Front Cover

Genetics of Epilepsy

Copyright

Contributors

Preface

Contents

Chapter 1: Genetic heterogeneity in familial nocturnal frontal lobe epilepsy

1. Introduction

2. CHRNA4 and CHRNB2: The ``classical´´ ADNFLE Genes

3. The Clinical Spectrum of nAChR-Caused ADNFLE

4. CHRNA2: A Rare Cause of Familial NFLE

5. Biopharmacological Profiles of nAChR Mutations

6. Severe ADNFLE Caused by KCNT1 Mutations

7. DEPDC5 as a Cause of Familial Focal Epilepsy

8. Conclusions

References

Chapter 2: Potassium channel genes and benign familial neonatal epilepsy

1. Introduction

2. Potassium Channels

2.1. How Potassium Channels Regulate Neuronal Excitability

2.2. Potassium Channels in Epilepsy and Related Disorders

2.2.1. Mutations in KV1.1 Cause Episodic Ataxia

2.2.2. KCa1.1 Mutation Linked to Paroxysmal Dyskinesia and Epilepsy

2.2.3. KV4.2 and Acquired Epilepsy

3. Biology of KCNQ2 and KCNQ3 Channels

3.1. Meet the KCNQs

3.1.1. KCNQ1

3.1.2. KCNQ2 and KCNQ3

3.1.3. KCNQ4

3.1.4. KCNQ5

3.2. Structural and Functional Hallmarks of KV7.2/3 Channels

3.2.1. What Happens at the C-terminus?

3.2.1.1. Assembly of KV7 Channels

3.2.1.2. Regulation of the M-current

3.2.1.3. Targeting and Localization of KV7.2/7.3 Channels

3.3. Expression Pattern of Neuronal KV7 Channels

3.4. Insights from the Mouseland

3.5. Functional Analysis of Disease-Related Mutations

3.6. KCNQ2 and KCNQ3 Channelopathies

3.7. KCNQ2/3 Mutations in BFNS

3.7.1. Clinical Features and Genetics of BFNS

3.7.2. Pathogenic Mechanisms in BFNS

3.7.2.1. Mechanisms of Spontaneous Seizure Remission in BFNS

3.8. KCNQ2-Related EE

3.8.1. Clinical and Genetic Features

3.8.2. Pathophysiologic Mechanisms of EE

3.9. KCNQ2 Mutations and PNH

3.9.1. Clinical Picture and Genetics

3.9.2. Mechanisms Underlying PNH

4. Antiepileptic Therapies Targeting KV7 Channels

4.1. The Novel Anticonvulsant Compound Retigabine Is a KV7 Channel Opener

4.1.1. Mapping the RTG Binding Site

4.1.2. Other KV7 Openers

4.2. Novel Therapies Involving KV Channels

4.2.1. KV Channel Gene Therapy

4.2.2. Human Cellular Models of Epilepsy

5. Conclusions

5.1. Five Things We Learned from KCNQ Channels Involved in Epilepsy

References

Chapter 3: Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy

1. GABAA Receptors

2. Mutations and Genetic Variations of the GABAA Receptor

3. Mutations of the α Subunit

3.1. Mutations of GABRA1

3.1.1. Mutations in Autosomal Dominant JME

3.1.2. Mutations in Genetic (Idiopathic) Generalized Epilepsy

3.1.3. Mutations in IS

3.2. Mutations of GABRA6

3.2.1. Mutations in CAE

3.2.2. Animals with Aberrant α Subunits

4. Mutations of the β Subunit

4.1. Mutations of GABRB1

4.1.1. Mutations in IS

4.2. Mutations and Variations of GABRB3

4.2.1. Mutations and Variations in CAE

4.2.2. Mutations in IS

4.2.3. Animals with Aberrant β Subunits

5. Mutations of the γ Subunit

5.1. Mutations in CAE and FS

5.2. Mutations in GEFS+

5.3. Mutations in Dravet Syndrome

5.4. Mutations in Idiopathic Genetic Generalized Epilepsy

6. Mutations of the δ Subunit

7. Therapeutic Implications of GABAA Receptor Mutations

8. Conclusions

Acknowledgment

References

Chapter 4: The role of calcium channel mutations in human epilepsy

1. Introduction

2. Calcium Channel Nomenclature and Biophysical Properties

3. Calcium Channels in Epilepsy

3.1. T-type Calcium Channel Mutations in Epilepsy

3.2. P/Q-type Calcium Channel Mutations in Epilepsy

3.3. Ancillary Subunits of Voltage-Gated Calcium Channels in Seizure Disorders

4. Conclusion

References

Chapter 5: Mechanisms underlying epilepsies associated with sodium channel mutations

1. Introduction

2. Voltage-gated Sodium Channels

3. Clinical Phenotypes Associated with Voltage-gated Sodium Channel Mutations

4. Pathogenetic Mechanisms of Sodium Channel Mutations in Epilepsy

5. Conclusions

References

Chapter 7: Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5

1. Autosomal Dominant Focal Epilepsy Syndromes

1.1. Familial Temporal Lobe Epilepsy

1.2. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

1.3. Familial Focal Epilepsy with Variable Foci

2. DEPDC5, A Common Cause for Familial Focal Epilepsies

2.1. Whole-Exome Sequencing Identifies a New Gene

2.2. DEPDC5 Protein

2.3. From Channelopathies to mTORopathies

3. Conclusions

Acknowledgments

References

Chapter 8: PRRT2: A major cause of infantile epilepsy and other paroxysmal disorders of childhood

1. Introduction

2. PRRT2-related Syndromes

2.1. PKD

2.2. BFIS

2.3. ICCA Syndrome

2.4. PNKD and PED

3. Other Forms of Infantile Seizures

3.1. EA

4. Familial HM

5. Intellectual Disability

6. PRRT2 Mutations

7. PRRT2 Protein and Function

8. Conclusions

References

Chapter 9: LGI1: From zebrafish to human epilepsy

1. Introduction

2. The LGI1-Related Epilepsy Syndrome

3. The LGI1 Gene

4. LGI1 Mutant Null Mice Experience Spontaneous Seizures

5. Lgi1 Depletion Causes Seizure-Like Behavior in Zebrafish

6. Role for LGI in Synaptic Transmission

7. Protein Interactions with LGI1 Define Specific Functions

8. LGI1 Auto Antibodies Are Responsible for Limbic Encephalitis

9. LGI1 Expression Suggests a Role in Early Development

10. Role for LGI1 in Normal Mammalian Brain Development

11. Are the Other LGI1 Family Members Responsible for Seizure Phenotypes?

12. Summary

References

Chapter 10: Morphogenesis timing of genetically programmed brain malformations in relation to epilepsy

1. Introduction

2. Concept of Maturational Arrest, Delay, and Precociousness

3. Application of Timing to Epileptogenic FCDs

3.1. Developmental Basis of Focal Cortical Dysplasia Type 1

4. Timing in Systemic Genetic/metabolic Diseases That Affect Cerebral Development

5. Infantile Tauopathies, Microtubules, and Pathogenesis of Dysplasias Involving Cytological Abnormalities of Neurons

6. Why Are Cortical Dysplasias Epileptogenic?

Acknowledgment

References

Chapter 11: Remind me again what disease we are studying? A population genetics, genetic analysis, and real data perspective.

1. Introduction

2. A Review of the Methods Used to Find Epilepsy-Related Genes

2.1. Large-Family Approach

2.2. Association Analysis

2.3. Small-Family Linkage Approach

2.4. Comments on the Three Methods

2.4.1. Large Dense Family Approach

2.4.2. Association Approach

2.4.3. Linkage in Many Small-Family Approach

3. A Tale of Three Loci

3.1. BRD2

3.2. ELP4 and Centrotemporal Spikes/Rolandic Epilepsy

3.3. JME in Mexicans and EFHC1

3.4. What We Learn from the Tale of Three Loci

4. What Can Studying CNVs Tell Us about Common Epilepsy?

5. Why Rare Mutations Do Not Cause Common Disease

6. What the Tale of Three Loci and the Results of CNV Studies Tell Us about Common Epilepsy

7. Conclusion

Acknowledgments

References

Chapter 12: Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thala

1. Introduction

2. Monogenic Mutations of Diverse Genes Converge on the Absence Epilepsy Phenotype

3. The Thalamocortical Loop: A Multisynaptic Framework for Interpreting Absence Epilepsy Mutations

4. Thalamocortical T-type Calcium Channels: necessary and Sufficient?

5. The Role of Tonic Inhibition: A Key to Unlock T-Type Calcium Channels

6. P/Q-type Calcium Channels: selective Impairment of Inhibitory Release?

7. AMPA Receptor-Related Mutations: Silencing Fast Feedforward Inhibition

8. GABAA Receptor Mutations: fast Synaptic Disinhibition

9. Feedforward Disinhibition: A Preeminent Role in Absence Epilepsy

10. Specificity of ``fast´´ Feedforward Disinhibition in Absence Epilepsy

11. Secondary Compensatory Changes with Impaired Feedforward Inhibition

12. Pharmacologic Models of Absence Epilepsy Arise from Either Direct Enhancement of Tonic Inhibition or Indirectly via Feedf

13. Other Monogenic Models

14. Continuing Challenges

Acknowledgments

References

Chapter 13: New technologies in molecular genetics: the impact on epilepsy research

1. Genetics Versus Genomics

2. Basics Concepts and the Genome in Numbers

2.1. Exome-A Technical, not a Philosophical Term

2.2. The Genome in Numbers

2.3. The Third Beast-Rare Genetic Variants

2.4. Microdeletions-The Search for Epilepsy-Associated Variants Goes Genome Wide

2.5. Recurrent and Nonrecurrent Microdeletions

2.6. Microdeletions from Genomic Disorders to Genome-First

2.7. Variant Classification and the Global Burden of Microdeletions in Epilepsy

2.8. Genome-Wide Association Studies-The Late Success

2.9. Massive Parallel Sequencing Studies

2.9.1. Family Studies

2.9.2. Panel Studies

2.9.3. Trio Studies

3. Summary

References

Chapter 14: Epigenetic mechanisms in epilepsy

1. ``Bookmarking´´ the Genome

2. Chromatin Structure

3. DNA Methylation: strategy for Transcriptional Silencing

4. Histone Modifications: determinants of Accessibility

5. ncRNAs: no Longer Junk

5.1. Small ncRNAs

5.2. Long ncRNAs

6. Epigenetics in CNS Development and Higher Order Brain Function

7. Epigenetics in Idiopathic Generalized Epilepsy and Epileptic Encephalopathies

8. Epigenetics in TLE

9. Metabolism and the Epigenome

10. Balancing the Epigenome: therapeutic Strategies

11. Summary

References

Index

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