Genetics of epilepsy

Handbook of Clinical Neurology, Vol. 148 (3rd series) Neurogenetics, Part II D.H. Geschwind, H.L. Paulson, and C. Klein, Editors https://doi.org/10.1016/B978-0-444-64076-5.00030-2 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 30

Genetics of epilepsy DANIELLE NOLAN1 AND JOHN FINK2* Departments of Pediatrics and Pediatric Neurology, University of Michigan, Ann Arbor, MI, United States

1 2

Department of Neurology, University of Michigan and the Ann Arbor Veterans Affairs Medical Center, Ann Arbor, MI, United States

Abstract Discovery of nearly 200 genes implicated in epilepsy and insights into the molecular and cellular pathways involved are transforming our knowledge of the causes, classifications, diagnosis, and in some cases, treatments for individuals with chronic seizure disorders. Numerous disorders once considered “idiopathic” are now recognized as genetic conditions. Despite these remarkable advances, the cause of epilepsy for most individuals is unknown. We present a clinical approach to patients with epilepsy, presenting an algorithm for clinical and genetic testing, and review genes implicated in epilepsy and their associated syndromes.

INTRODUCTION AND OVERVIEW Advances in genetic research are transforming knowledge of the causes and treatments of epilepsy. Gene mutations have been identified as major pathogenic factors for epilepsy syndromes occurring in families as well as for epilepsy occurring in subjects with no known family history of epilepsy for whom the disorder was previously considered idiopathic. The greatest advances have been made in understanding epilepsy syndromes occurring in families as autosomal-dominant, autosomal-recessive, or X-linked traits. Extensive clinical variation in these “single-gene” disorders is attributed to the specific gene mutation (genotype–phenotype correlation) and to unidentified modifying gene and environmental factors. In addition to “single-gene” forms, at least 45% of epilepsy syndromes are considered to be either genetically complex (due to multiple genes) or multifactorial (due to both genetic and nongenetic factors) (Thomas and Berkovic, 2014). Many epilepsy syndromes are genetically heterogeneous: mutations in different genes cause the same or very similar clinical syndromes. Furthermore, many causative gene mutations exhibit phenotypic pleomorphy:

mutations in one gene cause clinically distinct disorders. These factors make it difficult to diagnose the genetic basis of an epilepsy syndrome on clinical factors alone. For individuals with epilepsy and their family, discovery of the genetic basis of their disorder brings closure to an often prolonged and frustrating diagnostic odyssey, typically obviates the need for further investigations, may inform the prognosis and genetic counseling, and increasingly has direct therapeutic implications. Discovery of many genes that cause or contribute to epilepsy provides insight into the molecular basis of seizures and facilitates development of pathway-specific therapies. This chapter presents an approach to the genetic evaluation of subjects with epilepsy and reviews advances in understanding many genetically determined forms of epilepsy. For additional reviews of the genetics of these and other epilepsy syndromes, see Hildebrand et al. (2013) and Prasad and Prasad (2013).

APPROACH TO GENETIC EVALUATION OF EPILEPSY SUBJECTS Eventually perhaps, genetic and biochemical testing will provide insight into the cause, treatment, and prognosis for every patient with epilepsy. Indeed, clinical research now underway includes whole-genome sequencing for unselected patients with epilepsy, including those with

*Correspondence to: JK Fink, M.D., 5013 BSRB, 109 Zina Pitcher Place, Ann Arbor MI 48109-2200, United States. Tel: +1-734936-3087, E-mail: [email protected]

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D. NOLAN AND J. FINK Structural abnormality (excluding neoplasm and abscess) e.g. malformations, tuberous sclerosis, lissencephaly spectrum. cortical migration abnormality spectrum

Analysis of specific gene or syndrome-specific gene panel

Neuroimaging abnormality History including prenatal, developmental, and family history Physical and neurologic examination Routine laboratory tests including blood counts, serum glucose, electrolytes, calcium, ammonia, creatine, urea nitrogen, amino acids, lactate, pyruvate, thiamine, urine organic acids EEG Neuroimaging

Leukodystrophy

Dysmorphic features, congenital abnormalities, or history of frequent miscarriages or difficulty becoming pregnant

Syndromic classification e.g. Epileptic encephalopathy Myoclonic seizures Febrile seizures Generalized epilepsy Partial epilepsy

Laboratory testing for leukodystrophies

Specific enzyme and gene testing

Karyotype Chromosome microarray Likely

Specific biochemical, enzyme, and gene testing

Unlikely

1.Chromosome microarray 2.Analysis of epilepsy gene panels (syndrome specific, syndrome nonspecific) 3.Whole exome sequencing 4.Whole genome sequencing

Syndrome conforms to inherited metabolic disorder

Fig. 30.1. Approach to genetic evalulation of subjects with epilepsy. EEG, electroencephalogram.

and without family history of similar disorder. Presently, however, the expense and frequent lack of insurance reimbursement, often further complicated by ambiguous results, make it important to select subjects for whom genetic analysis is most likely to yield clinically useful information (Fig. 30.1).

Exclude nongenetic disorders Acquired brain injury as the primary (or contributing) cause of seizures should be excluded before investigating potential genetic factors that cause or contribute to epilepsy. This is true even for individuals who have a family history of epilepsy. Traumatic brain injury, encephalitis, vasculitis, hypoxia, abscess, neoplasm, metabolic disturbance (including those conditions resulting in hypoglycemia, hyponatremia, and amino acidopathy), drug (including alcohol) withdrawal or toxicity must be excluded through history, neuroimaging, and laboratory studies, including serum glucose, electrolytes, calcium, lactate, pyruvate, pyridoxine, creatine, biotin, amino acids, and cerebrospinal fluid as clinically indicated.

Family history It is essential to review the family history in detail, specifically inquiring about other individuals with the same syndrome or other seizure disorders, and those other neurologic diseases. A first-degree relative with a similar disorder suggests a single-gene disorder (Mendelian disorder) for which genetic testing has the highest likelihood of informative results. The mode of inheritance (autosomal-dominant, autosomal-recessive, X-linked, or maternal (mitochondrial) transmission) refines the list of epilepsy syndromes and causative genes. Family history of disparate seizure syndromes suggests either that the gene mutation results in variable clinical presentations (genetic pleomorphy) or that family

members do not share the same cause and type of epilepsy. A history of difficulty becoming pregnant or repeated miscarriage may suggest early fetal demise which could be on a genetic basis.

General physical and neurologic evaluations It is critical to consider whether epilepsy occurs in the context of other neurologic or systemic abnormalities that suggest specific epilepsy syndromes (see Table 30.1 for examples) or alternative systemic or neurologic disorders whose symptoms may include seizures. General physical and neurologic evaluations help define the epilepsy syndrome (e.g., epileptic encephalopathy versus myoclonic, versus focal seizure disorders), plan genetic investigations (e.g., chromosome microarray, analysis of individual genes or gene panels, and whole-exome sequencing), and evaluate the significance of identified gene variations. For these reasons, it is important to assess early developmental growth, head circumference and shape, vision and hearing, general health, frequent infections, malignancy, and the occurrence of dysmorphic features. Epilepsy syndromes associated with intellectual impairment and dementia are too numerous to review in this context. Intellect should be evaluated carefully in all subjects to determine if the cognition is affected by: (1) the underlying cause of epilepsy; (2) the direct consequences of frequent seizures (e.g., their effects on brain function and school participation); or (3) medication. It is important to consider the possibility that cognitive impairment and dysmorphic features in children of mothers with epilepsy could be due to fetal anticonvulsant toxicity rather than a manifestation of the spectrum of the parent’s seizure disorder. The possibility of identifying a causative gene mutation is higher in epilepsy subjects who have developmental delay, cognitive

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Table 30.1 Examples of genetic disorders associated with epilepsy that have abnormal physical examination findings Sign

Disorder

Organomegaly

Niemann–Pick type C (257220, 607625) Gaucher disease type III (231000) Sialidosis (256550) Neuronal ceroid lipofuscinosis DIAPH1 mutation (616632) Norrie disease (310600) Tuberous sclerosis (angiolipomas and hypopigmented macules) (191100, 613254) Sturge–Weber (“port-wine nevus”) (185300) Osler–Weber–Rendu (hemangioma) (187300) Incontinentia pigmenti (308300) Biotinidase deficiency (rash) (253260) Dentatopallido-luysian atrophy (125370) Niemann–Pick disease type C (257220, 607625) POLG1 mutation disorder spectrum (174763) Cerebrotendinous xanthomatosis (213700) Huntington disease (143100) Trisomy 21 (190685) Mabry syndrome (239300) Infantile encephalopathy due to TBCK mutation (616900) Cri-du-chat (del5p) (123450) Glycosylphosphatidylinositol disorders (610293) Wolf–Hirschhorn syndrome (194190) Angelman syndrome (105830) Miller–Dieker lissencephaly (247200) Periventricular nodular heterotopia Sialidosis (256550) Mucopolysaccharidoses, mucolipidosis FOXG1 deletion (613454) Long QT syndrome Arthrogryposis due to SLC35A3 mutation (615553) Limb anomalies due to ALG6-CDG mutation (603147) Mabry syndrome (239300) Sialidosis (256550) Hartsfield syndrome (holoprosencephaly spectrum and ectrodactyly spectrum disorders) (615465) Greig cephalopolysyndactyly syndrome (175700) North sea myoclonus (syndactyly) Calcium channel (CACNA1C) gene mutation (611875) Mitochondrial disorder Sodium-gated, potassium channel (KCNT1) gene mutation (608167)

Blindness

Dermatologic abnormalities

Ataxia

Extrapyramidal signs Abnormal facies

Skeletal abnormality

Syndactyly Cardiomyopathy, including arrhythmia

impairment, and particularly dementia compared to subjects who do not have cognitive impairment (Srivastava et al., 2014; Nolan and Carlson, 2016). The occurrence of dysmorphic facies or abnormal head shape or size raises the possibility that epilepsy is a symptom of abnormal brain development involving cortex and subcortical structures. This could be due to specific gene mutation (Jellinger and Rett, 1976) or more commonly to chromosome abnormality such as trisomy 21 (Down syndrome), cri-du-chat syndrome (15p-), 1p36 monosomy, Wolf–Hirschhorn syndrome, ring 20 chromosome syndrome, Miller–Dieker syndrome,

or 18p- syndrome (Sorge and Sorge, 2010). The occurrence of multiple dysmorphic features raises the possibilities of a contiguous gene disorder (i.e., a chromosome abnormality affecting multiple genes) or the pleomorphic effects of a single-gene disorder. Certainly, features of tuberous sclerosis (facial or subungual angiolipomas and hypopigmented macules) would prompt imaging and disease-specific testing. Cleft lip or palate abnormalities in an individual with epilepsy whose mother also has epilepsy could be part of a genetic syndrome or potentially attributable to anticonvulsant toxicity (Weston et al., 2016).

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Table 30.2 Representative metabolic disorders frequently associated with epilepsy (Goldman and Comella, 2013) Disorder

Laboratory test

Aminoacidopathy including nonketotic hyperglycinemia Organic aciduria including maple syrup urine disease, multiple carboxylase deficiency, and propionic, methylmalonic, isovaleric, and glutaric acidurias Urea cycle disorders

Serum amino acid analysis

Biotinidase deficiency (253260) Menkes disease (309400) Glucose transporter protein (GLUT1) deficiency (606777) Molybdenum cofactor deficiency (252150, 252160) Isolated sulfite oxidase deficiency (272300) Mitochondrial encephalomyopathy Sialidoses (256550) Pyruvate dehydrogenase complex deficiency (312170, 245349, 245348) Hypophosphatasia (24100, 241500, 241510, 146300) Pyridoxine (vitamin B6) disorder, including pyridoxinedependent epilepsy (PDE) and pyridoxamine 50 -phosphate oxidase (PNPO) deficiency Serine deficiency Holocarboxylase synthetase deficiency (253270) Cerebral creatine deficiency syndrome 1 (CCDS1) (300352) and arginine:glycine amidinotransferase (AGAT) deficiency (612718) Succinic acid semialdehyde dehydrogenase deficiency (271980)

Inherited metabolic disorders Inherited metabolic disorders are those genetic disorders for which biochemical abnormalities are detectable by analytic methods employed in clinical laboratories. The distinction between inherited metabolic disorders causing epilepsy (Table 30.2) (Goldman and Comella, 2003) and other genetic causes of epilepsy is useful in the sense that some inherited disorders have clinically assayable biomarkers that can be used for diagnosis and sometimes as therapeutic outcome parameters. Inherited metabolic disorders, including those in Table 30.2, are particularly important in the differential diagnosis of newborn and infantile-onset epilepsy because many have specific treatments (Goldman and Comella, 2003). Cerebrospinal fluid (CSF) examination may be recommended in the course of excluding nongenetic causes of refractory epilepsy and may be useful for subjects who

Serum amino acids, urine organic acid analysis

Serum ammonia, amino acids, liver enzymes, specific enzyme testing as clinically indicated Serum lactic acid, urine organic acids (often, but not always, abnormal), serum ammonia, serum biotinidase activity Serum and urine copper Serum and cerebrospinal fluid glucose analysis Serum amino acids and sulfite oxidase analysis (fibroblasts); genetic testing Urine sulfocystein Serum and cerebrospinal fluid lactate and pyruvate; histologic and biochemical analysis of muscle biopsy Urinary oligosaccharides, specific enzyme analysis in serum and fibroblasts Serum lactate, specific enzyme analysis in fibroblasts, genetic testing Serum alkaline phosphate, serum calcium PDE: a-aminoadipic semialdehyde/pyrroline 6’ carboxylate (in urine, plasma, or cerebrospinal fluid); PNPO: urine vanillactate, cerebrospinal fluid pyridoxal 5’-phosphate Serum amino acids Serum lactate, amino acids CCDS1: increased urine creatine:creatinine ratio urinary guanidinoacetate concentration (reduced), serum AGAT enzyme activity (reduced) Increased serum and urine gamma-aminobutyric acid (GABA)

remain undiagnosed. CSF examination may identify cerebral folate deficiency (Mangold et al., 2011), neurotransmitter abnormalities suggestive of pyridoxine-dependent epilepsy (Segal et al., 2011), and lactate and pyruvate elevation consistent with mitochondrial disturbance.

Course Over time, most individuals with epilepsy exhibit either a relatively stable seizure pattern and frequency or decreasing seizure frequency with age and anticonvulsants. In general, there is an increased likelihood of identifying genetic etiology in subjects who have intractable epilepsy (e.g., those failing two anticonvulsant therapies) (Ream and Patel, 2015). In Dravet syndrome (SCN1A mutation), for example, infantile-onset febrile seizures (often evident as unilateral clonic movements) increase in frequency and progress to afebrile partial seizures

GENETICS OF EPILEPSY associated with myoclonus and generalized seizures that may be temperature- or photo-sensitive. While worsening of severity and increasing seizure patterns may suggest a genetic disorder, the converse is not always true. Genetic factors have been identified in subjects with long-standing, relatively unchanging seizure patterns, previously considered “idiopathic.”

Seizure evaluation Defining the seizure type (or types) and electroencephalographic (EEG) pattern in the patient and similarly affected relatives is essential for classifying the epilepsy syndrome and provides important insight into selecting potential candidate genes (and gene panels) for analysis. Further, knowing the type of seizures provides insight into evaluating the significance of identified gene variations. Following the Operational Classification of Seizure Types by the International League Against Epilepsy (Fisher et al., 2017), seizures are classified according to: (1) their cerebral origin (focal, generalized, unknown); (2) as motor, nonmotor, or absence disturbances (each further classified by movement and sensory patterns); and (3) whether or not awareness is affected. In addition to guiding anticonvulsant selection, seizure classification informs the initial selection of genetic testing panels containing genes implicated in specific syndromes (e.g., progressive myoclonic epilepsy (PME)). Although seizure classification can guide the initial selection of candidate epilepsy genes, this cannot be relied on completely. Increasingly, it is

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clear that mutations in a specific “epilepsy gene” cause disparate seizure types.

ELECTROENCEPHALOGRAPHY EEG is important to assess interictal cortical function and classify epilepsy syndromes, which in turn provides important direction in the investigation of potential genetic (and nongenetic) causes. Epileptic discharges are often affected by sleep–wake cycle and circadian rhythms and therefore, at least 24 hours. EEG recording that captures natural sleep may provide greater detection (compared to random EEG) of epileptic discharges. In general, EEG findings correlate more closely with the type of seizure than with the underlying cause. Nonetheless, some EEG patterns (e.g., hypsarrhythmia) suggest specific genetic epilepsy syndromes (Table 30.3).

NEUROIMAGING Beyond the value in excluding nongenetic disorders, brain magnetic resonance imaging (MRI) may provide insight into the classification and cause of inherited syndromes associated with epilepsy (Noh et al., 2012). In some circumstances, brain magnetic resonance spectroscopy may identify metabolic abnormalities (e.g., indicating amino acidopathy, g-aminobutyric acid transaminase deficiency, GLUT1 deficiency, or mitochondrial abnormality) even when the MRI is normal (Cendes et al., 2016).

GENETIC TESTING Genetic testing has the highest likelihood of yielding unambiguous information for subjects with epilepsy

Table 30.3 Examples of neuroimaging findings suggesting inherited epilepsy syndromes Finding

Differential diagnosis includes:

Cortical migration abnormality Forebrain division abnormality Megalencephaly Schizencephaly spectrum including porencephaly Tuberous sclerosis Focal cortical dysplasia Cavernoma Leukodystrophy Multiple strokes Thin corpus callosum

Lissencephaly, agyria, pachygyria subcortical band heterotopia Holoprosencephaly spectrum Megalencephaly, hemimegalencephaly

TORCH infections, genetic causes of focal cortical dysplasia Familial cavernomas Alexander disease, peroxisomal disorder, mitochondrial disorder and other causes Mitochondrial disorder Extended differential diagnosis, including epileptic encephalopathy due to STXBP1 mutation, West syndrome due to ARFGEF2 mutation, MED-23-associated ketogenic diet-treatable, refractory epilepsy, GNAO1 mutations associated with epileptic encephalopathy

TORCH, toxoplasmosis, syphilis, varicella-zoster, parvovirus B19, rubella, cytomegalovirus, herpesvirus.

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who have: (1) family history of epilepsy; (2) dysmorphic features, cognitive impairment, or nonacquired neuroimaging abnormality; or (3) one of the following syndromes: epileptic encephalopathy, myoclonic seizures, febrile convulsions. Such individuals are most likely to harbor an identified mutation in an epilepsy-associated gene. Nonetheless, it is important to note that with greater application of increasingly comprehensive testing (e.g., moving from karyotype to chromosome microarray and from individual gene testing to wholeexome/genome analysis), genetic abnormalities are increasingly identified in individuals who do not conform to any of these syndromes. This includes subjects with apparently sporadic, nonsyndromic, generalized, and focal epilepsy. Genetic testing includes karyotype (particularly highresolution, metaphase analysis), chromosome microarray analysis, evaluation of candidate genes (individually or in gene panels), whole-exome sequencing, mitochondrial gene sequencing, and whole-genome sequencing. Transcription profiling, examining the relative expression of individual genes and groups of genes, is not yet available for clinical application. Using a combination of these methods, typically sequentially (Fig. 30.1), overcomes the limitations of individual approaches. Contiguous gene syndromes (suggested by the occurrence of multiple congenital abnormalities) raise the possibility of chromosome abnormality. These may be detected by karyotype (if the genomic abnormality is large enough) or chromosome microarray analysis which has higher sensitivity than karyotype (e.g., for a 1000basepair abnormality) as long as the disturbance occurs within the coverage region. Gene copy number variation (duplication or deletion of one or more genes) is identified by chromosome microarray in 10% of subjects in which generalized epilepsy is associated with intellectual delay (Mefford, 2014). Some copy number variants (CNVs: e.g., those on chromosomes 16p13.11 and 15q11.2) (Mefford, 2014) are specifically associated with epilepsy. Gene sequencing includes analysis of individual genes, panels of genes, and whole-exome and wholegenome sequencing. Decisions to analyze individual genes versus multigene panels are based on the degree of the syndrome’s genetic heterogeneity. Testing of individual genes is most useful, firstly, for those relatively uncommon syndromes that are associated specifically with one gene variation (e.g., SCN1A-related Dravet syndrome), and secondly, for those syndromes when genetic test results would indicate specific treatment (such as SLC2A1 and the use of the ketogenic diet). In contrast, it is appropriate to analyze multigene panels for genetically heterogeneous syndromes (i.e., broad syndrome classifications such as myoclonic

epilepsy or epileptic encephalopathy in which mutations in more than one gene can cause the same or very similar clinical syndrome). Whole-exome sequencing and whole-genome sequencing provide nonbiased evaluation and are most useful when the clinical syndrome is not associated specifically with one or more candidate genes (those known to cause similar syndromes), and when the number of candidate genes or their inclusion in several gene panels makes their analysis by whole-exome sequencing more cost-effective. In addition to DNA sequence variations, the genome contains many deletions and duplications that are variable within a population, may be normal variants, and may be disease-associated. Depondt (2016) points out that, collectively, these gene CNVs have been described in up to 28% of subjects with epilepsy and are the single largest risk factor for epilepsy that is not ascertained as a familial disorder (i.e., sporadically occurring epilepsy). Chromosome microarray analysis usually provides more sensitive detection of CNVs. It is important to note that CNVs, including whole-gene or exon deletion, may not be detected reliably with next-generation sequencing, the method used for whole-exome and whole-genome analysis.

Interpreting the results of genetic analysis The goal of genetic testing is to confirm and add molecular precision to the clinical diagnosis that informs counseling (including genetic counseling), prognosis, and treatment. Genetic abnormalities that are diseasespecific (previously reported to be associated with the same syndrome and absent in ethnically matched control subjects) and associated with predicted or demonstrable change in the encoded protein’s function can be used to confirm the clinical diagnosis. As noted by Poduri et al. (2014), “a negative result must be considered within the limits and complexities of the technology and data interpretation, and does not rule out a genetic cause of epilepsy in the individual tested.” On the other hand, genetic test results that are “novel” (never reported previously) or which occur (in very low frequency) in unaffected subjects may be regarded as of uncertain significance. Reporting these to a publicly available database (e.g., www.ncbi.nlm.nih.gov/clinvar) may eventually help understand their significance, although there is the possibility of an ascertainment bias for identifying and reporting mutations in these genes in this patent cohort. In general, as one analyzes more genes (e.g., moving from the analysis of single genes to analysis of gene panels and entire exomes), the more frequently one encounters “off-target” gene variations (e.g., those that

GENETICS OF EPILEPSY are unrelated to epilepsy) that are clinically significant, as well as gene variations of uncertain clinical significance. Subjects should be fully informed of all gene variations and, for those with clinically significant gene variations, should be referred for genetic counseling and appropriate medical specialty evaluation. Variations of uncertain significance should be re-evaluated at periodic intervals because their clinical relevance may become clear as databases of pathogenic and benign variations expand. Identifying a gene mutation as a probable cause of the patient’s seizure disorder can bring closure to an often long diagnostic odyssey. Nonetheless, genetic test results alone do not change the clinical or syndromic diagnosis but rather establish its cause. Specifically, it is increasingly common for gene mutations associated initially with one epilepsy syndrome to be identified in subjects with a different epilepsy syndrome. For example, GABRA1 mutations originally identified in juvenile myoclonic epilepsy (JME) (Cossette et al., 2002) were subsequently identified in multiple generalized epilepsy syndromes (discussed below) (Maljevic et al., 2006; Lachance-Touchette et al., 2011; Carvill et al., 2014). Identifying a pathogenic epilepsy gene mutation does not indicate that the patient (or family members) will necessarily develop an alternative clinical syndrome. Similarly, finding a “probably pathogenic” gene mutation does not completely determine the prognosis. Particularly for mutations reported in only a small number of subjects, it is generally prudent to base prognosis on the individual patient’s demonstrated course, instead of generalizing from limited clinical information obtained in ethnically diverse subjects (for whom background genes and other modifying factors are heterogeneous). The full spectrum of disease and the extent of its clinical variability may not be adequately reported in only a few subjects. Genetic counseling must consider such factors as genetic penetrance, variable age of symptom onset, and gender influences on phenotype severity, none of which may be sufficiently known when the mutation has been reported in only a limited number of subjects. A cautious, wait-and-see attitude is recommended.

REPRESENTATIVE GENETICALLY DETERMINED EPILEPSY SYNDROMES Epileptic encephalopathies Epileptic encephalopathies (reviewed by McTague et al., 2016) are a large group of disorders characterized by slowed psychomotor development or psychomotor regression, early-onset myoclonic seizures (discussed below) and other seizure semiologies, and burst suppression patterns on interictal EEG. Epileptic encephalopathies are

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classified according to age of symptom onset, EEG characteristics, and seizure progression. Genes have been identified for 50 types of early infantile epileptic encephalopathy (Tables 30.4 and 30.5). The most common epileptic encephalopathies are West syndrome and Dravet syndrome (McTague et al., 2016).

WEST SYNDROME West syndrome is recognized by the triad of infantile spasms, developmental arrest, and interictal EEG demonstrating hypsarrhythmia (disorganized high-voltage slow waves and spikes). Genetic etiologies have been identified in >15% of West syndrome patients (Wirrell et al., 2015), including trisomy 21 (Down syndrome), tuberous sclerosis, and mutations in CDKL5, KCNQ3, STXBP1, KANSL1, POLG1, ARX, and SCN1A genes (Kalscheuer et al., 2003; Gecz et al., 2006).

DRAVET SYNDROME Dravet syndrome, also known as early infantile epileptic encephalopathy type 6, is characterized by multiple seizure types (tonic, clonic, and tonic-clonic seizures) beginning in the first year of life, initially induced by fever, and then occurring without fever and becoming pharmacoresistant. Interictal EEG of Dravet syndrome can progress from normal to paroxysmal epileptiform abnormalities. Mutations in SCN1A are found in 80% of Dravet syndrome patients. More than 95% of these mutations arise de novo (Wallace et al., 2001; Gursoy and Ercal, 2015). There is some genotypic– phenotype correlation insofar as SCN1A truncating mutations are associated with earlier onset of seizures and more severe phenotype (Brunklaus et al., 2012; Brunlaus and Zuberi, 2014). It is recommended that lamotrigine, phenytoin, and carbamazepine be avoided in patients with SCN1A-related Dravet syndrome (Brunklaus et al., 2012). Instead, Ceulemans et al. (2016)proposed fenfluramide as add-on treatment to first-line anticonvulsants (e.g., clobazam).

OHTAHARA SYNDROME Ohtahara syndrome (early infantile epileptic encephalopathy with suppression burst) is characterized by earlyonset tonic spasms, intractable seizures, and severe intellectual disability. Interictal EEG in Ohtahara syndrome demonstrates a burst suppression. Some STXBP1 gene mutations cause Ohtahara syndrome, while other STXBP1 gene mutations cause a wider range of syndromes, including delayed cognitive development without seizures (Fauth et al., 2016).

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Table 30.4 Electroencephalogram (EEG) patterns that suggest specific genetic epilepsy syndromes Syndrome

EEG findings

West syndrome

Hypsarrhythmia: very high-amplitude asynchronous slow waves, multifocal spikes, and polyspikes Infantile spasms Burst suppression: periods of high-voltage activity alternating with periods of very depressed, low-voltage activity Interictal high-amplitude 1.5–2.5-Hz generalized and multifocal polyspike and spike-and-wave discharges and slow background. This pattern is present in <30% of subjects initially and may take months to evolve Epileptiform discharges involving multiple independent sites, moving from one cortical area to another in consecutive seizures 3-Hz generalized, monomorphic, high-voltage spike-and-wave discharges 3–4-Hz generalized monomorphic high-voltage spike-and-wave discharges 4–6-Hz generalized polyspike and wave discharges Often a photoparoxysmal response Ictal rhythm of sharp waves or repetitive 8–11-Hz spikes Ictal EEG recordings may be normal Temporoparietal-occipital discharges with marked spread and potentiation during non-REM sleep Continuous 1.5–2.5-Hz spike-and-wave activity, most prominent during non-REM sleep High-amplitude, diphasic, unilateral or bilateral, centrotemporal spikes or sharp and slow waves with a horizontal dipole. Discharges are markedly activated in drowsiness and non-REM sleep. Otherwise normal background

Ohtahara syndrome Lennox–Gastaut syndrome

Migrating partial epilepsy of infancy Childhood absence epilepsy Juvenile absence epilepsy Juvenile myoclonic epilepsy Autosomal-dominant nocturnal frontal-lobe epilepsy (ADNFLE) Landau–Kleffner syndrome Electric status epilepticus in sleep (ESES)/continuous spikes and waves during slow sleep (CSWS) Benign epilepsy with centrotemporal spikes (BECTS)

REM, rapid eye movement.

Table 30.5 Early infantile epileptic encephalopathy (EIEE) EIEE type

Alternative name (OMIM #)

1 2 3 4 5 6

X-linked West syndrome, X-linked Ohtahara syndrome, (308350) (300672) (609304) Ohtahara syndrome (612164) (613477) Dravet syndrome (607208) (613720) (300607) (300088) (613402) (613721) (613722) (614558) Malignant migrating partial epilepsy of infancy (614959) (615006)

7 8 9 10 11 12 13 14 15

Gene (gene #) ARX CDKL5 SLC25A22 STXBP1 SPTAN1 SCN1A

(300382) (300203) (609302) (602926) (182810) (182389)

KCNQ2 ARHGEF9 PCDH19 PNKP SCN2A PLCB1 SCN8A KCNT1 ST3GAL3

(602235) (300429) (300460) (605610) (182390) (607120) (600702) (608167) (606494)

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Table 30.5 Continued EIEE type

Alternative name (OMIM #)

16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

(615338) (615473) (615476) (615744) Multiple congenital anomalies–hypotonia–seizures syndrome 2 (300868) (615833) Congenital disorder of glycosylation type IIm (300896) (615859) (615871) (615905) (616056) (616139) (616211) (616339) (616341) (616346) (616366) (616409) (616645) (616647) Congenital disorder of glycosylation type Is (300884) (616981) (617020) (612949) (617065) (617105) (617106) (617113) (617132) (617153) (617162) (617166) GLUT1 deficiency syndrome (606777) Glycine encephalopathy (605899)

Aicardi-Goutieres syndrome 1 (225750) Rett’s syndrome (300673)

MIGRATING PARTIAL EPILEPSY OF INFANCY Migrating partial epilepsy of infancy (MPEI) is characterized by pharmacoresistant focal seizures starting at age 6 months that are associated with a seizure focus that moves (migrates) to various areas of both hemispheres. MPEI is associated with progressive encephalopathy and marked neurodevelopmental regression. Barcia et al. (2014) implicated gain-of-function KCNT1 mutations in 50% of nonfamilial MPEI patients. Quinidine

Gene (gene #) TBC1D24 GNAO1 SZT2 GABRA1 PIGA NECAP1 SLC35A2 DOCK7 HCN1 SLC13A5 KCNB1 GRIN2B WWOX AARS SIK1 DNM1 KCNA2 EEF1A2 SLC12A5 ITPA ALG13 FRRS1L ARV1 SLC25A12 GUF1 SLC1A2 CACNA1A GABRB3 UBA5 GABRB1 GRIN2D FGF12 SLC2A1

(613577) (139311) (615463) (137160) (311770) (611623) (314375) (615730) (602780) (608305) (600397) (138252) (605131) (601065) (605705) (602377) (176262) (602959) (606726) (147520) (300776) (604574) (611647) (603667) (617064) (600300) (601011) (137192) (610552) (137190) (602717) (601513) (138140)

AMT GLDC GCSH TREX1

(238310) (238300) (238330) (606609)

MECP2

(300005)

administration in a child with a KCNT1 mutation markedly reduced seizure frequency (Bearden et al., 2014).

EMERGING GENOTYPE-SPECIFIC THERAPEUTIC RECOMMENDATIONS IN EPILEPTIC ENCEPHALOPATHY

As noted above, lamotrigine and phenytoin should be avoided in patients with SCN1A-related Dravet syndrome (Bearden et al., 2014). Ezogabine has been recommended for patients with KCNQ2 mutations (Gunthorpe et al.,

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2012). Quinidine has been recommended for patients with KCNT1 mutations (Bearden et al., 2014). Subjects with SCN8A mutation have increased risk (10%) of sudden unexpected death in epilepsy (Hammer et al., 2016).

Febrile seizures Febrile seizures occur in 4% of children, frequently have a major genetic predisposition (Camfield and Camfield, 2015), and are genetically heterogeneous. Familial febrile seizures (FFS) typically begin between ages 6 months and 6 years, and are not usually associated with subsequent epilepsy (Nabbout et al., 2002). Neither FFS nor the clinically related syndrome generalized epilepsy with febrile seizures plus (GEFS+) has specific electrographic patterns. Subjects with GEFS+ (Scheffer and Berkovic, 1997) usually have a family history of febrile seizures

consistent with autosomal-dominant inheritance (albeit with incomplete genetic penetrance). GEFS+ subjects experience febrile seizures (between 6 months and 6 years), can have febrile seizures occurring outside the upper age (6 years) usually associated with FFS, and have seizures not associated with fever of varying semiology, including focal and generalized seizures. FFS and GEFS + illustrate the complexity of epilepsy genetics: multiple phenotypes arise from the mutations in a given gene (e.g., SCN1A mutations are associated with both FFS and GEFS + as well as Dravet syndrome and familial hemiplegic migraine), and mutations in different genes result in clinically similar (sometimes indistinguishable) syndromes (e.g., single-gene mutations in SCN1A, SCN9A, ADGRV1, GABRG2, and CPA6 each cause familial febrile convulsions) (Table 30.6).

Table 30.6 Genetic febrile seizure disorders Mutations in this gene are associated with: Other febrile seizure disorder Familial febrile seizures

FEB3A (604403) FEB3B (604403)

GEFS +

SCN1A (182389) SCN9A (603415)

FEB4 (604352) FEB8 (611277) FEB11 (614418)

ADGRV1 (602851) GABRG2 (137164) CPA6 (609562)

GEFS + 1 (604233)

SCN1B (600235)

GEFS + 2 (3604403)

SCN1A (182389)

GEFS + 3 (611277)

GABRG2 (137164)

GEFS + type 10 (613060)

GABRD (137163)

GEFS + type 7 (613863)

SCN9A (603415)

GEFS + type 9 (616172)

STX1B (601485)

GEFS + (604403) GEFS + (613863)

Other disorder Dravet syndrome (607208), familial hemiplegic migraine (604403) Dravet syndrome (607208), primary erythermalgia (133020), hereditary sensory autonomic neuropathy (243000), congenital insensitivity to pain (243000) Usher syndrome (605472)

GEFS + (611277)

Familial febrile seizures (604403) Familial febrile seizures (611277)

Familial febrile seizures (613863)

Autosomal-dominant temporal-lobe epilepsy (614417) Familial atrial fibrillation (615377), Brugada syndrome (ST segment elevation, sudden death, 612838), cardiac conduction defect (612838) Dravet syndrome (607208), familial hemiplegic migraine (609634) Susceptibility to childhood absence epilepsy 2 (607681) Generalized epilepsy (613060), susceptibility to juvenile myoclonic epilepsy (613060) Primary erythermalgia (133020), hereditary sensory autonomic neuropathy (243000), paroxysmal extreme pain disorder (167400), small fiber neuropathy (133020)

GENETICS OF EPILEPSY

Genetic generalized epilepsy Genetic generalized epilepsy (GGE) refers to three syndromes: generalized tonic-clonic seizures, childhood (CAE) and juvenile absence epilepsy (JAE), and JME (Table 30.7). These syndromes are accompanied by EEG findings of 3–6 Hz or faster generalized discharges on an otherwise normal background. Neuroimaging and cognition typically are normal. Ninety percent concordance between identical twins with GGE indicates a major genetic influence in these syndromes (Helbig, 2015). One-third of patients with CAE have a family history of epilepsy, including childhood absence and other syndromes. GGEs are genetically diverse, with mutations found in a number of genes, including GABRG2, GABRA1, GABRB3, and CACNA1H. Mutations in these genes are associated not only with GGE but also with other epilepsy syndromes. For example, GABRA1 mutations, which have been implicated in three different types of GGE (JME (Cossette et al., 2012), CAE (Maljevic et al., 2006), and idiopathic generalized epilepsy (Lachance-Touchette et al., 2011)) are also associated with early infantile epileptic encephalopathy (Carvill et al., 2014). As another example, SLC2A1 mutations initially identified as causing GLUT-1 deficiency syndrome (Wang et al., 2000) have been recently implicated in early-onset absence epilepsy and myoclonic astatic epilepsy (Dibbens et al., 2009; Cendes et al., 2016). Identifying SLC2A1 mutation guides treatment by indicating a ketogenic diet.

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CNVs have also been demonstrated in GGE, including JME, JAE, and CAE (Helbig et al., 2009; Mulley and Dibbens, 2009). For example, CNVs were identified in 15 of 144 children (10.5%) (Addis et al., 2016) with absence epilepsy. These CNVs included chromosome 15q13.3 microdeletion, which has been found in 1% of subjects with GGE (Mulley and Dibbens, 2009; Helbig, 2015).

CHILDHOOD AND JUVENILE ABSENCE EPILEPSY The concordance for CAE and for JAE among monozygotic twins significantly exceeds that for dizygotic twins, indicating major genetic contribution to these syndromes (Berkovic et al., 1998; Corey et al., 2011; Vadlamudi et al., 2014). For example, concordance rate for CAE in monozygotic twin pairs is 70–85% (Crunelli and Leresche, 2002). CAE typically begins between the ages of 4 and 8 years. The characteristic ictal EEG pattern is 3-Hz monomorphic, high-voltage spike-and-wave discharges with a normal interictal background. Absence seizures are characterized by behavioral arrest, automatisms, and brief or lack of a postictal phase, and are often provoked by hyperventilation. In subjects with CAE, generalized tonic-clonic seizures are very frequent (40–60%) (Loiseau et al., 1995). Seventy percent of CAE patients experience seizure remission during adolescence. GABRG2 mutations and GABRB3 have been associated with CAE (Feucht et al., 1999; Wallace, 2001).

Table 30.7 Representative genetic generalized epilepsy syndromes Syndrome

Causative gene or chromosome locus

Glut1 deficiency syndrome, infantile onset (606777) Juvenile myoclonic epilepsy, type 1 (254770) Juvenile myoclonic epilepsy, type 5 (611136) Juvenile absence epilepsy, type 1 (607631) Juvenile absence epilepsy, type 2 (607628) Juvenile myoclonic epilepsy, type 6 (607682) Juvenile myoclonic epilepsy, type 2 (604827) Juvenile myoclonic epilepsy, type 3 (608816) Juvenile myoclonic epilepsy, type 4 (611364) Juvenile myoclonic epilepsy, type 9 (614280) Childhood absence epilepsy, type 1 (600131) Childhood absence epilepsy, type 2 (607681) Childhood absence epilepsy, type 4 (611136) Childhood absence epilepsy, type 5 (612269) Childhood absence epilepsy, type 6 (611942) Genetic generalized epilepsies (childhood absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy)

SLC2A1 (138140) EFHC1 (608815) GABRA1 (137160) EFHC1 (608815) CLCN2 (600570) CACNB4 (601949), one subject reported 15q14 locus 6p21 locus 5q12-q14 locus 2q33-q36 locus 8q24 locus GABRG2 (137164) GABRA1 (137160), one subject reported GABRB3 (137192) CACNA1H (607904), one subject reported Numerous copy number variants, including deletions on chromosomes15q11.2, 15q13.3, and 16p13.11

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JAE begins between 10 and 17 years. Although absence seizure semiology is similar to CAE, JAE subjects have fewer absence seizures and a higher incidence of generalized tonic-clonic seizures. Like CAE, the characteristic ictal EEG pattern is 3–4 Hz monomorphic, high-voltage spike-and-wave discharges. Despite twin studies indicating major genetic influence in JAE (Berkovic et al., 1998; Corey et al., 2011; Vadlamudi et al., 2014), only a few specific gene mutations have been identified. Sander43 found evidence that variants in GRIK1 contribute to JAE. Reported association of CLCN2 mutation was retracted (Haug et al., 2003) and not confirmed (Niemeyer et al., 2010).

JUVENILE MYOCLONIC EPILEPSY JME typically begins in adolescence. Symptoms include early-morning myoclonic jerks, generalized tonic-clonic seizures, and occasionally absence seizures. Interictal pattern typically is 4–6-Hz polyspike-and-wave discharges. Photoparoxysmal response occurs in 30–50% of subjects (Lu et al., 2008). In total, 3–9% of JME patients have EFHC1 mutation (Cossette et al., 2002; Suzuki et al., 2004; Medina et al., 2008). Other genes implicated in JME include GABRA1, CACNB4, GABRD, and CLCN2. Gene mutation-specific therapy has not yet been identified for JME. The overall good prognosis for JME (with anticonvulsants, 60–90% of subjects becoming seizurefree) sharply contrasts with that of PME, in which myoclonic seizures become associated with tonic-clonic seizures and progressive neurologic deterioration with ataxia and dementia (Shahwan et al., 2005).

Familial focal epilepsies Familial focal epilepsies account for 60% of all chronic seizure disorders. Clinical presentations are variable and

include childhood epilepsy syndromes such as benign epilepsy with centrotemporal spikes (BECTS), earlyonset childhood occipital epilepsy with predominant autonomic disturbance (Panayiotopoulous syndrome: Covanis, 2006), as well as familial focal epilepsies more often identified in adults (e.g., autosomal-dominant nocturnal frontal-lobe epilepsy and autosomal-dominant partial epilepsy with auditory features). Subjects with these familial focal epilepsy syndromes usually have normal development (Wirrell, 2016), although seizure onset may be preceded by speech disorder, reading disability, and attention impairment (Strug et al., 2009). Interictal EEG is usually normal but occasionally demonstrates focal discharges. A large range of de novo mutations have been implicated in subjects with focal epilepsies, including subjects who do not have family history of similar disorder (Hildebrand et al., 2016). These genes include DEPDC5, KCNT1, and LIS1 (in which mutations are not exclusively associated with focal epilepsy but have also been identified in other seizure syndromes) (Table 30.8).

Familial temporal-lobe epilepsy (TLE) TLE represents the most common adult focal epilepsy (Baulac, 2001, 2014; Skidmore, 2016). Familial TLEs are grouped according to the temporal-lobe region (e.g., mesial or lateral) of seizure onset. Familial mesial TLE is characterized by aura (typically dejà vu, rising epigastric sensation, and autonomic features), and relatively good prognosis. Although genetic linkage studies in several large pedigrees with familial mesial TLE have identified candidate loci (Maurer-Morelli et al., 2012; Chahine et al., 2013; Fanciulli et al., 2014), these loci have not yet been confirmed in other families.

Table 30.8 Representative familial focal epilepsies Syndrome (OMIM#)

Causative gene (gene #)

Epilepsy with speech disorder, with or without mental retardation (245570) Autosomal-dominant nocturnal frontal-lobe epilepsy (ADNFLE) type 1 (600513) Nocturnal frontal-lobe epilepsy type 3 (605375) Nocturnal frontal-lobe epilepsy type 5 (615005) Nocturnal frontal-lobe epilepsy type 4 (610353) Familial focal epilepsy with variable foci (FFEVF) (604364) Familial temporal-lobe epilepsy type 1 (600512) Familial temporal-lobe epilepsy type 5 (614417) Familial temporal-lobe epilepsy type 7 (616436) Familial temporal-lobe epilepsy type 8 (616461) Familial focal epilepsy with variable foci type 1 (604364) Familial focal epilepsy with variable foci type 2 (617116) Familial focal epilepsy with variable foci type 3 (617118)

GRIN2A (138253) CHRNA4 (20q13.33) (118504) CHRNB2 (118507) KCNT1 (608167) CHRNA2 (118502) DEPDC5 (614191) LGH (604619) CPA6 (609562) RELN (600514) GAL (137035) DEPDC5 (614191) NPR2L (607072) NPRL3 (600928)

GENETICS OF EPILEPSY Familial lateral TLE includes autosomal-dominant nocturnal frontal-lobe epilepsy (ADNFLE) and autosomaldominant partial epilepsy with auditory features (ADPEAF). ADNFLE is characterized by clusters of brief, stereotyped motor seizures occurring during sleep that typically begin in the first two decades of life. Seizure semiology varies from simple arousals to complex, hyperkinetic events. EEG recordings demonstrate 8–11-Hz spike-and-wave discharges. Mutation in nicotinic acetylcholine receptor subunits are present in 20% of ADNFLE patients with a family history of this disorder but only rarely (<5%) of patients’ family history (Ottman et al., 2010). Specific mutations in nicotinic acetylcholine receptor complex subunits include CHRNB2 (in 10% of ADNFLE patients), CHRNA2 (less common), and CHRNA4 (rare). ADNFLE-associated mutations also involve genes other than nicotinic actetylcholine receptor subunits, including DEPDC5 (10%), KCNT1 (<5%), and CRH (Kurahashi and Hirose, 2015). In general, KCNT1 pathogenic variants are associated with more severe phenotypes, younger age of onset, higher genetic penetrance, and cognitive impairment (Heron et al., 2012). Although carbamazepine is particularly effective in ADNFLE, subjects with one specific CHRNA4 mutation, p.Ser284Leu, respond better to zonisamide than carbamazepine (Karahashi and Hirose, 2002). There are several reports of improved seizure frequency with nicotine administration (Willoughby et al., 2003; Pavlakis and Douglass, 2015). ADPEAF is characterized by auditory symptoms or receptive aphasia occurring during seizures. LGI1 gene mutations have been identified in 50% of ADPEAF families (Ottman et al., 2010). RELN gene mutation has been identified in seven ADPEAF families (Dazzo and Douglass, 2015). De novo mutations of either RELN or LGl1 resulting in ADPEAF are infrequent. Treatment for ADPEAF is empiric and not yet influenced by results of gene evaluation.

Focal epilepsy with speech disorder Focal epilepsy with speech disorder, variably accompanied by intellectual disability, occurs in diverse syndromes, including BECTS and Landau–Kleffner syndrome. BECTS, also known as rolandic epilepsy because seizures localize to the rolandic (central) gyrus with characteristic interictal centrotemporal sharp waves, is the most common idiopathic epilepsy syndrome in childhood (Neubauer et al., 1998). As reviewed by Strug et al. (2009), disturbance of speech, reading, or attention often begins before seizures manifest. BECTS seizure semiology typically includes vocalizations, sensory and motor symptoms

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involving the face and mouth, and speech arrest. Seizures in BECTS syndrome typically resolve in adolescence. Dimassi et al. (2014) demonstrated frequent CNVs in patients with BECTS, including those in the location of GRIN2A. Association of ELP4 mutations with BECTS is controversial (Strug et al., 2009). Landau–Kleffner syndrome manifests as childhoodonset epileptic aphasia. Interictal EEG demonstrates temporoparietal-occipital discharges with marked spread and potentiation of epileptiform activity during nonrapid eye movement sleep. Continuous, 1.5–2.5-Hz spike-andwave activity of slow-wave sleep (CSWS), also called electric status epilepticus of slow sleep, may be part of the Landau–Kleffner syndrome spectrum. CSWS occurs only in children and adolescents and is characterized by neuropsychologic regression ranging from new-onset school difficulty to dementia. GRIN2A mutations are a major genetic determinant of Landau–Kleffner syndrome and CSWS, found in up to 20% of subjects (Lesca et al., 2013). CHRNA7, PCYT1B, and DOK5 gene mutations have also been identified in subjects with CSWS (Sanchez-Ferrero et al., 2013).

Progressive myoclonic epilepsies Myoclonus – brief jerks involving an entire muscle or group of muscles that may be focal, segmental, or generalized, when accompanied by epileptiform discharges – is termed myoclonic seizure. Electrographically, myoclonic seizures manifest as bursts of generalized fast activity lasting 10–100 ms, often preceded by an epileptiform discharge. The PMEs are rare, and characterized not simply by myoclonic seizures but also by tonicclonic or other seizures, as well as by other neurologic impairments such as dementia and ataxia. Progression and severity of PME vary from moderately progressive to rapidly progressive and fatal. PMEs are typically inherited as autosomal-recessive disorders. Exceptions to this include dentatorubralpallido-luysian atrophy (autosomal-dominant) and mitochondrial encephalomyopathy with ragged-red fibers (MERRF, which may be maternally transmitted). Unverricht–Lundborg disease is an autosomalrecessive disorder due to mutations in cystatin B (CSTB) (Lalioti et al., 1997). Unverricht–Lundborg disease is characterized by severe, stimulus-sensitive myoclonic epilepsy, often associated with progressive encephalopathy that may include generalized tonicclonic and absence seizures, ataxia, tremor, and dysarthria. Symptoms typically begin between 6 and 13 years of age and progress slowly over 10–20 years (DelgadoEscueta et al., 2001). Unverricht–Lundborg disease differs from other PMEs in that the symptoms often stabilize

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in early adulthood, following which there is minimal to no further cognitive decline despite continuation of often severe myoclonus, ataxia, and epilepsy (Ramachandran et al., 2009; Malek et al., 2015). Electrographic findings are similar to those seen in GGE with 3–5-Hz spike-andwave discharges. Background activity deteriorates over time. Autosomal-recessive mutations in CSTB are causative (greater than 90% of the time) (Ramachandran et al., 2009) in this monogenetic disorder (Lalioti et al., 1997).

Lafora disease Lafora disease (Corcia et al., 2014) is an autosomalrecessive polyglucosan storage disorder due to mutations in either EPM2A or NHLRC1 genes (Chan et al., 2003; Ganesh et al., 2006). EPM2A and NHLRC1 (also known as EPM2B) physically interact and participate in the regulation of glycogen synthesis (Solaz-Fuster et al., 2008) Lafora bodies, accumulations of poorly branched, insoluble, glycogen-like carbohydrates (polyglucosans) (Corcia et al., 2014) are found in brain, hepatocytes, sweat glands, and other tissues (Turnbull et al., 2016). Lafora disease is characterized by adolescentonset, stimulus-sensitive myoclonus, generalized tonic-clonic seizures, and progressive neurologic deterioration. Progression is often more rapid than in Unverricht–Lundborg disease, with death often occurring by 10 years after epilepsy onset (DelgadoEscueta et al., 2001). EEG initially shows normal background with generalized bursts of spikes and polyspikes that become increasingly disorganized as the disease progresses.

Other progressive myoclonic epilepsies A number of inherited metabolic disorders are associated with PME include Gaucher disease type III, sialidosis type 1, and MERRF. Other PME-implicated genes include KCNC1 (Muona et al., 2015) and PRICKLE1, P (Bassuk et al., 2008).

Benign familial neonatal and infantile epilepsy Relative to many other seizure disorders, these syndromes are considered “benign” because neurodevelopment is normal and seizures usually remit after weeks or months. Seizure semiology includes focal onset that may become generalized. Benign familial neonatal and infantile epilepsies differ in age of onset and genetic etiology. These syndromes are typically inherited as autosomal-dominant traits with a high genetic penetrance (Deprez et al., 2009) (Table 30.10).

BENIGN FAMILIAL NEONATAL EPILEPSY (BFNE) BFNE typically manifests on postnatal days two or three with clonic or apneic seizures. Although seizures usually remit by 12 months of age, 14% of subjects later develop epilepsy. KCNQ2 mutations are found in 50% of families with BFNE (Singh et al., 1998; Ottman et al., 2010). Mutations in this gene are associated not only with BFNE but also with severe neonatal epilepsy syndromes (Weckhuysen et al., 2012). Mutations in KCNQ3 (Charlier et al., 1998) have been identified in 6% of BFNE patients (Grinton et al., 2015).

Neuronal ceroid lipofuscinoses Neuronal ceroid lipofuscinoses are a group of clinically and genetically heterogeneous, heredito-degenerative neurologic disorders that share the neuropathologic features of nerve cell loss, particularly in cerebral cortex and cerebellar cortex and accumulation of lipopigments (lipofuscin) that have characteristic ultrastructural appearance (curvilinear, fingerprint pattern, granular pattern) (Radke et al., 2015). Myoclonic and other seizure types occur. Developmental delay, dementia, and visual impairment (particularly in childhood-onset forms) are variably associated with specific neuronal ceroid lipofuscinosis syndromes. There are 14 forms of neuronal ceroid lipofuscinosis classified according to age of symptom onset and causative gene mutation (Geraets et al., 2016) (Table 30.9). Ongoing studies are investigating gene therapy in neuronal ceroid lipofuscinosis (Worgall et al., 2008).

BENIGN FAMILIAL INFANTILE EPILEPSY (BFIE) BFIE is characterized by onset of seizures not associated with fever between 3 and 24 months of age. Psychomotor development is normal and seizures often remit by 2 years of age. Seizures often respond well to treatment with a sodium channel blocker. Mutations in PRRTZ, SCN8A, CHRNA2, and SNC2A genes have been identified in BFIE subjects. There is a loose correlation of age of symptom onset with particular gene mutations insofar as subjects with KCNQ2 and KCNQ3 tend to have earlier symptom onset (days two or three) than subjects with PRRTZ, SCN2A, SCN8A, or CHRNA2 mutations. PRRTZ mutation is the most common cause of BFIE (80% of subjects). Some patients with SC8Arelated BFIE-5 develop paroxysmal kinesiogenic dyskinesia in puberty (Gardella et al., 2016).

Table 30.9 Representative progressive myoclonic epilepsies Age of symptom onset

Birth

Infancy

Late infancy

Childhood and teenage

Adult

Vision impairment*

Epilepsya

Progressive motor and cognitive impairment

+

+

+

–

+

+

+

+

+ (not in adult forms) +

+

Classic infantile, Haltia–Santavuori

+

Eponyms and comments

Syndrome

Gene

Neuronal ceroid lipofuscinosis (CLN)10 (610127) CLN1 (256730)

CTSD (116840)

PPT1 (600722)

+

+

CLN14 (61172)

KCTD7 (611725)

+

+

+ (not in adult forms) –

CLN8 (600143)

CLN8 (607837)

+

+

+

+

CLN2 (204500) CLN5 (256731) CLN6 (601780) CLN7 (610951) Unverricht– Lundborg, progressive myoclonic epilepsy 1 (254800) Lafora disease, Progressive myoclonic epilepsy 2A (254780) CLN3 (204200)

TPP1 (607998) CLN5 (608102) CLN6 (602780) MFSD8 (611124) CSTB (601145)

+ + + +

+

+ + + +

+ + + +

+ + + +

Infantile onset of progressive myoclonic epilepsy (EPM3) Epilepsy-progressive, mental retardation (EPMR), late-infantile variant Late-infantile, Janský–Bielschowsky Late-infantile, Finnish variant Early-juvenile / late-infantile, Late-infantile variant

+

–

+

+

Ataxia, tremor, dysarthria, dementia

NHLRC1 608072), EPM2A (607566)

+

–

+

+

Dementia, typically fatal within 10 years

CLN3 (607042)

+

+

+

+

CLN12 (606693)

ATP13A2 (610513)

+

–

Variable

+

Microcephaly +

+ +

+ +

+

Batten, Vogt–Spielmeyer, Spielmeyer–Sjogren Mutations in this gene also cause Kufor–Rakeb syndrome and juvenile parkinsonism Continued

Table 30.9 Continued Age of symptom onset

Adult

Vision impairment*

Epilepsya

Progressive motor and cognitive impairment

CLN6 (606725)

+

–

+

+

GRN (138945) CTSF (603539)

+ +

+

+ +

+ +

+

+

Syndrome

Gene

CLNA4 (204300)

CLN11 (614706) CLN13 (615362)

Birth

Infancy

Late infancy

Childhood and teenage

– CLNA4B (162350)

DNAJC5 (611203)

+

Modified from Mole and Williams (1993, 2011); Mole et al. (2005); Malek et al. (2015); Nita et al. (2016). a Frequently or constantly present

–

Eponyms and comments Adult-onset, Kuf’s type A; CLN6 gene mutations also cause early-juvenile/ late-infantile neuronal ceroid lipofuscinosis (with vision impairment) Kufs type B: dementia with cerebellar and/or extrapyramidal motor symptoms

GENETICS OF EPILEPSY Table 30.10 Representative benign neonatal and infantile epilepsies Age of symptom onset Postnatal day 2 or 3 Postnatal day 2 to 7 months 3–24 months

Associated genes KCNQ2 (602235) KCNQ3 (602232) SCN2A (182390) PRRT2 (614386) (80% of subjects); also SCN2A (182390), SCN8A (600702), CHRNA2 (118502)

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signaling, and intracellular calcium hemostasis) and consequent central nervous system structural changes (subacute necrosis (stroke-like episodes) and leukodystrophy) (Feissner et al., 2009; Steele and Chinery, 2015; Kadlec et al., 2016). Epilepsy is a common feature of mitochondrial disorders, occurring in 40% of subjects (Finsterer and Zarrouk Mahjoub, 2013; Steele and Chinery, 2015). Seizure semiology is variable (see review by Steele and Chinery, 2015), although myoclonic epilepsy is the most common form of epilepsy in patients with mitochondrial disorders. Mitochondrial disorders associated with epilepsy are numerous, varied, and clinically overlapping; they include MERRF, mitochondrial encephalomyopathy

Table 30.11 Representative mitochondrial disorders associated with epilepsy Syndrome

Causative gene (OMIM#)

MERRF (545000)

Multiple nuclear and mitochondrial genes, including MTTK gene (590060) Multiple nuclear or mitochondrial genes; most common mutation is mitochondrial MTTL1 gene (590050) Multiple nuclear and mitochondrial genes (>75), particularly SURF1, PDHA1 mitochondrial ATP synthase (mt DNA nt8993), COX1 POLG (174763)

MELAS (540000) LS (256000) POLG syndromes, including MEMSA, SCAE (607459), and Alpers–Huttenlocher (203700)

LS, Leigh syndrome; MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke; MEMSA, myoclonic epilepsy myopathy sensory ataxia; MERRF, mitochondrial encephalomyopathy with ragged-red fibers; POLG, polynmerase-gamma; SCAE, spinocerebellar ataxia with epilepsy.

EPILEPSY RELATED TO MITOCHONDRIAL DISORDER Genetic disorders affecting mitochondria include those due to mutation in a gene on the mitochondrial circular chromosome and those due to mutation in a nuclear gene (autosome) affecting mitochondrial function. Disorders due to mitochondrial gene mutation exhibit maternal transmission (i.e. transmitted from mothers to sons (who do not transmit the disorder) and to daughters (who may transmit the disorder)). The nature and severity of symptoms for disorders due to mitochondrial gene mutations are often quite variable between individuals (even for precisely the same gene mutation), owing in part to variable proportions of normal and mutationcontaining mitochondria occurring in each tissue (mitochondrial heteroplasmy) (Table 30.11). Pathologic mechanisms by which mitochondrial disorders cause seizures and other neurologic disturbances are quite variable, depending on the specific gene mutation, and are associated with biochemical disturbances (impaired oxidative phosphorylation, intracellular

with lactic acidosis and stroke (MELAS), neuropathy ataxia retinitis pigmentosis, Alpers–Huttenlocher syndrome, chronic progressive ophthalmoplegia, Kearns– Sayre syndrome, and maternally inherited diabetes and deafness. With the exception of Alpers–Huttenlocher syndrome (due to POLG1 mutation), each syndrome is genetically heterogeneous. Consistent with most of the disorders discussed in this chapter, although certain gene mutations are more frequently associated with one syndrome than another, a given gene mutation may cause more than one syndrome. For these reasons, when evaluating epilepsy patients for potential mitochondrial disorders, it is generally prudent to test a panel of mitochondrial genes (i.e., mitochondrial genome sequencing, including mitochondrial gene deletion and panels of nuclear-encoded mitochondrial proteins) rather than testing specific mitochondrial syndrome-associated genes.

Leigh syndrome Leigh syndrome (subacute necrotizing encephalomyelopathy) typically begins in infancy, although it may

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begin in childhood through adulthood (Steele and Chinery, 2015). Diagnosis is made by the occurrence of neurodegeneration (which initially may be stepwise in progression), accompanied by typical neuroimaging findings (Bonfante et al., 2016) (bilaterally symmetric T2-intense foci in brainstem, basal ganglia, subthalamic nuclei, thalami, cerebellum, and spinal cord but sparing mammillary bodies), and supported by elevated lactate and pyruvate in serum and CSF (Chinnery, 1993). Seizures are common in Leigh syndrome patients and occasionally may be the only feature (Tsao et al., 2001; Finsterer and Zarrouk Mahjoub, 2013). Seizure type is usually generalized, tonic-clonic, although may include focal seizures and infantile spasms (Steele and Chinery, 2015). Leigh syndrome is genetically heterogeneous and associated with >75 genes (Lake et al., 2016). These include autosomal, X-linked (i.e., pyruvate dehydrogenase E1 alpha, PDHA1), and mitochondrial genes (e.g., nt8993) (Santorelli et al., 1993) and, therefore, depending on the particular gene mutated, Leigh syndrome may be transmitted as an autosomal-recessive, X-linked, or maternal trait (DiMauro and De Vlaeminck, 1996). Leigh syndrome-associated gene mutations may disturb any mitochondrial enzyme complex (I through V). Among these, disturbance in cytochrome C oxidase (complex IV) is common, either due to mutations in the nuclearencoded COX1 gene or more commonly to SURF1 gene mutation, which participates in cytochrome C oxidase assembly (Pequignot et al., 2001).

Mitochondrial encephalomyopathy with lactic acidosis and stroke MELAS is characterized by infantile onset (although it may begin in childhood through adulthood) (Steele and Chinery, 2015) of multiple stroke-like events leading to neurodegeneration, associated with hypotonia, lactic acidosis, and seizures. Seizure semiology is variable, with both focal seizures (including focal status epilepticus) (Karkare et al., 2009; Demarest et al., 2014; Steele and Chinery, 2015) and less commonly, primary generalized seizures reported. Gerards et al. (2016) found dramatic encephalopathy improvement in 3 SLC19A3 patients given thiamine supplementation, with 1 patient showing complete clinical and radiographic recovery (OrtigozaEscobar et al., 2014). Similar treatment in older patients did not lead to improvement. Response to thiamine supplementation has been reported in patients with PDHA1- and TPK1-related Leigh syndrome (Brown, 2014; Gerards et al., 2016). MELAS is genetically heterogeneous and due to mutation in a mitochondrial or nuclear genes (transmitted as maternal or autosomal-recessive trait, respectively). Mutation in the mitochondrial MTTL1 gene (Steele and

Chinery, 2015) (specifically, mt.3243A > G) is the most common cause of MELAS.

Myoclonic epilepsy with ragged-red fibers MERRF is characterized by refractory myoclonic and generalized seizures, ataxia, and neurocognitive degeneration. EEG findings include generalized spike-andwave discharges. MERRF is genetically heterogeneous. The most frequent MERRF-associated mutation is in the mitochondrial DNA MTTK gene.

Mitochondrial DNA polymerase gamma (POLG)-related syndromes Mutations in the mitochondrial POLG gene are associated with diverse epilepsy syndromes, including myoclonic epilepsy myopathy sensory ataxia, spinocerebellar ataxia with epilepsy, and Alpers–Huttenlocher syndrome (progressive neurocognitive degeneration, liver dysfunction, and intractable seizures). POLG-related epilepsy may be suggested by occipital symptom predominance and asymmetric occipital-lobe epileptic discharges. POLG mutations (e.g., pQ1236H) have also been associated with valproate-induced hepatotoxicity (Stewart et al., 2010).

EPILEPSY DUE TO INHERITED DISTURBANCE OF CORTICAL AND SUBCORTICAL DEVELOPMENT Epilepsy is a typical feature of disorders affecting cerebral cortical development. These disorders include lissencephaly spectrum disorders, focal cortical dysplasia (FCD), schizencephaly spectrum disorders, hamartomas (e.g., tuberous sclerosis), and cerebral cavernomas. Each of these syndromes is genetically heterogeneous and diagnosed by a combination of clinical findings and neuroimaging.

Focal cortical dysplasia FCD involves abnormal neuron proliferation in periventricular germinal zones; abnormal cell-guided migration of neurons to cortical layers; or abnormal neuron differentiation and synaptic organization in cortical laminae (Siedlecka et al., 2016). FCD is usually (77–90% of subjects) associated with epilepsy, although FCD also occurs in low frequency (1.7%) in normal subjects (Mencke and Veith, 1992; Raymond et al., 1995; Bingaman, 2004). Diverse causes of FCD include prenatal infections (e.g., TORCH organisms: toxoplasmosis, syphilis, varicella-zoster, parvovirus B19, rubella, cytomegalovirus, herpesvirus). Detection of human papillomavirus 16 oncoprotein E6 FCD in surgically resected samples is intriguing, though controversial, because it was not

GENETICS OF EPILEPSY confirmed in some studies (Coras et al., 2015; Crino, 2015; Shapiro et al., 2015). FCD has been associated with mutations in mechanistic target of rapamycin (mTOR), an important element in signal transduction pathway important in brain development (Jansen et al., 2015; Citraro et al., 2016; Weckhuysen et al., 2016). For example, mosaic, activating mutations in PIK3CA and AKT3 were identified in surgically resected cortical samples not only from subjects with FCD but also from subjects with megalencephaly and hemimegalencephaly (Jansen et al., 2015). There is also evidence that the tuberous sclerosis (TSC1) gene may contribute to FCD: (1) TSC1 genetic polymorphisms are associated with FCD; (2) loss of TSC1 heterozygosity has been demonstrated in FCD; and (3) TSC1 interacts with tuberin, a negative regulator of mTOR pathway, which, as discussed above, is implicated in FCD (Siedlecka et al., 2016). These findings implicate the PI3K/AKT/mTOR signaling pathway in diverse brain development disorders associated with epilepsy, including megalencephaly, hemimegalencephaly, FCD, and tuberous sclerosis. A recent study with everolimus, a rapamycin analog and mTOR inhibitor, in patients with tuberous sclerosis showed that 12 of 20 subjects had at least 50% seizure reduction (Krueger et al., 2016).

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Lissencephaly spectrum disorders Refractory epilepsy and intellectual disability are typical features of lissencephaly spectrum disorders, a group of conditions characterized by reduced or abnormal patterns of gyral and sulcal development. Lissencephaly spectrum disorders include isolated lissencephaly sequence disorder, agyria (absence of gyri), pachygyria (a few broad gyri), subcortical band heterotopia (arrested migration of cortical neurons), microlissencephaly, and cobblestone cortical malformations (Spalice et al., 2009; Pavone et al., 2010; Kato and Dobyns, 2003). Chromosome 17p13.3 deletions cause Miller– Dieker syndrome, in which lissencephaly is associated with dysmorphic facies and dysmorphic male genitalia. This finding led to discovery that deletion (haploinsufficiency) of LIS1 and YWHAE underlie Miller–Dieker syndrome (Wynshaw-Boris, 2007) and that mutations and intragenic deletions of LIS1 cause isolated lissencephaly sequence disorder (Wynshaw-Boris, 2007; Pavone et al., 2010). Among genes associated with lissencephaly spectrum disorders (Table 30.12, reviewed in Wynshaw-Boris, 2007; Pavone et al., 2010), mutations in ARX are also associated with infantile spasms in the absence of lissencephaly.

Table 30.12 Representative genetic causes of cortical malformations associated with epilepsy Syndrome

Causative genes (OMIM#)

Comment

Lissencephaly spectrum, including subcortical band heterotopia

Chromosome 17p13.3 deletions involving LIS1 and YWHAE PAFAH1B1 (602508) DCX (300121)

Miller–Dieker syndrome (247200)

TUBA1A (602529) RELN (600514) VLDLR (192977)

Focal cortical dysplasia

ARX (300382) LAMB1 (150240) POMT1 (607423), POMT2 (607439), FKTN (607440), FKRP (606596), LARGE (603590) GPR56 (604110) ACTG1 (102560) EML1 (602033) PIK3CA (171834) AKT3 (611223) DEPDC5 (604364), NPRL2 (607072), NPRL3 (600928) TSC1 (605284)

Lissencephaly (LS)1 (607432) X-linked lissencephaly (LS1), subcortical band heterotopia (300067) Lissencephaly-3 (611603) Lissencephaly-2 (257320) Associated with cataracts, brainstem, and cerebellar hypoplasia (224050) X-linked lissencephaly-2 (300215) Lissencephaly-5 (615191) Cobblestone cortical malformation (e.g., Walker–Warburg syndrome (236670) and Fukuyama congenital muscular dystrophy (253800))

Polymicrogyria (606854, 615752) Pachygyria (e.g., Barraitser–Winter syndrome) (243310) Subcortical band heterotopia mTOR pathway mTOR pathway Elements of GATOR complex involved in the inhibition of mTOR Interacts with PIK3CA/AKT3 Continued

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Table 30.12 Continued Syndrome

Causative genes (OMIM#)

Comment

Tuberous sclerosis Schizencephaly spectrum

TSC1 (605284) EMX2 (600035) COL4A1 (120130) SIX3 (603714) SHH (600725) Col4A1(120130) Chromosome abnormalities

Interacts with PIK3CA/AKT3

Holoprosencephaly spectrum

Vascular malformations

HPE2 (157170) HPE3 (142945) HPE4 (142946) HPE5 (609637) HPE7 (610828) HPE9 (610829) HPE11 (614226) SHH (600725) ZIC2 (603073) SIX3 (603714) TGIF (602630) PTCH1 (601309) GLI2 (165230) TDGF1 (187395) KRIT1(604214) C7ORF 22 (607929) PDCD10 (609118) ACTA2 (102620) GUCY1A3 (139396)

Autosomal-dominant porencephaly e.g., Tris. 13, chromosome 13q deletion, CMA-detectable rearrangements

Famililal CCM1 Familial cerebral cavernoma CCM2 Familial cerebral cavernoma CCM3 Familial moya moya disease Familial moya moya disease

CMA, chromosome microarray analysis.

Schizencephaly is characterized by a full-thickness, gray-matter-lined cleft within the cerebral hemispheres, most commonly involving the parasylvian region. Schizencephaly is generally attributed to hypoxic-ischemic injury during fetal brain development, rather than a developmental disturbance in cerebral cortical development or neuron maturation per se. The spectrum of neurologic consequences in schizencephaly ranges from no neurologic sequelae to seizures, encephalopathy, and motor impairment. EMX2 mutations had been proposed to contribute to schizencephaly (Brunelli et al., 1996) though this observation was subsequently not confirmed (Merello et al., 2008). Type IV collagen gene (COL4A1) mutations have been identified in schizencephaly and also in hereditary porencephaly and intracerebral hemorrhage (Gould et al., 2005; Breedveld et al., 2006; Hehr et al., 2010; Yoneda et al., 2013), indicating that shared molecular mechanisms contributing to vascular disturbance may underlie these developmental abnormalities. Mutations in SIX3 and SHH have been implicated in both schizencephaly

and holoprosencephaly (HPE) (discussed below) (Hehr et al., 2010).

Holoprosencephaly Normally, between embryonic days 18 and 28, the developing forebrain (prosencephalon) divides into right and left hemispheres. Varying degrees of incomplete division result in HPE spectrum disorders (alobar, semilobar, lobar, and middle interhemispheric forms) (Golden, 1999; Dubourg et al., 2016; Kaliaperumal et al., 2016). As a regional or “developmental field” defect, varying degrees of orofacial dysmorphism typically accompany HPE spectrum disorders. In addition, there may be extracraniofacial malformations of the heart, viscera, kidneys, limbs, and/or genitalia (Mercier et al., 2011). Nongenetic factors contributing to HPE spectrum disorders include prenatal infection with TORCH organisms, maternal diabetes, retinoic acid, and fetal alcohol exposure (reviewed in Croen et al., 1996; Johnson and Rasmussen, 2010). Chromosome abnormalities are

GENETICS OF EPILEPSY 487 common (Croen et al., 1996) in HPE spectrum disorders. extent to which these pathways converge into a limited In one series of 39 karyotyped HPE subjects number of final common biochemical processes is not (Kaliaperumal et al., 2016), 20 (51%) had normal karyoknown. Molecular pathway sharing or pathway convertype, 14 (33%) had trisomy 13, 2 (5%) had 13q deletion, gence would permit targeting therapeutics to molecular and 1 patient each had trisomy 18, trisomy 2p, 6q delemechanisms that would be useful in treating multiple tion, and triploidy. HPE spectrum disorder has been assoseizure types. ciated with mutations in seven genes: HPE, SHH The identification of epilepsy-associated gene muta(important in ventral neural tube differentiation), ZIC2, tions provides insight not only into the physiology underSIX3, TGIF, PTCH1, GLI2, and TDGF1. Mercier et al. lying these paroxysmal events, but also into frequently (2011) evaluated SHH, ZIC2, SIX3 and TGIF , GLI2 accompanying comorbid syndrome features (e.g., cogniin a large series (645 probands) and 25.8%. A further tive deficits). On the one hand, the “nonparoxysmal” 22% of 260 patients screened by chromosome microardisorders (e.g., cognitive or motor impairment) could ray had evidence of chromosome rearrangements. Conreflect the primary consequences of epilepsy gene abnorsistent with previous studies, Mercier et al. (2011) also mality affecting cellular function and synapse structure noted that some disturbance in more than one gene (polyin brain regions in addition to those directly mediating genic causation) may have contributed to HPE. For examthe seizure. Alternatively, such impairments could be ple, they noted seven subjects to have both a chromosome secondary to (i.e., the developmental consequence of) rearrangement as well as a mutation in SHH, ZIC2, or clinical and nonclinical seizures and their impact on corSIX3, and one subject to have both ZIC2 deletion and tical physiology, including cerebral metabolism and GLI2 mutation. microvascular regulation. Increasingly, for individuals and their family, identifying a gene mutation as the likely cause of a chronic seiCONCLUSIONS zure disorder brings closure to the typically frustrating Increasing identification of the gene variations associsearch for underlying diagnosis, informs genetic counated with epilepsy is changing the way epilepsy is classeling, may suggest a range of clinical symptoms and sified and underlying causes diagnosed. Molecular prognosis, and sometimes influences therapy. Nonethegenetic classifications are adding precision and laboraless, improvements in genetic testing have not dimintory confirmation to clinical or syndromic diagnoses. ished the importance of clinical diagnosis and Increasingly, “genetically determined” is replacing thorough characterization of the often extended syn“idiopathic” as the cause of chronic seizure disorders. drome elements. In general, interpreting the signifiUnderstanding the molecular basis facilitates rational cance of gene variations often relies on the precision treatment development and gene- and pathway-specific of clinical (syndromic) diagnosis. Interpreting genetic clinical trials. In addition, the discovery that different test results is most straightforward when the patient’s mutations in the same gene can cause multiple seizure clinical diagnosis conforms with those reported in subtypes (genotype–phenotype correlation) highlights the jects who have mutations in the same gene. Even with role of the encoded protein’s specific functional in silico analysis suggesting the mutation alters protein domains (variably disturbed by different mutations) structure or function, the potential pathogenic signifiand the contribution of the degree of residual protein cance is less certain when: (1) subjects have a different activity on the extent and tissue-specificity of pathogensyndrome than previously associated with the mutant esis. Furthermore, the finding that subjects who share gene; (2) there has been no precedent for mutations the identical gene mutation can have quite different synin this gene to be associated with neurologic disease; dromes indicates the important contribution of modifyand (3) the mutation exists as a low-frequency variant ing genes and potentially environmental factors in in normal subjects. With these caveats, it is generally determining the epilepsy syndrome. prudent to limit clinical decision making, including Major advances in understanding epilepsy genetics declarative counseling and prognosis statements, to notwithstanding, there are major challenges. Despite those mutations that have established pathogenicity. identification of pathogenic gene mutations for more The major impact of exomic (transcribed sequence than 100 epileptic syndromes, the cause of epilepsy analysis) and genomic (gene CNV) advances on the abilfor a majority of patients remains unknown. With few ity to diagnose epilepsy and understand its pathogenesis exceptions (e.g., Dravet syndrome), most of the is only the beginning. Increased investigation of multiple epilepsy-associated gene mutations have each been gene interactions, gene expression (transcriptome) analdescribed in only a limited number of subjects. While ysis, and identification and analysis of modifying genes identification of 200 epilepsy-associated gene mutapromise further advances in our ability to understand, tions implicates numerous molecular pathways, the treat, and prevent seizure disorders.

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