Steinlein Genetics of Epilepsy

1. Auflage 2014
ISBN: 978-0-444-63333-0
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 213, 346 Seiten

Reihe: Progress in Brain Research

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

Autoren/Hrsg.

Steinlein, Ortrud

Inhaltsverzeichnis

1;Front Cover;1
2;Genetics of Epilepsy;4
3;Copyright;5
4;Contributors;6
5;Preface;8
6;Contents;10
7;Chapter 1: Genetic heterogeneity in familial nocturnal frontal lobe epilepsy;18
7.1;1. Introduction;18
7.2;2. CHRNA4 and CHRNB2: The ``classical´´ ADNFLE Genes;19
7.3;3. The Clinical Spectrum of nAChR-Caused ADNFLE;21
7.4;4. CHRNA2: A Rare Cause of Familial NFLE;22
7.5;5. Biopharmacological Profiles of nAChR Mutations;23
7.6;6. Severe ADNFLE Caused by KCNT1 Mutations;23
7.7;7. DEPDC5 as a Cause of Familial Focal Epilepsy;26
7.8;8. Conclusions;28
7.9;References;28
8;Chapter 2: Potassium channel genes and benign familial neonatal epilepsy;34
8.1;1. Introduction;34
8.2;2. Potassium Channels;36
8.2.1;2.1. How Potassium Channels Regulate Neuronal Excitability;37
8.2.2;2.2. Potassium Channels in Epilepsy and Related Disorders;38
8.2.2.1;2.2.1. Mutations in KV1.1 Cause Episodic Ataxia;38
8.2.2.2;2.2.2. KCa1.1 Mutation Linked to Paroxysmal Dyskinesia and Epilepsy;39
8.2.2.3;2.2.3. KV4.2 and Acquired Epilepsy;39
8.3;3. Biology of KCNQ2 and KCNQ3 Channels;39
8.3.1;3.1. Meet the KCNQs;39
8.3.1.1;3.1.1. KCNQ1;40
8.3.1.2;3.1.2. KCNQ2 and KCNQ3;40
8.3.1.3;3.1.3. KCNQ4;41
8.3.1.4;3.1.4. KCNQ5;41
8.3.2;3.2. Structural and Functional Hallmarks of KV7.2/3 Channels;42
8.3.2.1;3.2.1. What Happens at the C-terminus?;43
8.3.2.1.1;3.2.1.1. Assembly of KV7 Channels;43
8.3.2.1.2;3.2.1.2. Regulation of the M-current;43
8.3.2.1.3;3.2.1.3. Targeting and Localization of KV7.2/7.3 Channels;44
8.3.3;3.3. Expression Pattern of Neuronal KV7 Channels;45
8.3.4;3.4. Insights from the Mouseland;45
8.3.5;3.5. Functional Analysis of Disease-Related Mutations;46
8.3.6;3.6. KCNQ2 and KCNQ3 Channelopathies;47
8.3.7;3.7. KCNQ2/3 Mutations in BFNS;47
8.3.7.1;3.7.1. Clinical Features and Genetics of BFNS;47
8.3.7.2;3.7.2. Pathogenic Mechanisms in BFNS;48
8.3.7.2.1;3.7.2.1. Mechanisms of Spontaneous Seizure Remission in BFNS;51
8.3.8;3.8. KCNQ2-Related EE;51
8.3.8.1;3.8.1. Clinical and Genetic Features;52
8.3.8.2;3.8.2. Pathophysiologic Mechanisms of EE;52
8.3.9;3.9. KCNQ2 Mutations and PNH;54
8.3.9.1;3.9.1. Clinical Picture and Genetics;54
8.3.9.2;3.9.2. Mechanisms Underlying PNH;54
8.4;4. Antiepileptic Therapies Targeting KV7 Channels;55
8.4.1;4.1. The Novel Anticonvulsant Compound Retigabine Is a KV7 Channel Opener;55
8.4.1.1;4.1.1. Mapping the RTG Binding Site;56
8.4.1.2;4.1.2. Other KV7 Openers;57
8.4.2;4.2. Novel Therapies Involving KV Channels;58
8.4.2.1;4.2.1. KV Channel Gene Therapy;58
8.4.2.2;4.2.2. Human Cellular Models of Epilepsy;59
8.5;5. Conclusions;60
8.5.1;5.1. Five Things We Learned from KCNQ Channels Involved in Epilepsy;60
8.6;References;60
9;Chapter 3: Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy;72
9.1;1. GABAA Receptors;73
9.2;2. Mutations and Genetic Variations of the GABAA Receptor;75
9.3;3. Mutations of the a Subunit;77
9.3.1;3.1. Mutations of GABRA1;77
9.3.1.1;3.1.1. Mutations in Autosomal Dominant JME;77
9.3.1.2;3.1.2. Mutations in Genetic (Idiopathic) Generalized Epilepsy;78
9.3.1.3;3.1.3. Mutations in IS;78
9.3.2;3.2. Mutations of GABRA6;79
9.3.2.1;3.2.1. Mutations in CAE;79
9.3.2.2;3.2.2. Animals with Aberrant a Subunits;79
9.4;4. Mutations of the ß Subunit;80
9.4.1;4.1. Mutations of GABRB1;80
9.4.1.1;4.1.1. Mutations in IS;80
9.4.2;4.2. Mutations and Variations of GABRB3;81
9.4.2.1;4.2.1. Mutations and Variations in CAE;81
9.4.2.2;4.2.2. Mutations in IS;82
9.4.2.3;4.2.3. Animals with Aberrant ß Subunits;82
9.5;5. Mutations of the . Subunit;83
9.5.1;5.1. Mutations in CAE and FS;83
9.5.2;5.2. Mutations in GEFS+;87
9.5.3;5.3. Mutations in Dravet Syndrome;88
9.5.4;5.4. Mutations in Idiopathic Genetic Generalized Epilepsy;89
9.6;6. Mutations of the d Subunit;90
9.7;7. Therapeutic Implications of GABAA Receptor Mutations;91
9.8;8. Conclusions;92
9.9;Acknowledgment;93
9.10;References;93
10;Chapter 4: The role of calcium channel mutations in human epilepsy;104
10.1;1. Introduction;104
10.2;2. Calcium Channel Nomenclature and Biophysical Properties;105
10.3;3. Calcium Channels in Epilepsy;108
10.3.1;3.1. T-type Calcium Channel Mutations in Epilepsy;108
10.3.2;3.2. P/Q-type Calcium Channel Mutations in Epilepsy;109
10.3.3;3.3. Ancillary Subunits of Voltage-Gated Calcium Channels in Seizure Disorders;111
10.4;4. Conclusion;111
10.5;References;112
11;Chapter 5: Mechanisms underlying epilepsies associated with sodium channel mutations;114
11.1;1. Introduction;114
11.2;2. Voltage-gated Sodium Channels;115
11.3;3. Clinical Phenotypes Associated with Voltage-gated Sodium Channel Mutations;117
11.4;4. Pathogenetic Mechanisms of Sodium Channel Mutations in Epilepsy;119
11.5;5. Conclusions;121
11.6;References;122
12;Chapter 7: Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5;140
12.1;1. Autosomal Dominant Focal Epilepsy Syndromes;141
12.1.1;1.1. Familial Temporal Lobe Epilepsy;141
12.1.2;1.2. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy;143
12.1.3;1.3. Familial Focal Epilepsy with Variable Foci;144
12.2;2. DEPDC5, A Common Cause for Familial Focal Epilepsies;146
12.2.1;2.1. Whole-Exome Sequencing Identifies a New Gene;146
12.2.2;2.2. DEPDC5 Protein;148
12.2.3;2.3. From Channelopathies to mTORopathies;148
12.3;3. Conclusions;149
12.4;Acknowledgments;150
12.5;References;150
13;Chapter 8: PRRT2: A major cause of infantile epilepsy and other paroxysmal disorders of childhood;158
13.1;1. Introduction;158
13.2;2. PRRT2-related Syndromes;159
13.2.1;2.1. PKD;159
13.2.2;2.2. BFIS;160
13.2.3;2.3. ICCA Syndrome;161
13.2.4;2.4. PNKD and PED;161
13.3;3. Other Forms of Infantile Seizures;162
13.3.1;3.1. EA;162
13.4;4. Familial HM;162
13.5;5. Intellectual Disability;163
13.6;6. PRRT2 Mutations;163
13.7;7. PRRT2 Protein and Function;169
13.8;8. Conclusions;170
13.9;References;171
14;Chapter 9: LGI1: From zebrafish to human epilepsy;176
14.1;1. Introduction;177
14.2;2. The LGI1-Related Epilepsy Syndrome;177
14.3;3. The LGI1 Gene;178
14.4;4. LGI1 Mutant Null Mice Experience Spontaneous Seizures;180
14.5;5. Lgi1 Depletion Causes Seizure-Like Behavior in Zebrafish;181
14.6;6. Role for LGI in Synaptic Transmission;182
14.7;7. Protein Interactions with LGI1 Define Specific Functions;183
14.8;8. LGI1 Auto Antibodies Are Responsible for Limbic Encephalitis;184
14.9;9. LGI1 Expression Suggests a Role in Early Development;185
14.10;10. Role for LGI1 in Normal Mammalian Brain Development;187
14.11;11. Are the Other LGI1 Family Members Responsible for Seizure Phenotypes?;189
14.12;12. Summary;190
14.13;References;190
15;Chapter 10: Morphogenesis timing of genetically programmed brain malformations in relation to epilepsy;198
15.1;1. Introduction;199
15.2;2. Concept of Maturational Arrest, Delay, and Precociousness;199
15.3;3. Application of Timing to Epileptogenic FCDs;201
15.3.1;3.1. Developmental Basis of Focal Cortical Dysplasia Type 1;201
15.4;4. Timing in Systemic Genetic/metabolic Diseases That Affect Cerebral Development;204
15.5;5. Infantile Tauopathies, Microtubules, and Pathogenesis of Dysplasias Involving Cytological Abnormalities of Neurons;205
15.6;6. Why Are Cortical Dysplasias Epileptogenic?;208
15.7;Acknowledgment;209
15.8;References;209
16;Chapter 11: Remind me again what disease we are studying? A population genetics, genetic analysis, and real data perspective.;216
16.1;1. Introduction;217
16.2;2. A Review of the Methods Used to Find Epilepsy-Related Genes;218
16.2.1;2.1. Large-Family Approach;218
16.2.2;2.2. Association Analysis;219
16.2.3;2.3. Small-Family Linkage Approach;219
16.2.4;2.4. Comments on the Three Methods;220
16.2.4.1;2.4.1. Large Dense Family Approach;220
16.2.4.2;2.4.2. Association Approach;220
16.2.4.3;2.4.3. Linkage in Many Small-Family Approach;221
16.3;3. A Tale of Three Loci;222
16.3.1;3.1. BRD2;222
16.3.2;3.2. ELP4 and Centrotemporal Spikes/Rolandic Epilepsy;223
16.3.3;3.3. JME in Mexicans and EFHC1;224
16.3.4;3.4. What We Learn from the Tale of Three Loci;225
16.4;4. What Can Studying CNVs Tell Us about Common Epilepsy?;226
16.5;5. Why Rare Mutations Do Not Cause Common Disease;228
16.6;6. What the Tale of Three Loci and the Results of CNV Studies Tell Us about Common Epilepsy;230
16.7;7. Conclusion;231
16.8;Acknowledgments;232
16.9;References;232
17;Chapter 12: Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thala;240
17.1;1. Introduction;241
17.2;2. Monogenic Mutations of Diverse Genes Converge on the Absence Epilepsy Phenotype;242
17.3;3. The Thalamocortical Loop: A Multisynaptic Framework for Interpreting Absence Epilepsy Mutations;246
17.4;4. Thalamocortical T-type Calcium Channels: necessary and Sufficient?;246
17.5;5. The Role of Tonic Inhibition: A Key to Unlock T-Type Calcium Channels;248
17.6;6. P/Q-type Calcium Channels: selective Impairment of Inhibitory Release?;250
17.7;7. AMPA Receptor-Related Mutations: Silencing Fast Feedforward Inhibition;253
17.8;8. GABAA Receptor Mutations: fast Synaptic Disinhibition;254
17.9;9. Feedforward Disinhibition: A Preeminent Role in Absence Epilepsy;255
17.10;10. Specificity of ``fast´´ Feedforward Disinhibition in Absence Epilepsy;256
17.11;11. Secondary Compensatory Changes with Impaired Feedforward Inhibition;256
17.12;12. Pharmacologic Models of Absence Epilepsy Arise from Either Direct Enhancement of Tonic Inhibition or Indirectly via Feedf;257
17.13;13. Other Monogenic Models;258
17.14;14. Continuing Challenges;259
17.15;Acknowledgments;260
17.16;References;260
18;Chapter 13: New technologies in molecular genetics: the impact on epilepsy research;270
18.1;1. Genetics Versus Genomics;270
18.2;2. Basics Concepts and the Genome in Numbers;272
18.2.1;2.1. Exome-A Technical, not a Philosophical Term;272
18.2.2;2.2. The Genome in Numbers;273
18.2.3;2.3. The Third Beast-Rare Genetic Variants;273
18.2.4;2.4. Microdeletions-The Search for Epilepsy-Associated Variants Goes Genome Wide;274
18.2.5;2.5. Recurrent and Nonrecurrent Microdeletions;275
18.2.6;2.6. Microdeletions from Genomic Disorders to Genome-First;276
18.2.7;2.7. Variant Classification and the Global Burden of Microdeletions in Epilepsy;278
18.2.8;2.8. Genome-Wide Association Studies-The Late Success;279
18.2.9;2.9. Massive Parallel Sequencing Studies;280
18.2.9.1;2.9.1. Family Studies;281
18.2.9.2;2.9.2. Panel Studies;282
18.2.9.3;2.9.3. Trio Studies;283
18.3;3. Summary;285
18.4;References;286
19;Chapter 14: Epigenetic mechanisms in epilepsy;296
19.1;1. ``Bookmarking´´ the Genome;296
19.2;2. Chromatin Structure;297
19.3;3. DNA Methylation: strategy for Transcriptional Silencing;297
19.4;4. Histone Modifications: determinants of Accessibility;300
19.5;5. ncRNAs: no Longer Junk;302
19.5.1;5.1. Small ncRNAs;303
19.5.2;5.2. Long ncRNAs;304
19.6;6. Epigenetics in CNS Development and Higher Order Brain Function;305
19.7;7. Epigenetics in Idiopathic Generalized Epilepsy and Epileptic Encephalopathies;306
19.8;8. Epigenetics in TLE;310
19.9;9. Metabolism and the Epigenome;314
19.10;10. Balancing the Epigenome: therapeutic Strategies;318
19.11;11. Summary;320
19.12;References;320
20;Index;334
21;Volume in series;344

Leseproben

Chapter 1

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: [e-mail]

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 a4-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).

Figure 1 Schematic overview summarizing the seizure origin of the known ADNFLE genes. Arrows indicate the migrating seizures reported for several patients with KCNT1 mutations.

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 (3a4/2ß2 or 2a4/3ß2) 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...