GENETICS AND GENOMICS OF NEURO- PSYCHIATRIC DISEASES, I: SEIZURE DISORDERS
Epilepsy is one of the most common neurological disorders. It is defined as an ongoing tendency to experience epileptic seizures. The prevalence of epilepsy is around 1% (higher in resource-poor areas),1 and at least 50 million people are affected worldwide.2 There is significant morbidity associated with the disease, and although appropriate treatment can offer freedom from seizures for some people with epilepsy, a significant minority will continue to have seizures that are refractory to treatment.
There is a clear link between genetics and epilepsy: first-degree relatives of people with epilepsy are around two to four times more likely to develop epilepsy than the general population,3 and monozygotic twins show a higher rate of concordance than do dizygotic twins.4 This link has been known for a long time: Hippocrates wrote of epilepsy, circa 300 bc: “Its origin is hereditary, like that of other diseases.”5 The insightful London neurologist John Reynolds wrote in 1861 that an inherited influence was present in around 31% of his own cases.6 This figure is remarkably similar to the estimate that is widely used today—genetic factors account for around 40% of all epilepsies.7
It is only during the last 15 years or so that real progress has been made into understanding some of the complicated genetics involved with epilepsy. The ability to use powerful new genomic technology marks an exciting time, promising to yield further significant advances in our understanding, with the ultimate aim to improve the treatment and quality of life of people with the disease.
This chapter briefly describes the classification of seizures and epilepsy before moving on to consider some of the predominantly monogenetic, genetic, and symptomatic epilepsies. The study of other genetic epilepsies is then considered. The chapter concludes by discussing some aspects of epilepsy treatment that have been influenced by genomics. (For further reference, the reader is directed to the excellent text by Shorvon et al.,8 and recent reviews.9,10,11)
DEFINING AND CLASSIFYING SEIZURES AND EPILEPSY
An epileptic seizure is a transient occurrence of signs and symptoms due to abnormal excessive or synchronous neuronal activity in the brain.12
Seizures that originate from neuronal networks in both cerebral hemispheres are classified as generalized seizures. The most common types of generalized seizures are generalized tonic clonic seizures and absence seizures (see Table 31.1 for more types of generalized seizures).
Seizures that originate from neuronal networks limited to one hemisphere are classified as focal seizures.13 The clinical manifestations of a focal seizure are wide-ranging and depend on the location in the brain of the abnormal activity (see Table 31.1 for some features of focal seizures). Sometimes focal seizures can evolve into generalized seizures as the abnormal neuronal activity spreads to both hemispheres. This may manifest as an aura (partial seizure); for example, a feeling of déjà-vu, before a generalized tonic clonic seizure. (Such a manifestation points to a temporal-lobe focus for the seizure.)
Table 31.1 SOME DIFFERENT TYPES OF EPILEPTIC SEIZURE
|Tonic- clonic||Loss of consciousness with an initial period of stiffness (tonic) followed by rhythmic generalized jerking (clonic). Gradual recovery of consciousness, with post-ictal confusion lasting minutes to hours.|
|Absence (typical)||Sudden, brief (generally <10 sec) periods of loss of awareness with behavioral arrest (staring episodes) with rapid recovery, occasional eye movements, automatisms.|
|Absence (atypical)||Longer-than-typical absences and frequently associated with myoclonic or atonic attacks. Start and finish more gradually; focal features more prominent, and more retained awareness than in typical absences|
|Clonic||Rare; loss of consciousness with repetitive symmetrical and rhythmical jerking. Rapid onset and cessation.|
|Tonic||Sustained contraction of musculature, generally sudden-onset <1 min in duration.
Abrupt onset and rapid recovery.
|Atonic||Sudden loss of muscle tone, frequently causing a fall to the ground. Rapid recovery.|
Myoclonic Brief muscle contractions with sudden onset and cessation. Single muscle to generalized jerking. Consciousness generally not impaired.
|Frontal lobe||Frequently nocturnal; brief, rapid onset and cessation. Prominent motor features, sometimes with posturing and head version. Frequent bizarre automatisms/behaviors and vocalization.|
|Temporal lobe||Generally longer in duration than frontal lobe seizures. Variety of sensory disturbances, including psychic (déjà-vu, jamais-vu, fear), gustatory and olfactory hallucinations. Sensation of epigastric disturbance. Oro-facial automatisms (e.g., chewing, sucking) or fidgety hand movements. Frequently, altered awareness (complex partial seizures) and post-ictal confusion. Auditory features may point to lateral temporal lobe involvement.|
|Occipital lobe||Visual disturbance/hallucinations, typically elementary color images in the contralateral eye field.|
|Unknown Sometimes there is insufficient evidence available to classify a seizure as generalized, focal, or both.
a These are the main types of focal seizure; there are other types. See also Berg et al. 2010.13
THE CLASSIFICATION OF EPILEPSY
Epilepsy is best thought of, not as a single disease, but rather as a collection of several underlying brain disorders that all cause an increased tendency to experience epileptic seizures. There are several different ways of classifying the epilepsies.
A useful distinction is that between the symptomatic epilepsies, where the epilepsy occurs with a concurrent underlying structural or metabolic problem, such as tuberous sclerosis; and the idiopathic epilepsies, where the epilepsy occurs in otherwise normal individuals with no detectable metabolic or structural problem, such as childhood absence epilepsy (these were previously known as genetic epilepsies).13 There is some overlap, however, between genetic and symptomatic epilepsy, and in some cases the dividing line is not so clear. For example, epilepsy due to glucose transporter (GLUT- 1) deficiency is a symptomatic epilepsy, as it is caused by a metabolic problem, but it also can be thought of as a genetic epilepsy, as it is caused by mutations in the SLC2A1 gene.
The concept of a seizure threshold can be used to explain the effect of genetics on the tendency to develop epilepsy. People with a tendency to develop seizures spontaneously can be thought of as having a low seizure threshold, whereas people who develop seizures only after extremely provoking circumstances; for example, severe head trauma patients can be thought of as having a high seizure threshold. The interplay of genetic and environmental mechanisms underpins an individual’s seizure threshold. Figure 31.1 illustrates the spectrum of some of the causes of epilepsy and the relevant influence of genetic and environmental factors.
Figure 31.1 Some of the causes of epilepsy, with the relative influence of genetic and environmental factors and the “division” between symptomatic and genetic epilepsies. In some cases the distinction between symptomatic and genetic epilepsy is blurred; for example, disorders of cortical malformation clearly cause a structural change in the brain (symptomatic), but they may be caused by a mutation in one gene and thus be genetically predetermined (genetic). The figure is not to scale, and the size of the captions does not reflect the number of patients with epilepsy due to each cause. BNFS = benign neonatal familial seizures; CVD = cerebrovascular disease; JME = juvenile myoclonic epilepsy; NCL = neuronal ceroid lipofuscinoses.
MONOGENIC INHERITED EPILEPSIES
Monogenic inherited epilepsies are rare, accounting for a small fraction of all epilepsies, and are predominately caused by mutations in single genes encoding ion-channels. Despite their rarity, they are of interest as their study has led to a better understanding of some of the molecular mechanisms underpinning epilepsy. Despite being predominately monogenic, these epilepsies show locus heterogeneity (i.e., the same phenotype caused by mutations in different genes); variable expression (mutations in the same gene causing different phenotypes); and their causative mutations are rarely found in the more common sporadic genetic epilepsies. Table 31.2 lists the main types of monogenetic genetic epilepsy, and the next few sections describe some of the more important of these epilepsies and the mechanisms involved.
Table 31.2 SOME OF THE MORE IMPORTANT GENES ASSOCIATED WITH MONOGENETIC GENETIC EPILEPSIES
OMIM = Online Mendelian Inheritance in Man database: http://www.ncbi.nlm.nih.gov/omim a Also known as Dravet’s syndrome.
b GABAA= Gamma-aminobutyric acid type A.
Adapted with permission from Johnson MR, The genetic contribution to epilepsy: the known and missing heritability. In: The Causes of Epilepsy, eds. Shorvon SD, et al., pp. 63–67. Cambridge, UK:
Cambridge University Press, 2011.
NICOTINIC ACETYLCHOLINE CHANNEL EPILEPSIES
Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand- gated cationic channels. nAChRs are encoded by 9α and 3β subunit genes. nAChRs are widely distributed throughout the central nervous system (CNS), and different combinations of subunit types in nAChRs give rise to channels with different functions and locations.14
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare epilepsy consisting of frequent, brief frontal lobe seizures occurring during sleep. The seizures tend to start suddenly, often with vocalization, and involve hyperkinetic, sometimes bizarre, movements. They occasionally will evolve into generalized tonic clonic seizures. A mutation in the CHRNA4 gene, which encodes the nAChR α4 subunit, was the first epilepsy-causing gene mutation to be discovered.26 Mutations in the genes CHRNB2 and CHRNA4, which encode the nAChR β2 and α4 subunits, respectively, also cause ADNFLE.27,25
Studies have shown that the mutations associated with ADNFLE increase the sensitivity of nAChR to ACh in vitro,25 with variation in this gain-of- function between different mutations.30 The intriguing fact that ADNFLE manifests as seizures that arise exclusively from sleep and the frontal lobe remains unexplained at present.
POTASSIUM CHANNEL EPILEPSIES
There are five channels in the voltage-gated potassium 7 (KV7) family: KV7.1 channels are mainly expressed in cardiac muscle, and KCNQ1 mutations cause long QT syndrome; KV7.2–5 are mainly expressed in the central nervous system; KV7.1 and KV7.4 are also expressed in the inner ear, and mutations in KCNQ4 cause a slowly progressive deafness.15
Mutations in the genes KCNQ2 and KCNQ3, which encode KV7.2 and KV7.3, respectively, are associated with benign familial neonatal seizures (BFNS).14,16 In this rare autosomal dominant syndrome, seizures normally start in the first week of life and usually remit within a few weeks to months, although around 10% of patients may develop further seizures in later life.
KV7 channels act as a “brake” to neuronal firing by producing a slowly activating K+ current known as the M-current. Mutations in KCNQ2 and KCNQ3 cause a reduction in this M-current and hence enhanced neuronal excitability, which is the presumed mechanism for seizures.16 Retigabine, a new anti-epileptic drug used as an additional therapy for refractory partial- onset seizures, acts by enhancing the activity of KV7.2–5 channels, increasing M-current and therefore reducing neuronal excitability.17
A perplexing question is, why do the seizures in BFNS stop after a few months of life? Heterozygous mutations in KCNQ2 and KCNQ3 typically only cause a small reduction of 25–30% in the M-current,32 and it may be that, after the neonatal period, the additional ion-channels expressed in the brain mean that this small reduction in current is less problematic. Alternatively, the fact that the GABAergic system switches from being an excitatory to an inhibitory system after the neonatal period might provide the additional “inhibition” that is required to prevent seizures in patients with KCNQ2/3 mutations.7 Recently, KCNQ2 mutations have been discovered in 10% of patients with a neonatal/early infantile encephalopathy,15,18 suggesting a role for this gene in other types of more severe epilepsy.
SODIUM CHANNEL EPILEPSIES
Voltage-gated sodium channels (VGSC) are well characterized to date and play an important part in initiating and propagating action potentials in electrically excitable tissue by allowing a flux of inward sodium current in response to depolarization. Neuronal sodium channels consist of an α-subunit and two β-subunits. The α-subunit consists of four domains and forms the central ion-conducting pore and the channel gate for activation and inactivation. There are nine different α-subunit subtypes, designated NaV1.1–1.9.19 The β subunits are thought to affect VGSC trafficking and gating, and there are four different types of β subunit.20
Genetic Epilepsy with Febrile Seizures
Genetic epilepsy with febrile seizures+ (GEFS+) is a familial epilepsy syndrome with a broad phenotype. By definition, febrile seizures and febrile seizures+ (febrile seizures beyond the age of 6 years) are the prominent feature. Other, afebrile seizures also occur, both generalized seizures (absences, tonic clonic, myoclonic) and, less commonly, focal (frontal and temporal lobe) seizures. Mutations in the SCN1A gene, which encodes the α1- subunit18 and, less commonly, the SCN1B gene, which encodes the β1- subunit,19,21 have all been associated with GEFS+ as well as mutations in genes encoding the GABA receptor which are discussed in the next section.
Severe Myoclonic Epilepsy in Infancy
Severe myoclonic epilepsy in infancy (SMEI) or Dravet’s syndrome is a severe epilepsy syndrome usually starting at around 6 months of age, usually with a febrile seizure and progressing to multiple drug-refractory seizures and developmental delay. Around 80% of all Dravet’s syndrome cases are caused by mutations in SCN1A, with around 95% of these mutations occurring de novo.17,36 The fact that SCN1A mutations cause the relatively mild phenotype of GEFS+ as well as the devastatingly severe SMEI is partly explained by the fact that the specific, mostly de novo, nonsense mutations associated with SMEI give rise to more severe truncated or non-expressed proteins. This is compared to the mostly missense mutations that are associated with GEFS+. However, there are probably additional factors that explain variable expression such as modifier genes, genetic mosaicism, or other undiscovered influences.
Both loss- and gain-of-function mutations in SCN1A have been described in GEFS+, although it generally seems that loss-of-function mutations are more common. The fact that NaV1.1 is predominantly expressed in inhibitory interneurons may explain how loss-of-function mutations can lead to increased seizures.35
Benign Familial Neonatal Infantile Seizures
Benign familial neonatal infantile seizures (BFNIS) are a rare “mild” autosomal dominant phenotype wherein patients suffer both partial and general seizures between the first week and the first few months of life, which remit by the age of 12 months. BFNIS is associated with mutations in the SCN2A gene, which encodes the α2-subunit of the voltage-gated sodium channel.20,22 The mutations in SCN2A associated with BFNIS seem to increase neuronal excitability, which offers a plausible explanation of the cause of the seizures. Although the expression of the α2-subunit is initially high in the neonate, it decreases with age. This, together with the fact that the expression of another subtype—the α6-subunit—increases and seems to replace the α2-subunit, gives an explanation of why the seizures in this syndrome remit.23 Similar explanations might underpin the remission of seizures in other self-terminating epilepsy syndromes.
A mutation in SCN1A has been associated with a type of familial hemiplegic migraine.24 Migraine is similar to epilepsy in that it is a common disease of the central nervous system with symptoms caused by a transient disturbance of the CNS, and SCN1A mutations are an interesting link between the two diseases.
GABAA RECEPTOR EPILEPSIES
Gamma-aminobutyric acid type A receptors (GABAA) are ligand-gated ion- channels and are the major inhibitory ion-channels within the human brain. Binding of GABA to these receptors causes an influx of chloride, which results in inhibition of neuronal activity. GABAA receptors have a heteropentameric structure formed from at least seven sub-unit classes, but most GABAA receptors found within the brain contain two α subunits, two β subunits, and a γ or δ subunit.25 Mutations in the GABRA1, GABRG2, and GABRD genes, which encode the α1, γ2 and δ subunit, respectively, have been implicated in a wide variety of epilepsy phenotypes, including febrile seizures, absence seizures, GEFS+, and familial juvenile myoclonic epilepsy (JME).
The majority of mutations seem to cause a loss of function of the GABAA receptor and a reduction in GABAA-mediated current. This would then cause a reduction in inhibition, which seems a plausible mechanism for seizure generation.
The leucine-rich glioma-inactivated 1 (LGI1) gene derives its name from the leucine-rich regions on the protein it encodes and the fact that its expression is absent or significantly downregulated in many high-grade gliomas.28 It was the first non–ion channel gene to be associated with genetic epilepsy in humans, although it seems likely that its function is closely linked to glutametergic synapses.
LGI1 encodes a protein with three leucine-rich repeats in the N-terminal region and seven tandem repeats named epilepsy-associated repeats (EAR) or epitempin repeats (EPTP) in its C-terminal region. These repeats are predicted to form a propeller structure that links presynaptic ADAM23 and Kv1.1 potassium channels and postsynaptic ADAM22 and AMPA receptor scaffolds on glutamatergic synapses. Mouse models with targeted disruption of any of these components of the suggested LGI1-associated synapse bridging complex cause seizures.39 Mice models suggest that LGI1 has a role in mediating glutamatergic synapse pruning and maturation in the hippocampus and that LGI1 deficiencies can markedly increase excitatory synapse transmission.26
Autosomal Dominant Lateral Temporal Lobe Epilepsy; Autosomal Dominant Partial Epilepsy with Auditory Features
Autosomal dominant lateral temporal lobe epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epilepsy arising in early adulthood with predominantly focal seizures arising from the lateral temporal lobe. Focal seizures consist mainly of auditory hallucinations, such as a ringing or buzzing, with occasional visual hallucinations. Approximately 50% of patients with ADLTE have mutations in the LGI1 gene.27 Interestingly, antibodies to LGI1 have recently been described in cases of limbic encephalitis, which causes cognitive disturbance and seizures, offering further evidence of the role of LGI1 in seizure generation.39
MONOGENIC SYMPTOMATIC EPILEPSIES
Currently, there are more than 200 Mendelian disorders in which epilepsy is present as the result of a defect in genes involved in a wide variety of functions. The genetics and molecular biology of these disorders continue to be unravelled. A few of these epilepsies are described here; the reader is advised to consult texts such as Shorvon et al.8 for a more comprehensive description.
PROGRESSIVE MYOCLONIC EPILEPSIES
The progressive myoclonic epilepsies (PMEs) are a heterogeneous group of disorders characterized by epilepsy, myoclonus, and progressive neurological deterioration, including ataxia and dementia. The genetic bases of many of the PMEs have been elicited, and the more common types are here briefly described.
Unverricht-Lundborg disease (EPM1) is the most common of the PMEs (Online Mendelian Inheritance in Man [OMIM] 254800; also known as Baltic myoclonic epilepsy as it was initially described in Finland) and is an autosomal recessive disorder caused by mutations in the CSTB gene,28 which encodes cystatin B, a cysteine proteinase inhibitor. Onset is typically around 6–15 years of age with severe, progressive, stimulus-sensitive myoclonus; generalized tonic-clonic seizures; followed by further neurological signs, including ataxia, dysarthria, and mild dementia. Around 90% of EPM1 cases are caused by a dodecamer repeat in the CSTB-promoter region. Disease- causing expansions contain at least 30 repeats, whereas normal alleles typically contain two or three repeats.29
The exact physiological function of CSTB and the pathophysiology of mutations associated with EPM1 are currently unknown; however, mice lacking cystatin B develop progressive myoclonic seizures and ataxia, and cellular changes associated with apoptosis.44
EPM1B (OMIM 612437), which is caused by a mutation in the PRICKLE1 gene, is very similar to EPM1, although patients may present at a slightly younger age and may also have an impaired upgaze.30
Lafora disease (OMIM 254780) is an autosomal recessive disorder caused by mutations in the EPM2A31 or NHLRC132 genes. Onset is typically in adolescence with progressive epilepsy, with several seizure types, including myoclonic and generalized tonic clonic seizures. Ataxia and cognitive decline follow, with death typically within 10 years of onset. Lafora bodies (periodic acid-Schiff-positive intracellular inclusions), found in various organs, including heart, skeletal muscle, and neurons, are pathognomonic.
EPM2A encodes laforin, which is a protein tyrosine phosphatase, whilst NHLRC1 encodes malin, a ubiquitin ligase. Malin and laforin seem to suppress the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system.33
Neuronal Ceroid Lipofuscinoses
The neuronal ceroid lipofuscinosis (NCL) are the most common inherited cause of neurodegenerative disease in childhood and are characterized by visual failure, epilepsy, progressive dementia, ataxia, and early death (second or third decade). There is a presence of intracellular lipopigment storage material—ceroid lipofuscin. Currently, mutations in at least 10 genes are known to cause the disease (see Table 31.3), and inheritance is mostly in an autosomal recessive form.34
Table 31.3 THE NEURONAL CEROID LIPOFUSCINOSES50
Other Causes of Progressive Myoclonic Epilepsies
Other causes of progressive myoclonic epilepsies include Sialidoses (OMIM 256550) caused by mutations in NEU1, which lead to neuraminidase deficiency; dentate-rubro-pallido-lusian atrophy (DRPLA) (OMIM 125370), caused by an unstable CAG repeat on chromosome 12p13.31; and Gaucher disease (OMIM 23100), caused by mutations in GBA, which lead to deficient β-glucocerebrosidase activity.
MALFORMATIONS OF CORTICAL DEVELOPMENT
Malformations of cortical development (MCD), generally readily detectable on magnetic resonance imaging (MRI), can cause epilepsy, and the genetic basis for many is being elicited. Knowledge of the causative mutations, with increasing understanding of gene function, is helping scientists unravel the neurobiology behind brain development, discover possible mechanisms for epileptogenesis, and also define criteria for further refining the phenotypes of these heterogeneous disorders. A few of the more important MCDs are described here.
A group of disorders with the common feature of microcephaly— significantly reduced head circumference (defined as an occipital-frontal circumference less than two standard deviations below the mean)—is associated with epilepsy. Epilepsy is more common in the types of microcephaly with accompanying structural changes and cortical malformation. Some of the microcephalies with a greater association with epilepsy and their causative genes are listed in Table 31.4.
Table 31.4 TYPES OF MICROCEPHALY MORE ASSOCIATED WITH EPILEPSY, AND THEIR ASSOCIATED GENES81
a ARX is also linked to early infantile epileptic encephalopathy.
Lissencephaly and Subcortical Band Heterotopia
Lissencephaly literally means “smooth brain” and is a neuronal migration disorder in which there are absent or reduced gyra on the surface of the brain. Subcortical band heterotopia (SBH) is a less severe form wherein bands of gray matter are present within the white matter of the brain.35 Both cause learning difficulties and epilepsy. Most lissencephaly is caused by mutations in PAFAH1B1 (LIS1) or DCX.36 DCX is located on the X-chromosome, and mutations in females cause SBH, whereas mutations in males cause lissencephaly.37 Deletion of PAFAH1B1 as well as neighboring genes causes a more severe phenotype with characteristic dysmorphic features (Miller- Dieker syndrome). Both PAFAH1B1 and DCX regulate microtubule function, important in the regulation of migrating neurones.38
Periventricular Nodular Heterotopia
Periventricular nodular heterotopia is a neuronal migration disorder in which grey matter is positioned abnormally within the brain, typically along the walls of the lateral ventricles. Mutations in FLN1 on the X chromosome account for most “classical cases.” Most females with the condition develop epilepsy, while males tend to die before birth. FLN1 encodes a protein with a role in neuronal maturation. There is also an autosomal recessive form of the disease associated with microcephaly and mutations in the ARFGEF gene (see Table 31.4).39
SYMPTOMATIC EPILEPSIES DUE TO METABOLIC AND OTHER CAUSES
Glucose Transporter Type 1 Deficiency Syndrome (GLUT-1 DS)
GLUT-1 DS is a rare disorder due to mutations in the SLC2A1 gene, which encodes GLUT-1 (OMIM 606777). The mutation results in defective transport of glucose across the blood–brain barrier, depriving the brain of essential glucose. The disorder was discovered in 1991 and is characterized by hypoglycorrhachia (low CSF glucose) with normoglycemia, drug- refractory epilepsy with a variety of seizure types, acquired microcephaly, and episodic movement disorders.40 Although GLUT-1 DS is rare, it is an important diagnosis not to miss, as treatment with some conventional anti- epileptic drugs and other medications can inhibit GLUT-1 and worsen symptoms, whereas treatment with a ketogenic diet can reduce seizure frequency dramatically.41
Pyridoxine-dependent epilepsy is an autosomal recessive disease, usually presenting in neonates with seizures, which respond to treatment with pyridoxine (OMIM 266100). The disease is caused by homozygous or compound heterozygous mutations in the ALDH7A1 gene, which encodes antiquitin, an aldehyde dehydrogenase. This causes an elevation in α- aminoadipic semialdehyde (AASA), resulting in an intracellular reduction in pyridoxal-5′-phosphate (PLP)—the active vitamin B6 co-factor essential for neurotransmission.42,43 Although rare, this is another example of an important disease to diagnose, as lifelong treatment with pyridoxine causes seizure freedom.
Other Genetic Conditions
There are many other genetic conditions in which epilepsy is a prominent feature. These include: tuberous sclerosis (OMIM 191100, autosomal dominant disease with widespread multi-organ hamartomatous lesions, frequently associated with TSC1 or TSC2 mutations); neurofibromatosis 1 (OMIM 162200, autosomal dominant neurocutaneous disease caused by mutations in the tumor-suppressor gene NF1); Rett syndrome (OMIM 312750, X-linked neurodevelopmental disorder with seizures in childhood caused by mutations in MECP2 gene—mutations in CDKL5 also cause a similar phenotype).
OTHER GENETIC EPILEPSIES
The predominantly monogenetic epilepsies described above, generally inherited in a Mendelian fashion, account for only about 1% of all epilepsies. Genetic focal and generalized epilepsies occurring sporadically and inherited in a non-Mendelian manner account for about 30% of all epilepsies. To date, no convincing genetic mechanism has been discovered to entirely explain these epilepsies, and they are most likely caused by an interaction of multiple genetic influences, with the influence of some environmental factors. Over 100 gene defects have been associated with these epilepsies, however. The Epilepsy Genetic Association Database (epiGAD; www.epigad.org) listed 327 epilepsy gene-association studies involving 120 different genes at the time of writing and is a useful reference source.44
The next section describes some of the strategies that are being used to study the complicated genetics of these epilepsies, and some avenues for future study.
GENOME-WIDE ASSOCIATION STUDIES
Genome-wide association studies (GWAS) use a large number (typically around 0.5 to 1 million) of single-nucleotide polymorphism (SNP) markers spread throughout the entire genome of patients and controls to look for any associations between common genetic variants and disease status (see Chapters 2 and 6). Typically, a GWAS study requires a large number of samples to be adequately powered to detect the relatively weak genetic effects (odds ratios of 1.2–1.3) associated with the common disease–common variant hypothesis. From the publication of the first GWAS in 2005 to the end of 2011, 1617 published associations had been identified for 249 conditions.45
There have been two GWAS in epilepsy published as of this writing. The first study included 3445 patients with genetic and symptomatic focal epilepsies and 6935 controls of European ancestry, and did not identify any significant genome-wide associations.46 The second study looked at 1087 patients of Han Chinese descent with genetic and symptomatic focal epilepsies, and 3444 ethnically matched controls. One variation on 1q32.1 in the CAMSAP1L1 gene, which encodes a cytoskeletal protein, was significant on a genome-wide scale.47 Interestingly, neither of these GWAS seemed to identify any significant variations from within ion-channel encoding regions.
The lack of positive findings in these studies might be due in part to the large amount of phenotypical heterogeneity. Further GWAS are currently being undertaken in other forms of epilepsy. However, the lack of success of GWAS suggests that the complex genetics of epilepsy may be more due to rare genetic variants than to common variants—the common disease–rare variant hypothesis.
COPY NUMBER VARIANTS
One possible source of rare genetic variants are copy number variants (CNVs). CNVs are genomic structural variants, including insertions, deletions, and duplications, which are typically kilobases to megabases in size (see also Chapters 2 and 10). With the advent of technologies such as comparative genome hybridization (CGH) array platforms, and their ability to detect CNVs at an increased resolution, attention has turned to the role of CNVs in diseases with a complicated genetic basis, like epilepsy.
Several recent studies have published an association of three microdeletion CNVs with epilepsy. The regions containing the CNVs all contain possible candidate genes; for example, 15q13.3 includes the CHRNA7 gene, which encodes a nAChR. All three microdeletions have also been associated with other diseases,; for example, the 15q13.3 microdeletion is associated with intellectual disability,48 autism,49 and schizophrenia.50 See Table 31.5 for a summary of the major CNVs found to date.
Table 31.5 SIGNIFICANT CHROMOSOMAL MICRODELETIONS ASSOCIATED WITH EPILEPSY
|15q13.3||Present in 1% of 1223 patients with genetic generalized epilepsy (absent in 3699 controls)
Present in 1.3% of 539 patients with genetic generalized epilepsy (absent in 3777 controls)
Present in 1% of 517 patients with genetic generalized and focal epilepsy (absent in 2493 controls)
|Helbig et al. 200989
Dibbens et al. 200990
Mefford et al. 201091
|15q11.2||Present in 1% of 1234 patients with genetic generalized epilepsy (0.1% of 3022 controls)
Present in 1% of 517 patients with genetic generalized and focal epilepsy (0.2% of 2493 controls)
|De Kovel et al. 201092
Mefford et al. 201076
|16p13.11||Present in 0.5% of 1234 patients with genetic generalized epilepsy (0.1% of 3022 controls)
Present in 1% of 517 patients with genetic generalized and focal epilepsy (absent in 2493 controls)
|De Kovel et al. 201077Mefford et al. 201076|
Therefore, although CNVs seem a reasonable explanation as a genetic risk factor for epilepsy, there is much that is unexplained in terms of the mechanisms whereby they cause disease.
NEXT-GENERATION SEQUENCING AND EPILEPSY
The advent of next-generation sequencing (NGS) technologies in the last few years has seen a remarkable advance in our ability to acquire detailed genetic data on individuals (see also Chapter 10). The main technologies associated with NGS are whole-exome sequencing (WES), wherein the entire protein- coding region of the genome is sequenced; and whole-genome sequencing (WGS), wherein the entire human genome is sequenced.
Already there have been several published examples of how NGS has been used to identify causative genes in several disorders (Chapter 10). A recently published study used WGS to identify a mutation in the sodium-channel gene SCN8A as a cause of a severe epileptic encephalopathy.51 These NGS studies have used small sample sizes (nuclear family units of three or four, or very small cohorts).
Next-Generation Sequencing Panels
Lemke et al.52 used NGS technology to test a “panel” of genes with a known association with epilepsy in 33 patients with a wide range of sporadic and familial epilepsy phenotypes (see Chapters 6 and 10). They found, on average, 326 variants per patient from within the panel of 265 genes. Filtering, using criteria such as including only variants within coding regions and not present on publically available databases, reduced the average number of variants to 15 per patient. Software was then used in order to predict the pathogenicity of the variants. This led to mutations being found in 16 of the patients, including all eight of the patients with a well-defined phenotype (some of whom had already had candidate genes sequenced using traditional methods with no success).
NGS gene panel methods have the advantage of being able to offer increased coverage of genes of interest compared to WGS or WES methods. They also produce less ‘noise,’ albeit at the cost of missing variation in genes not present on the panel. The cost of gene panels continues to decrease and is already cheaper than sequencing several genes using traditional methods. Gene panels are beginning to be used in clinical practice and are likely to be increasingly used in the future.
Large-Scale Next-Generation Sequencing Studies
Heinlein and colleagues have recently published the results of a study in which 118 unrelated patients with genetic generalized epilepsy (GGE), and 242 controls were exome-sequenced.53 No statistically significant variants were identified. From the list of 87,255 variants identified at the exome- sequencing stage, 3897 were identified and genotyped in a larger cohort of 878 patients with IGE and 1830 controls. Again none of these candidate variants met significance criteria (p <0.05) after Bonferonni correction for the large number of variants tested. The study had 80% power to detect single- nucleotide variants (SNVs) with a frequency of 0.5% and a relative risk of 5.4. Although the study did not produce any statistically significant findings, the list of nearly 2000 variants observed exclusively in cases with IGE is likely to contain several real risk factors and will be a useful reference for future studies. It is interesting to note that, as in the GWAS studies described above, none of the variations detected were in ion channel genes or known ion-channel modifiers. Several studies are now underway to use NGS technology with different methodologies in large-scale cohorts, such as Epi4k.54
Mechanisms other than changes in nucleotide sequence; that is, epigenomic changes, may play a part in the etiology and hereditability of epilepsy (see also Chapter 4).55 Some examples of epigenetic mechanisms associated with epilepsy follow.
DNA methylation has a role in regulating gene expression, and several genes associated with DNA methylation have been associated with epilepsy; for example, MECP2 and the X-linked Rett syndrome (autism, learning difficulties, and epilepsy—OMIM 312750).56
Histone proteins have a crucial role in gene regulation as well as in organizing and packaging DNA. Kainate-induced seizures in animals are important models for research. Kainate administration causes changes in histone proteins; for example, hyperacetylation of histones on the brain- derived neurotrophic factor (BDNF) promoter. Sodium valproate, an anti- epileptic drug, can inhibit histone deacetylases.57
Another epigenetic mechanism is that of post- transcriptional RNA editing. For example: Adenosine to inosine (A to I) editing of the AMPA receptor subunit GluR2 was found to be significantly increased in hippocampal tissue from temporal lobe epilepsy patients. This caused an increase in the permeability of calcium ions in the receptor mediating excitotoxicity.58
GENOMICS AND MANAGEMENT OF EPILEPSY
GENETIC DIAGNOSIS AND TREATMENT
Currently, there are several examples of a genetic diagnosis being clinically useful for a patient with epilepsy. For instance, a positive genetic diagnosis of benign neonatal familial seizures in a neonate avoids the need for potentially more invasive tests; drugs that can potentially worsen seizures can be avoided in a person with a diagnosis of Dravet’s syndrome; and the ketogenic diet can be initiated in a person with GLUT-1 DS. As our understanding of epilepsy genomics increases, the role of a genetic diagnosis will play a greater role for people with epilepsy.
Although surgery is a possible option for some focal epilepsies, drug therapy with anti-epileptic drugs (AEDs) remains the mainstay of epilepsy treatment. There is a wide and often unpredictable variation in the individual’s response to AED treatment in terms of AED efficacy and adverse effects. The epiGAD database (www.epigad.org)67 listed 178 epilepsy pharmacogenetic association studies at the time of writing and is a useful reference source (see also Chapter 7).
It has been postulated that the drug transporter PGP, encoded by the gene ABCB1, has a role in AED response, and a polymorphism in ABCB1 has been associated with drug-resistant epilepsy.59 These findings have not always been consistently replicated, however, and it seems that variations in ABCB1 do not convincingly explain AED resistance.60
Several studies have looked at gene-expression patterns in brain samples from epilepsy surgery patients. Nine studies using microarray technology to compare patterns of gene expression in hippocampal sections from patients with drug-resistant epilepsy and control samples were included in a recent meta-analysis.61 They identified 233 genes with altered expression in drug- resistant samples, with significant overlap between the studies.
Some AEDs can cause serious adverse reactions; for example, carbamazepine-induced Stevens-Johnson syndrome. One of the more important findings to date has been the association of HLA-B*1502 with this reaction in Asian populations.62 No cases of Stevens-Johnson syndrome occurred in a Taiwanese group that had tested negative for the HLA-B*1502 allele.63 This finding has led to the recommendation that HLA-B*1502 testing should be performed individuals of a high-risk ethnicity before carbamazapine therapy is commenced. The HLA-A*3101 allele has been associated with carbamazepine-induced Stevens-Johnson syndrome in Caucasian patients.64
Although the influence of genetics on the etiology of epilepsy has been understood for several hundred years, it is only during the last 15 years or so that significant advances have been made in our understanding of the mechanisms. Discovering the genes responsible for rare genetic and symptomatic Mendelian epilepsies has improved our understanding of the mechanisms of seizure-generation and of neurophysiology as a whole, but it has not explained the genetic mechanism underlying the majority of the epilepsies.
Genome-wide association studies have provided little evidence for the common disease–common variant hypothesis in epilepsy to date. The common disease–rare variant hypothesis might provide more of an explanation for the genetics of epilepsy. Ongoing work using next-generation sequencing technologies seems likely to yield further results in this area. Genetic testing as an aid to diagnosis and treatment is beginning to be used in the clinical domain, and we hope that, as our understanding increases, genomics will begin to have a greater impact on the treatment of patients with epilepsy.
Thanks to Professor Philip Smith, Professor Mark Rees, and Doctor Seokyung Chung for their support and comments.
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