental delay, deafness, dysmorphic features, microcephaly

Hemimegalencephaly

Ataxia, dementia, slurred speech, headache, back pain, hypermotor activity, hyperventilation, vomiting, motor dyspraxia

Mental retardation, language impairment, hypotonia

Progressive cognitive and motor dysfunction, visual dysfunction

614886

612164, 613477

Mental retardation, hypotonia, dyskinesia

Epileptic encephalopathy, partial complex seizures, tonic and tonic-clonic seizures

Craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, chondrodysplasia punctata

615338, 605021

Dysarthria, ataxia, intellectual disability

Epilepsy, myoclonus, myoclonic seizures, febrile convulsions, tonic-clonic seizures

300438

Developmental regression, choreoathetosis, visual loss, metabolic disturbance

Epilepsy

[155]

614019

607459

OMIM # [Ref.]

Hemimegalencephaly, brain malformations

Mental retardation, microcephaly

Hypotonia, short stature, neurosensory hearing loss, celiac disease, liver dysfunction, gastrointestinal defect, ataxic neuropathy, dysarthria, ophthalmoparesis, myopathy




Generalized epilepsy, epileptic encephalopathy, myoclonus

Epilepsy phenotype



Review Ferraro


Scaffold protein Scaffold protein Scaffold protein

Scaffold protein

v-erb-a erythroblastic leukemia viral oncogene homolog 4

Heterogeneous nuclear ribonucleoprotein U (scaffold attachment factor A)

Caveolin 3

Cerebral cavernous malformation 2

Filamin A

Gephyrin

Spectrin, a, non-erythrocytic 1

STE20-related kinase adaptor a

Tubulin, a-1a

Cytochrome P450, family 27, subfamily A, polypeptide 1

Aristaless related homeobox

Forkhead box G1

Myocyte enhancer factor 2C

ERBB4


HNRNPU

CAV3 (LQT9)

CCM2

FLNA

GPHN

SPTAN1

STRADA

TUBA1A

CYP27A1

ARX

FOXG1

MEF2C

Transcription factor



Steroid lipid biosynthesis

Scaffold protein

Scaffold protein

Generalized epilepsy, myoclonic, febrile, tonicclonic seizures

Focal and myoclonic seizures, infantile spasms

Generalized epilepsy, infantile spasms, tonic seizures, hypsarrhythmia

Epilepsy

Generalized epilepsy, absence epilepsy



Temporal lobe epilepsy

Epilepsy

Generalized epilepsy, generalized tonic-clonic seizures, status epilepticus

Epilepsy

Epilepsy

RNA binding protein Scaffold protein

Generalized epilepsy, early myoclonic encephalopathy

Generalized epilepsy, febrile seizures

Epilepsy phenotype

Protein kinase

Protein kinase

Dual-specificity tyrosine-(Y)phosphorylation regulated kinase 1A

DYRK1A

Functional class

Gene name

Gene symbol


613454

600662 Delayed motor development, mental retardation, poor eye contact, absent speech, stereotypic movements, dysmorphic features

308350, 300419, 300215

Developmental abnormalities, psychomotor arrest, mental retardation Involuntary or jerky movements, midline stereotypies, mental retardation, apraxia, aphasia, gastrointestinal abnormalities

[161]

611603

[160]

613477, 612164

[159]

Cerebellar ataxia, spinal cord involvement, atherosclerosis, cataracts

Mental retardation, motor delay, spastic tetraplegia, lissencephaly

Polyhydramnios, megalencephaly, neurocognitive delay, craniofacial dysmorphism, cortical heterotopia

Mental retardation, lack of visual attention and speech development, spastic quadriplegia

Autism spectrum disorder, psychiatric symptoms, schizophrenia

300049

603284

Myalgia, muscle stiffness, fatigue

Nodular brain tissue lining the ventricles, cardiac defects

611818

[158]

[157]

614104

OMIM # [Ref.]

Intellectual disability, craniofacial anomalies, long QT, sudden death

Intellectual disability, craniofacial anomalies

Psychomotor delay

Microcephaly, mental retardation without speech, anxious autistic behavior, dysmorphic features




Review

343

602066, 605751 Involuntary movements, choreoathetosis Unknown/Synapse PRRT2

Proline-rich transmembrane protein 2


226750 Developmental delay, spasticity, amelogenesis imperfecta causing yellow or brown discoloration Unknown/Nucleus ROGDI

Rogdi homolog

Generalized epilepsy, infantile or early-onset epileptic encephalopathy

206900 Anophthalmia or microphthalmia, developmental organ anomalies, motor disability, neurocognitive delays, sensorineural hearing loss, esophageal atresia Temporal lobe epilepsy Transcription factor Sry-Box 2 SOX2

Transcription factor Transcription factor 4 TCF4

Functional class


Mental retardation, wide mouth distinctive facial features, intermittent hyperventilation followed by apnea, microcephaly, gastrointestinal abnormalities

610954

Ferraro

Gene name

Epilepsy phenotype

Additional phenotypes 344

Gene symbol



OMIM # [Ref.]

Review

and mitochondria [63]. Two mitochrondrial syndromes in particular, myoclonic epilepsy with ragged red fibers and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, include a specific epilepsy phenotype, progressive myoclonic epilepsy, a condition which is associated with inexorable cognitive decline [64]. Other major forms of progressive myoclonic epilepsy include Unverricht–Lundborg disease (Baltic myclonus), Lafora disease, neuronal ceroid lipofuscinoses and type I sialidosis. Lysosomal storage disorders are caused by dysfunction of cellular lysosomes that results from a deficiency of an enzyme required for the metabolism of lipids, glycoproteins or mucopolysaccharides. There are over 50 known mutations that affect lysosomal function. These disorders have variable phenotypes depending on the specific protein involved and along with seizures may include developmental delay, movement disorders, dementia, deafness and/or blindness. Associated phenotypes in some individuals include hepatomegaly, splenomegaly as well as skeletal, pulmonary and cardiac defects. A unifying treatment-related concept that emerges from consideration of the broad range of clinical syndromes that include myoclonic epilepsy might focus on compensation for defective cellular processes. Given that functionally similar genes are involved in specific types of progressive myoclonus epilepsy, whereas functionally diverse sets of genes are involved between clinical categories that include this form of epilepsy, general strategies based on targeting cellular energetics (mitochondria) or cellular recycling and repair (lysosomes) could be pursued as a means of novel therapy development. Taken together, it is evident that diverse clinical disorders may co-exist with epilepsy in syndromes that are transmitted according to Mendelian (monogenic) inheritance. Apart from the challenge of treating epilepsy within a given syndrome, using specific genetic information from these syndromes as leads for therapy development that may be relevant to larger groups of epilepsy patients, even those with more common forms, poses an even greater challenge. The varied combinations of phenotypic signs and symptoms associated syndromically with epilepsy suggest complex pleiotropic gene effects and/or overlap of genetic susceptibility factors. Pleiotropy may present an obstacle to therapy development for epilepsy based on genes discovered in broad clinical syndromes due to the potential for off-target side effects. In such instances, it is possible that a pathway approach may aid in identifying a linked target that is specific for the required action in the brain [65]. It is possible that better understanding of brain-specific genetic expression pathways affected by pleiotropy and susceptibility factors will lead to novel entry points for therapy. Personalized medicine & other novel therapeutic strategies

Current therapeutic strategies in epilepsy focus on reducing seizure burden and are based upon the direct action of drugs on electrophysiological processes in neurons. Whereas this approach has achieved some success, and is likely to be enhanced further as the molecular mechanisms of the epilepsies are better Expert Rev. Neurother. 14(3), (2014)

Review

elucidated, major advances in treating epilepsy will require personalized medicines 100 with unique mechanisms that extend outside the realm of traditional pharmacotherapy. In order to have the highest possible impact, new treatments for epilepsy will also need to address critical co-morbidities including cognitive, behavioral and motor abnormalities [66]. A paradigm shift in con50 cepts of epilepsy treatment is needed to achieve this goal. Genetic information may aid the development of personalized treatments in numerous ways, but primarily, the ability to identify specific DNA alterations that elucidate mechanisms of disease risk or causality 0 allows treatments to be guided more by the l l l r l l r r nature of the variation and less by the ve o e gy n a ia e ta e m ry a ry lic ac a e ity a d tic iti ot uag olo atio isu tax th ele ord pto ato stin dito bo rdi gic ach es en ona pa n O M r a o R b a l d i nature of the defective gene. For example, ng ph rm V A og He og Sk t dis sym sp inte Au et C ato ea O C M yp La mor alfo H n ric Re tro in rare cases, pyridoxine-dependent epilepsy m H e r s m t e as D em hia Dy ain G is caused by a homozygous intronic mutaov syc Br M P tion in ALDH7A1 gene that results in two types of transcripts: a major transcript conFigure 1. Phenotypes associated with epilepsy in clinical syndromes from TABLE 4 taining a pseudoexon and a minor tranwere derived from the Online Mendelian Inheritance in Man database and script representing the authentic spliced literature reports where noted. Cognitive phenotypes include mental retardation, transcript [67]. This mutation may be tarintellectual disability, developmental delay, autism spectrum and dementia. Motor geted with a personalized anti-sense therapy phenotypes include upper and lower motor neuron abnormalities as well as primary aimed at blocking expression of the pseudefects in muscle or the neuromuscular junction. Language phenotypes include delay in acquisition as well as mutism and motor speech disorders. Dysmorphologies primarily doexon. Such an approach is also feasible in involve facial features including deformities of the eye. Brain malformations include the case of dominant negative mutations, microcephaly, lissencephaly, cortical dysplasia, cortical heterotopia, tuberous sclerosis, where anti-sense molecules can be designed cavernous malformations, agenesis of corpus callosum and others. Visual phenotypes to block expression of defective alleles. refer to disturbances of vision including blindness. Skeletal phenotypes include Exon-specific expression mechanisms may abnormalities of bone and cartilage. Movement disorders include parkinsonism, dystonia, also be relevant to temporal lobe epilepsy, choreoathetosis and hyperekplexia. Psychiatric symptoms include psychosis, depression and anxiety. Respiratory phenotypes include apnea and other signs related to autonomic in which a non-mutational exon skipping function. Gastrointestinal phenotypes include pseudo-obstruction, esophageal atresia, defect has been documented in the gephryn esophageal reflex, peptic ulcer and vomiting. Auditory phenotypes refer primarily to gene [68]. The genetic mechanism is trigsensorineural deafness. Metabolic phenotypes include acute and chronic forms of acidogered by cellular stressors such as alkalosis sis and alkalosis. Cardiac phenotypes refer primarily to cardiomyopathy but also include long QT and other conduction defects. Headache includes migraine. Liver phenotype and hyperthermia and it results in altered refers to hepatomegaly. Phenotypes in the other category include endocrine disorders, postsynaptic gephyrin and GABA receptor blood disorders, brain tumor and other cancers. scaffolds, which are hypothesized to underData taken from [82] and references listed in TABLE 4. lie the temporal lobe epilepsy phenotype [68]. Thus, blocking the exon-skipping event would represent a rational approach to therapy development for more frequent repeat-expansion epilepsy mutations. For example, functional cystatin B variants containing longer repeats in temporal lobe epilepsy. Another personalized therapy that is relevant to epilepsy regulatory genic regions are associated with forms of myoclonic involves blocking the effect of polymorphic tandem repeat ele- epilepsy [71] and may also be amenable to targeting with exogements such as the CAG repeat expansion in SCA2, the gene nous anti-sense molecules. A number of gene mutations in epilepsy have been identified associated with spinocerebellar ataxia, which may include a form of epilepsy called infantile spasms [69]. An anti-sense as premature stop codons including the one produced in the approach to targeting these variants involves the use of 2´-O- KCNQ2 gene by a 5-bp insertion [72] or the one caused by a methyl phosphorothioate (CUG)n triplet-repeat oligonucleoti- 1-bp depletion in the SCN1A gene [73]. Stop codon mutations des to block expression at the mRNA level [70]. Although are potentially treatable by way of various approaches, collectively directly relevant to rare triplet repeat expansions, the above referred to as translational bypass therapy [74]. One strategy is to therapeutic strategy could potentially be modified to address promote enzymatic read-through of the stop codon, thus Frequency




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permitting translation of a full-length protein. Also, there are more distally positioned premature stop codons that would allow expression of a partially functional albeit truncated protein. Truncated proteins are generally not expressed as a result of the process of nonsense-mediated decay in which partial mRNAs are degraded enzymatically [75]. Thus, gene defects characterized by premature stop codons may be treated potentially by either inhibition of the enzymes that degrade incomplete transcripts or by effects on transcriptional machinery that allow in-frame stop codons to be by-passed. Antibiotic drugs such as emetine or aminoglycosides including gentamycin or geneticin allow stop-codon read-through [74]. This approach was shown to partially restore levels of full-length GABRG2 protein when used on cells transfected with a Q40X stop-codon mutation that causes Dravet syndrome, suggesting it has promise for being refined into a novel and effective treatment strategy in epilepsy [76]. Mitochondrial diseases can involve epilepsy and several approaches are being studied in attempts to rescue defective mitochondria and preserve cell viability. One strategy is peptide-mediated mitochondrial delivery. Using a cellpenetrating peptide, Pep-1, to transfer mitochondria into cells, this method has been shown to rescue a cybrid cell model of myoclonic epilepsy with ragged red fibers syndrome [77]. Another method involves targeted mitochondrial RNA import. The utility of this method was demonstrated by showing that normally non-imported mRNA transcripts may be incorporated into mitochondria as fusion transcripts by appending a 20-ribonucleotide stem-loop sequence from H1 RNA, the RNA component of the human RNase P enzyme [78]. These are two novel strategies that may be developed into effective treatments for epilepsy patients with mitochondrial gene defects. The large influence of ion channel gene variants on the development of epilepsy demands continued consideration of therapies focused specifically on ion channels. One strategy involves rebalancing the effects of altered neuronal excitability that are caused by specific genetic mutations. A pharmacological version of this approach was demonstrated in a model of Dravet in which a mouse strain heterozygous for a Dravet mutation in SCN1A was characterized as having reduced excitability of GABAergic interneurons and also as exhibiting an anti-seizure response to drugs that promote GABA-mediated neurotransmission [79]. Another promising approach is based on the concept that combinations of rare variants can have synergistic or antagonistic effects on network circuits relevant to the pathogenesis of seizures. Thus, the deleterious effects of some ion channel gene variants may be worsened [80] or ameliorated [81] by co-expression with other variants in the same gene network. To date, the utility of these strategies has been documented in cell systems and animal models and, in the future, gene transfer technologies may permit its use in epilepsy patients. Summary

There are many different kinds of genetic influences on the development of epilepsy, both with regard to the function of encoded protein products as well as the physical nature of genomic 346

variation. The value of delineating these influences is evident by the concordance of data on the mechanism of action of conventional anti-epileptic drugs and the biological nature of gene variants associated with epilepsy, wherein documented epilepsycausing variants or risk factors encode proteins that are members of families that are known anti-epileptic drug targets. A major challenge for the future is to exploit newly emerging genetic data so as to identify new and better therapeutic targets given that so many epilepsy patients experience inadequate seizure control. The phenotypic variability that is characteristic of syndromes involving mutations that cause epilepsy can offer new clues for therapeutic discovery in that pleiotropic effects of genes may reveal molecular pathways that offer alternative and more tractable targets. Apart from identifying new therapeutic targets, genetic information on causes of epilepsy can suggest personalized approaches to treatment that involve various forms of gene therapy, whether this refers to anti-sense strategies to knock down defective alleles, read-through methods to by-pass premature stop codons, direct replacement of defective genes or other emerging technologies. It is likely that continued pursuit of genetic information in the epilepsies will allow new ideas to be brought to bear on treatment development and that the promises of molecular medicine will eventually be fulfilled. Expert commentary

In order to best assess the relationship of epilepsy-related genes to the development of new treatment options for epilepsy patients, current perspectives on genetic influences in the epilepsies must integrate results from many types of studies, including genetic association, linkage and positional cloning, deep gene sequencing and even animal models. In taking these various sources of data into account, it is clear that many kinds of molecules play a role in seizures and epilepsy. By contrast, relatively few mechanisms of action are represented among the currently approved anti-epilepsy medications, with most of the drugs known to interact directly with ion channels. Given the genetic diversity associated with causes of epilepsy, there is substantial opportunity for identification and development of novel therapeutic targets. Genes such as SLC2A1 and LGI1 provide provocative potential entry points onto the road to new treatment discovery. Currently, there is a natural lag phase between reporting data on epilepsy-related genes and developing treatments. In fact, there has yet to be a new epilepsy treatment that has evolved from a genetic discovery. Nonetheless, therapy development programs are putting greater emphasis on exploiting novel genetic discoveries as a means of prioritizing lead compounds. On the other hand, about twothirds of epilepsy patients derive therapeutic benefit from currently approved drugs and therefore the view of epilepsy as an ‘ion channelopathy’ has proven value, specifically with regard to reduction of seizure burden. It is significant that the major anti-epilepsy drugs used in clinical practice today work via interaction with the NaV1.1 sodium channel, since it is a protein complex involving SCN1A, the product of the gene which is documented to have more epilepsy-causing mutations in it Expert Rev. Neurother. 14(3), (2014)


than any other gene. However, it is important to note that the vast majority of epilepsy patients who are treated effectively with sodium channel blocking drugs have no known defect in the SCN1A gene or protein. This fact underscores the importance of achieving proper balance within neural networks as a means of controlling seizures and it forms the conceptual basis of the major approaches used currently to treat epilepsy.


Five-year view

In the next 5 years, the discovery and validation of new epilepsy-related genes and genetic defects that cause epilepsy promises to lead to significant new advances in treatment. First and foremost, it will reveal additional molecules that can be targeted in the attempt to balance neural networks and prevent seizures. Such advances in therapy will have wide applicability and may be effective in treating both idiopathic (i.e., genetic) and symptomatic cases. Although it may very well take more than several years for a genetic discovery to lead to introduction into clinical practice of a truly unique and efficacious antiepilepsy drug, it is a goal that is being pursued currently and that could result in a near-term treatment breakthrough. Further, continued advances in laboratory technology will make targeted as well as global genetic analysis more routine, leading to an increase in the discovery of specific genetic defects that are sufficient in and of themselves to cause epilepsy. This will

Review

increase the possibility of instituting personalized therapies based on the structural features of the genetic defect rather than on the function of the product of the specific gene(s) that is altered. Applications of this approach may potentially be highly varied. For example, there may be trials of anti-sense nucleotides designed to prevent the expression of defective alleles that have dominant negative effects. Also, there is the potential for drugs to be further developed to allow premature stop codons to be by-passed and permit read-through of full-length gene transcripts. In addition, it is possible that drugs will be devised to prevent degradation of abnormally truncated gene transcripts and thereby allow expression of proteins with partial function that could ameliorate the severity of disease. Continued characterization of genetic factors involved in the etiology of epilepsy over the coming years, and ultimately, the full elucidation of the epilepsy genome, will facilitate the development of these and other novel approaches to therapy. Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Epilepsy is a common, multifactorial disease in which genetic factors play a major etiological role; however, many of the genes involved in epilepsy remain unknown. Better understanding of these factors will facilitate the identification of new molecular targets for therapy. • Advances in biotechnology have led to an increase in the discovery of both common genetic variants, which generally have minor effects in a large fraction of cases, and rare genetic variants, which may have large effects, and can even cause epilepsy, but in a small fraction of cases. Particularly with regard to rare variants, new methods of DNA sequence analysis have greatly expanded the number of documented epilepsy-related genes. A key issue is how best to translate genetic discoveries into potential treatments. • Regardless of whether a given genetic variant is rare, and has a large impact on disease in a small number of cases, or whether it is common, and has small impact on a large number of cases, discovering its identity is nonetheless important since any epilepsy gene can reveal molecules and molecular pathways that are associated with abnormal electrical activity in the brain, and can thus be used as leads for therapy development. • One of the genes involved in both common and rare forms of epilepsy is SCN1A. This gene encodes a subunit of the major brain sodium channel NaV1.1, a molecular target for a number of standard anti-epileptic drugs including phenytoin, carbamazepine and valproic acid. SCN1A serves as a prototype in linking anti-epilepsy drug action with epilepsy-related genes. • There is considerable overlap in the classes of genes involved in both common and rare forms of epilepsy and indeed there are a number of specific genes that have been documented to play a role in both forms. In addition to SCN1A, these genes include CACNA1H, CHRNA4, GABRB3, GABRG2, KCNJ10, KCNQ2, KCNQ3 and SLC2A1. The products of these genes and the pathways in which they function are logical targets for anti-epilepsy therapy development programs. • Epilepsy co-occurs in monogenic syndromes that involve other complex, diverse and severe clinical phenotypes. Further, causative genes have been identified for many of these syndromes, and in many cases they come from the same classes as those associated with pure epilepsy syndromes, and with genetically complex epilepsies. However, the pleiotropic gene effects documented in these phenotypically complex syndromes present an additional challenge in terms of translating such discoveries into leads for therapy development. • Advances in technology will allow screening of individual epilepsy patients for rare or private variants that may have a large effect on development of disease. In those cases where potentially deleterious structural DNA changes are documented, personalized therapies may be devised, which are based specifically on the nature of the genetic alteration rather than on the nature of the gene product or its functional pathway.


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identifies variants in CAMSAP1L1 as susceptibility loci for epilepsy in Chinese. Hum Mol Genet 2012;21(5):1184-9

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