The book chapters cover different aspects of epilepsy genetics, starting with the 'classical' concept of epilepsies as ion channel disorders. The second part of the book gives credit to the fact that by now non-ion channel genes are recognized as equally important causes of epilepsy. The concluding chapters are designed to offer the reader insight into current methods in epilepsy research. Each chapter is self-contained and deals with a selected topic of interest.
- Authors are the leading experts in the field of epilepsy research
- Book covers the most important aspects of epilepsy
- Interesting for both scientists and clinicians
The book chapters cover different aspects of epilepsy genetics, starting with the "e;classical"e; concept of epilepsies as ion channel disorders. The second part of the book gives credit to the fact that by now non-ion channel genes are recognized as equally important causes of epilepsy. The concluding chapters are designed to offer the reader insight into current methods in epilepsy research. Each chapter is self-contained and deals with a selected topic of interest. Authors are the leading experts in the field of epilepsy research Book covers the most important aspects of epilepsy Interesting for both scientists and clinicians
Front Cover 1
Genetics of Epilepsy 4
Copyright 5
Contributors 6
Preface 8
Contents 10
Chapter 1: Genetic heterogeneity in familial nocturnal frontal lobe epilepsy 18
1. Introduction 18
2. CHRNA4 and CHRNB2: The ``classical´´ ADNFLE Genes 19
3. The Clinical Spectrum of nAChR-Caused ADNFLE 21
4. CHRNA2: A Rare Cause of Familial NFLE 22
5. Biopharmacological Profiles of nAChR Mutations 23
6. Severe ADNFLE Caused by KCNT1 Mutations 23
7. DEPDC5 as a Cause of Familial Focal Epilepsy 26
8. Conclusions 28
References 28
Chapter 2: Potassium channel genes and benign familial neonatal epilepsy 34
1. Introduction 34
2. Potassium Channels 36
2.1. How Potassium Channels Regulate Neuronal Excitability 37
2.2. Potassium Channels in Epilepsy and Related Disorders 38
2.2.1. Mutations in KV1.1 Cause Episodic Ataxia 38
2.2.2. KCa1.1 Mutation Linked to Paroxysmal Dyskinesia and Epilepsy 39
2.2.3. KV4.2 and Acquired Epilepsy 39
3. Biology of KCNQ2 and KCNQ3 Channels 39
3.1. Meet the KCNQs 39
3.1.1. KCNQ1 40
3.1.2. KCNQ2 and KCNQ3 40
3.1.3. KCNQ4 41
3.1.4. KCNQ5 41
3.2. Structural and Functional Hallmarks of KV7.2/3 Channels 42
3.2.1. What Happens at the C-terminus? 43
3.2.1.1. Assembly of KV7 Channels 43
3.2.1.2. Regulation of the M-current 43
3.2.1.3. Targeting and Localization of KV7.2/7.3 Channels 44
3.3. Expression Pattern of Neuronal KV7 Channels 45
3.4. Insights from the Mouseland 45
3.5. Functional Analysis of Disease-Related Mutations 46
3.6. KCNQ2 and KCNQ3 Channelopathies 47
3.7. KCNQ2/3 Mutations in BFNS 47
3.7.1. Clinical Features and Genetics of BFNS 47
3.7.2. Pathogenic Mechanisms in BFNS 48
3.7.2.1. Mechanisms of Spontaneous Seizure Remission in BFNS 51
3.8. KCNQ2-Related EE 51
3.8.1. Clinical and Genetic Features 52
3.8.2. Pathophysiologic Mechanisms of EE 52
3.9. KCNQ2 Mutations and PNH 54
3.9.1. Clinical Picture and Genetics 54
3.9.2. Mechanisms Underlying PNH 54
4. Antiepileptic Therapies Targeting KV7 Channels 55
4.1. The Novel Anticonvulsant Compound Retigabine Is a KV7 Channel Opener 55
4.1.1. Mapping the RTG Binding Site 56
4.1.2. Other KV7 Openers 57
4.2. Novel Therapies Involving KV Channels 58
4.2.1. KV Channel Gene Therapy 58
4.2.2. Human Cellular Models of Epilepsy 59
5. Conclusions 60
5.1. Five Things We Learned from KCNQ Channels Involved in Epilepsy 60
References 60
Chapter 3: Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy 72
1. GABAA Receptors 73
2. Mutations and Genetic Variations of the GABAA Receptor 75
3. Mutations of the a Subunit 77
3.1. Mutations of GABRA1 77
3.1.1. Mutations in Autosomal Dominant JME 77
3.1.2. Mutations in Genetic (Idiopathic) Generalized Epilepsy 78
3.1.3. Mutations in IS 78
3.2. Mutations of GABRA6 79
3.2.1. Mutations in CAE 79
3.2.2. Animals with Aberrant a Subunits 79
4. Mutations of the ß Subunit 80
4.1. Mutations of GABRB1 80
4.1.1. Mutations in IS 80
4.2. Mutations and Variations of GABRB3 81
4.2.1. Mutations and Variations in CAE 81
4.2.2. Mutations in IS 82
4.2.3. Animals with Aberrant ß Subunits 82
5. Mutations of the . Subunit 83
5.1. Mutations in CAE and FS 83
5.2. Mutations in GEFS+ 87
5.3. Mutations in Dravet Syndrome 88
5.4. Mutations in Idiopathic Genetic Generalized Epilepsy 89
6. Mutations of the d Subunit 90
7. Therapeutic Implications of GABAA Receptor Mutations 91
8. Conclusions 92
Acknowledgment 93
References 93
Chapter 4: The role of calcium channel mutations in human epilepsy 104
1. Introduction 104
2. Calcium Channel Nomenclature and Biophysical Properties 105
3. Calcium Channels in Epilepsy 108
3.1. T-type Calcium Channel Mutations in Epilepsy 108
3.2. P/Q-type Calcium Channel Mutations in Epilepsy 109
3.3. Ancillary Subunits of Voltage-Gated Calcium Channels in Seizure Disorders 111
4. Conclusion 111
References 112
Chapter 5: Mechanisms underlying epilepsies associated with sodium channel mutations 114
1. Introduction 114
2. Voltage-gated Sodium Channels 115
3. Clinical Phenotypes Associated with Voltage-gated Sodium Channel Mutations 117
4. Pathogenetic Mechanisms of Sodium Channel Mutations in Epilepsy 119
5. Conclusions 121
References 122
Chapter 7: Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5 140
1. Autosomal Dominant Focal Epilepsy Syndromes 141
1.1. Familial Temporal Lobe Epilepsy 141
1.2. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy 143
1.3. Familial Focal Epilepsy with Variable Foci 144
2. DEPDC5, A Common Cause for Familial Focal Epilepsies 146
2.1. Whole-Exome Sequencing Identifies a New Gene 146
2.2. DEPDC5 Protein 148
2.3. From Channelopathies to mTORopathies 148
3. Conclusions 149
Acknowledgments 150
References 150
Chapter 8: PRRT2: A major cause of infantile epilepsy and other paroxysmal disorders of childhood 158
1. Introduction 158
2. PRRT2-related Syndromes 159
2.1. PKD 159
2.2. BFIS 160
2.3. ICCA Syndrome 161
2.4. PNKD and PED 161
3. Other Forms of Infantile Seizures 162
3.1. EA 162
4. Familial HM 162
5. Intellectual Disability 163
6. PRRT2 Mutations 163
7. PRRT2 Protein and Function 169
8. Conclusions 170
References 171
Chapter 9: LGI1: From zebrafish to human epilepsy 176
1. Introduction 177
2. The LGI1-Related Epilepsy Syndrome 177
3. The LGI1 Gene 178
4. LGI1 Mutant Null Mice Experience Spontaneous Seizures 180
5. Lgi1 Depletion Causes Seizure-Like Behavior in Zebrafish 181
6. Role for LGI in Synaptic Transmission 182
7. Protein Interactions with LGI1 Define Specific Functions 183
8. LGI1 Auto Antibodies Are Responsible for Limbic Encephalitis 184
9. LGI1 Expression Suggests a Role in Early Development 185
10. Role for LGI1 in Normal Mammalian Brain Development 187
11. Are the Other LGI1 Family Members Responsible for Seizure Phenotypes? 189
12. Summary 190
References 190
Chapter 10: Morphogenesis timing of genetically programmed brain malformations in relation to epilepsy 198
1. Introduction 199
2. Concept of Maturational Arrest, Delay, and Precociousness 199
3. Application of Timing to Epileptogenic FCDs 201
3.1. Developmental Basis of Focal Cortical Dysplasia Type 1 201
4. Timing in Systemic Genetic/metabolic Diseases That Affect Cerebral Development 204
5. Infantile Tauopathies, Microtubules, and Pathogenesis of Dysplasias Involving Cytological Abnormalities of Neurons 205
6. Why Are Cortical Dysplasias Epileptogenic? 208
Acknowledgment 209
References 209
Chapter 11: Remind me again what disease we are studying? A population genetics, genetic analysis, and real data perspective. 216
1. Introduction 217
2. A Review of the Methods Used to Find Epilepsy-Related Genes 218
2.1. Large-Family Approach 218
2.2. Association Analysis 219
2.3. Small-Family Linkage Approach 219
2.4. Comments on the Three Methods 220
2.4.1. Large Dense Family Approach 220
2.4.2. Association Approach 220
2.4.3. Linkage in Many Small-Family Approach 221
3. A Tale of Three Loci 222
3.1. BRD2 222
3.2. ELP4 and Centrotemporal Spikes/Rolandic Epilepsy 223
3.3. JME in Mexicans and EFHC1 224
3.4. What We Learn from the Tale of Three Loci 225
4. What Can Studying CNVs Tell Us about Common Epilepsy? 226
5. Why Rare Mutations Do Not Cause Common Disease 228
6. What the Tale of Three Loci and the Results of CNV Studies Tell Us about Common Epilepsy 230
7. Conclusion 231
Acknowledgments 232
References 232
Chapter 12: Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thala 240
1. Introduction 241
2. Monogenic Mutations of Diverse Genes Converge on the Absence Epilepsy Phenotype 242
3. The Thalamocortical Loop: A Multisynaptic Framework for Interpreting Absence Epilepsy Mutations 246
4. Thalamocortical T-type Calcium Channels: necessary and Sufficient? 246
5. The Role of Tonic Inhibition: A Key to Unlock T-Type Calcium Channels 248
6. P/Q-type Calcium Channels: selective Impairment of Inhibitory Release? 250
7. AMPA Receptor-Related Mutations: Silencing Fast Feedforward Inhibition 253
8. GABAA Receptor Mutations: fast Synaptic Disinhibition 254
9. Feedforward Disinhibition: A Preeminent Role in Absence Epilepsy 255
10. Specificity of ``fast´´ Feedforward Disinhibition in Absence Epilepsy 256
11. Secondary Compensatory Changes with Impaired Feedforward Inhibition 256
12. Pharmacologic Models of Absence Epilepsy Arise from Either Direct Enhancement of Tonic Inhibition or Indirectly via Feedf 257
13. Other Monogenic Models 258
14. Continuing Challenges 259
Acknowledgments 260
References 260
Chapter 13: New technologies in molecular genetics: the impact on epilepsy research 270
1. Genetics Versus Genomics 270
2. Basics Concepts and the Genome in Numbers 272
2.1. Exome-A Technical, not a Philosophical Term 272
2.2. The Genome in Numbers 273
2.3. The Third Beast-Rare Genetic Variants 273
2.4. Microdeletions-The Search for Epilepsy-Associated Variants Goes Genome Wide 274
2.5. Recurrent and Nonrecurrent Microdeletions 275
2.6. Microdeletions from Genomic Disorders to Genome-First 276
2.7. Variant Classification and the Global Burden of Microdeletions in Epilepsy 278
2.8. Genome-Wide Association Studies-The Late Success 279
2.9. Massive Parallel Sequencing Studies 280
2.9.1. Family Studies 281
2.9.2. Panel Studies 282
2.9.3. Trio Studies 283
3. Summary 285
References 286
Chapter 14: Epigenetic mechanisms in epilepsy 296
1. ``Bookmarking´´ the Genome 296
2. Chromatin Structure 297
3. DNA Methylation: strategy for Transcriptional Silencing 297
4. Histone Modifications: determinants of Accessibility 300
5. ncRNAs: no Longer Junk 302
5.1. Small ncRNAs 303
5.2. Long ncRNAs 304
6. Epigenetics in CNS Development and Higher Order Brain Function 305
7. Epigenetics in Idiopathic Generalized Epilepsy and Epileptic Encephalopathies 306
8. Epigenetics in TLE 310
9. Metabolism and the Epigenome 314
10. Balancing the Epigenome: therapeutic Strategies 318
11. Summary 320
References 320
Index 334
Volume in series 344
Genetic heterogeneity in familial nocturnal frontal lobe epilepsy
Ortrud K. Steinlein1 Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University, Munich, Germany
1 Corresponding author: Tel.: (+ 49)89-5160-4468; Fax: (+ 49)89-5160-4470 email address: ortrud.steinlein@med.uni-muenchen.de
Abstract
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first epilepsy in humans that could be linked to specific mutations. It had been initially described as a channelopathy due to the fact that for nearly two decades mutations were exclusively found in subunits of the nicotinic acetylcholine receptor. However, newer findings demonstrate that the molecular pathology of ADNFLE is much more complex insofar as this rare epilepsy can also be caused by genes coding for non-ion channel proteins. It is becoming obvious that the different subtypes of focal epilepsies are not strictly genetically separate entities but that mutations within the same gene might cause a clinical spectrum of different types of focal epilepsies.
Keywords
ADNFLE
nocturnal frontal lobe epilepsy
epileptic encephalopathy
acetylcholine receptor
KCNT1
DEPDC5
1 Introduction
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was first described as a distinct familial partial epilepsy in 1994 (Scheffer et al., 1995). Although rare, it is often referred to not least because of its status as the very first idiopathic epilepsy in humans for which the underlying genetic cause had been identified (Steinlein et al., 1995). This was achieved at a time when molecular genetics was still a rather new field, 300,000-marker genome-wide association studies unheard of, and high-throughput sequencing a vision rather than daily routine. Genotyping of only about 200 polymorphic markers led to the identification of a strong candidate locus for ADNFLE on the tip of the long arm of chromosome 20 in a large Australian family that included more than 25 affected individuals (Phillips et al., 1995). At that time, this chromosomal region was already in the process of being characterized due to the fact that some years previously it had been identified as a candidate region for another type of rare monogenic idiopathic epilepsy, named benign familial neonatal convulsions (BFNCs) (Leppert et al., 1989). It turned out that the region on chromosome 20q contains two different ion channel subunit genes, CHRNA4 encoding the α4-subunit of the neuronal nicotinic acetylcholine receptor and the voltage-gated potassium channel gene KCNQ2 (Steinlein et al., 1994). The latter one was proven to be the major gene for BFNC, while CHRNA4 (and some years later CHRNB2) was identified as one of the main genes that cause ADNFLE (Biervert et al., 1998; De Fusco et al., 2000; Singh et al., 1998; Steinlein et al., 1995). The identification of these first two seizure-related genes introduced the concept of epilepsies as channelopathies, a concept that has by now gotten firmly established by the discovery of several additional epilepsy-causing ion channel genes. Today, nearly 20 years later, ADNFLE is again attracting attention by teaching us that one and the same disorder can be both a channelopathy and a non-ion channel disorder (Dibbens et al., 2013; Ishida et al., 2013; Ishii et al., 2013; Martin et al., 2013) (Fig. 1; Table 1).
Table 1
Clinical phenotypes associated with ADNFLE genes
| CHRNA4/CHRNB2 | Ion channel | ADNFLE |
| CHRNA2 | Ion channel | NFLE (ADNFLE?) |
| KCNT1 | Ion channel (signaling function?) | Malignant migrating partial seizures |
| Early infantile epileptic encephalopathy |
| Severe ADNFLE |
| DEPDC5 | Non-ion channel | Focal epilepsy with variable foci |
| ADNFLE |
The question mark indicates that the clinical phenotype overlaps with that previously described in other ADNFLE families but might not be identical
2 CHRNA4 and CHRNB2: The “Classical” ADNFLE Genes
The nAChR subunit genes CHRNA4 and CHRNB2 are responsible for the clinical phenotype in about 12–15% of ADNFLE patients with a strong family history (Steinlein et al., 2012). Both genes are expressed throughout the brain and the proteins they encode ensemble to build one of the most widely expressed nAChRs (3α4/2β2 or 2α4/3β2) in mammalian brain. The ubiquitous expression pattern of this nAChR subtype is surprising given that mutations in these genes cause a seizure phenotype that originates from the frontal lobe and rarely shows secondary generalization. So far, it can only be speculated about the pathomechanisms that prevent CHRNA4 and CHRNB2 mutations from having a more widespread effect. A possible explanation for this phenomenon could be that in most parts of the brain the effect the mutations have on neuronal excitability can be compensated by other nAChR subunits. Another possibility would be that genes from other ion channel families or even non-ion channel genes are involved in this restricted seizure activity.
So far, nearly all of the ADNFLE mutations identified within CHRNA4 or CHRNB2 are missense mutations that cause amino acid exchanges within the second, less often the first, transmembrane domain (Bertrand et al., 2005; Cho et al., 2003; De Fusco et al., 2000; Hirose et al., 1999; Magnusson et al., 2003; Phillips et al., 1995; Steinlein et al., 1995). The nAChR genes encode receptor subunits with four transmembrane domains. These are either directly or indirectly contributing to the structure that forms the walls of the ion channel and to the governing of the channels opening and closing mechanism. The second transmembrane domain, consisting of helical segments forming an inner ring (TM2) that shapes the pore, can be regarded as a hot spot for ADNFLE mutations. Several of these mutations have been identified more than once in unrelated families from different countries or even continents. This includes the neighboring mutations CHRNA4-Ser280Phe and CHRNA4-Ser284Leu that are so far the most commonly detected ADNFLE mutations (Cho et al., 2003; Hirose et al., 1999; Ito et al., 2000; McLellan et al., 2003; Phillips et al., 2000; Rozycka et al., 2003; Steinlein et al., 1995, 2000). These two mutations are only separated by a few amino acids, but nevertheless differ markedly with respect to both their biopharmacological characteristics and the severity of the clinical phenotype they are associated with. Most of the patients carrying CHRNA4-Ser280Phe present with an “epilepsy-only” phenotype, while many of those with CHRNA4-Ser284Leu have additional neurological symptoms such as mild-to-moderate mental retardation. Furthermore, the latter group of patients tend to have an unusually early age of onset, while carriers of the CHRNA4-Ser280Phe mutation develop their seizures at an average age that is typical for most nAChR-caused nocturnal frontal lobe epilepsies (Bertrand et al., 2002; Cho et al., 2003; Hirose et al., 1999; Ito et al., 2000; McLellan et al., 2003; Phillips et al., 2000; Rozycka et al., 2003; Steinlein et al., 1995, 2000). On a molecular level, the two mutations differed significantly with respect to their carbamazepine sensitivity, an antiepileptic drug that in vivo was shown to be highly effective on CHRNA4-Ser280Phe carrying nAChRs but not on those with the mutation CHRNA4-Ser284Leu (Bertrand et al., 2002). These results, gained from the analysis of nAChRs expressed in Xenopus oocytes, fit in with the observation that patients with the mutation CHRNA4-Ser280Phe usually benefit from carbamazepine treatment, while sufficient seizure reduction is rarely achieved by carbamazepine monotherapy in patients carrying CHRNA4-Ser284Leu (Bertrand et al., 2002; Cho et al., 2003; Hirose et al., 1999; Ito et al., 2000; McLellan et al., 2003; Phillips et al., 2000; Rozycka et al., 2003; Steinlein et al., 1995, 2000).
3 The Clinical Spectrum of nAChR-Caused ADNFLE
The term nocturnal frontal lobe epilepsy describes a large group of partial epilepsies that are heterogeneous in origin. ADNFLE as a rare monogenic disorder only accounts for a small proportion of these epilepsies that are mostly either symptomatic or multifactorial. Patients with sporadic as well as familial nocturnal frontal lobe epilepsy mostly show hypermotoric seizures with movements and vocalizations. Due to their...
| Erscheint lt. Verlag | 4.9.2014 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie |
| Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik | |
| Naturwissenschaften ► Biologie ► Humanbiologie | |
| Naturwissenschaften ► Biologie ► Zoologie | |
| ISBN-10 | 0-444-63333-2 / 0444633332 |
| ISBN-13 | 978-0-444-63333-0 / 9780444633330 |
| Haben Sie eine Frage zum Produkt? |
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