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HANDBOOK OF PEDIATRIC
EPILEPSY CASE STUDIES,
SECOND EDITION

EDITED BY
MARIA AUGUSTA MONTENEGRO
AND JONG M. RHO

CRC Press
Taylor & Fr is Group
 Handbook of Pediatric
­Epilepsy Case Studies,
Second Edition
Research in the field of epilepsy will continue at a rapid pace, with the ultimate hope
of curing many intractable epilepsy syndromes. Fully updated, this new edition is
organized chronologically, from neonate through adolescence, and the handbook is
the culmination of a group effort involving leading physicians and researchers whose
contributions constitute a concise and practical reference for health professionals in
training. Here the contributors review the recent flood of new information on the
pathophysiology, genetics, and treatment of the various epilepsy syndromes, and the
volume is distilled into an ­easy-­​­­to-​­use guide.

• Fully updated text reviewing the latest research on the pathophysiology,

genetics, and treatment of the various epilepsy syndromes.
• Thorough descriptions of the different syndromes commonly encountered
in clinical practice across the pediatric range.
• Extensive resource section provided.
• Contributors describe why they chose each particular case, what they
learned, and how it changed their practice.
• The book includes the most recent classification and nomenclature p­ ublished
by the International League Against Epilepsy.
 Handbook of Pediatric
­Epilepsy Case Studies,
Second Edition

Edited by
Maria Augusta Montenegro
UC Sand Diego School of Medicine

Jong M. Rho
UC San Diego School of Medicine
Second edition published 2023
by CRC Press
6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL ­33487-​­2742

and by CRC Press

4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN

CRC Press is an imprint of Taylor & Francis Group, LLC

© 2023 selection and editorial matter, Maria Augusta Montenegro and Jong M. Rho; individual
chapters, the contributors

First edition published by CRC Press | Taylor and Francis, LLC 2008

Reasonable efforts have been made to publish reliable data and information, but the author and
­publisher cannot assume responsibility for the validity of all materials or the consequences of
their use. The authors and publishers have attempted to trace the copyright holders of all material
­reproduced in this publication and apologize to copyright holders if permission to publish in this
form has not been obtained. If any copyright material has not been acknowledged please write and
let us know so we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced,
transmitted, or utilized in any form by any electronic, mechanical, or other means, now known
or hereafter invented, including photocopying, microfilming, and recording, or in any information
storage or retrieval system, without written permission from the publishers.

For permission to photocopy or use material electronically from this work, access www.
copyright.com or contact the Copyright Clearance Center, Inc. (­
CCC), 222 Rosewood Drive,
Danvers, MA 01923, ­978-­​­­
750-​­
8400. For works that are not available on CCC please contact
­[email protected]

Trademark notice: Product or corporate names may be trademarks or registered trademarks and are
used only for identification and explanation without intent to infringe.

Library of Congress Cataloging‑in‑Publication Data

Names: Rho, Jong M., editor. | Montenegro, Maria Augusta, editor.
Title: Handbook of pediatric epilepsy case studies, second edition / edited by Jong M. Rho,
University of California, San Diego, Maria Augusta Montenegro,
Department of Neurology, University of Campinas/UNICAMP, Campinas, Brazil.
Other titles: Pediatric epilepsy case studies.
Description: Second edition. | Boca Raton, FL : CRC Press, 2023. | Revised
edition of: Pediatric epilepsy case studies / edited by Kevin Chapman,
Jong M. Rho. c2009. | Includes bibliographical references and index. |
Identifiers: LCCN 2022057002 | ISBN 9781032283548 (hbk) | ISBN
9781032283586 (pbk) | ISBN 9781003296478 (ebk)
Subjects: LCSH: Epilepsy in children–Case studies.
Classification: LCC RJ496.E6 P42 2023 | DDC 618.92/853–dc23/eng/20221214
LC record available at https://lccn.loc.gov/2022057002

ISBN: 9781032283548 (­hbk)

ISBN: 9781032283586 (­pbk)
ISBN: 9781003296478 (­ebk)

DOI: 10.1201/­9781003296478

Typeset in Times
by codeMantra
Contents
Preface.......................................................................................................................xi
Authors ................................................................................................................... xiii
Abbreviations & Acronyms ..................................................................................... xv
Contributors ............................................................................................................xix

Section i the Basics

Chapter 1 A Pediatric Epilepsy Primer.................................................................3

James W. Owens

Chapter 2 Epilepsy Genetics Primer ................................................................... 13

Kimberly Wiltrout and Annapurna Poduri

Chapter 3 Developmental Pharmacokinetics: Principles and Practice ............... 27

Melissa Barker-Haliski
­ ​­

Chapter 4 Dietary Therapies for Epilepsy .......................................................... 39

Eric H. Kossoff

Chapter 5 Vagus Nerve Stimulation Therapy ..................................................... 45

James W. Wheless, Nitish Chourasia, and Andrew J. Gienapp

Chapter 6 Neuromodulation Devices: Responsive Neurostimulation and

Deep Brain Stimulation ...................................................................... 59
Shifteh S. Sattar

Chapter 7 Epilepsy Surgery in Children ............................................................. 67

Ann Hyslop

Chapter 8 Status Epilepticus ............................................................................... 77

Sonali Sen and James J. Riviello

v
vi Contents

Chapter 9 Focal Cortical Dysplasias ................................................................... 83

Harvey B. Sarnat

Chapter 10 Malformations of Cortical Development ...........................................97

Marilisa M. Guerreiro and Maria Augusta Montenegro

Section ii the neonate

Chapter 11 Self-Limited
­ ​­ Neonatal Epilepsy Syndromes .................................... 107
Maria Augusta Montenegro and Jong M. Rho

Chapter 12 ­Self-Limited
​­ (Familial)
­ Infantile Epilepsy ...................................... 113
Heather Pekeles and Kenneth A. Myers

Chapter 13 Early Myoclonic Encephalopathy (Ohtahara Syndrome) ................. 117

Reega Purohit and Linda Laux

Chapter 14 Early Myoclonic Encephalopathy .................................................... 123

Juan Ignacio Appendino and Juan Pablo Appendino

Chapter 15 Hypoxic-Ischemic
­ ​­ Encephalopathy (Neonatal
­ Seizures) ................. 129
Jeffrey J. Gold

Chapter 16 Epilepsy of Infancy with Migrating Focal Seizures ........................ 135

Danielle deCampo and Eric Marsh

Section iii the infant

Chapter 17 Febrile Seizures ................................................................................ 143
Morris H. Scantlebury

Chapter 18 Genetic Epilepsy with Febrile Seizures Plus (GEFS+) .................... 149
Michaela Castello and Aliya Frederick
Contents vii

Chapter 19 Myoclonic Epilepsy of Infancy ........................................................ 155

Douglas R. Nordli, III and Douglas R. Nordli, Jr.

Chapter 20 Dravet Syndrome .............................................................................. 161

Douglas R. Nordli, III and Douglas R. Nordli, Jr.

Chapter 21 Glucose Transporter-1

­ ​­ Deficiency Syndrome................................... 167
Joerg Klepper

Chapter 22 Infantile Epileptic Spasms Syndrome .............................................. 173

Shaun A. Hussain

Chapter 23 Gelastic Seizures .............................................................................. 179

Samiya Ahmad and Yu-tze Ng

Chapter 24 Intractable Epilepsy after Herpes Simplex Encephalitis .................. 185

Daniel A. Freedman and Dave F. Clarke

Chapter 25 Refractory Status Epilepticus .......................................................... 193

Sonali Sen and James J. Riviello, Jr.

Chapter 26 Primary Mitochondrial Epilepsies ................................................... 199

Russell P. Saneto

Chapter 27 Tuberous Sclerosis Complex ............................................................ 213

Aimee F. Luat and Harry T. Chugani

Chapter 28 Sturge–Weber
­ ​­ Syndrome.................................................................. 223
Sabrina Tavella-Burka and Ajay Gupta

Section iV the child

Chapter 29 Self-Limited Epilepsy with Centrotemporal Spikes (Benign

Rolandic Epilepsy) ........................................................................... 233
Olivia Kim-McManus
­ ​­
viii Contents

Chapter 30 Self-Limited Epilepsy with Autonomic Seizures

(Panayiotopoulos
­ Syndrome) ........................................................... 237
Korwyn Williams

Chapter 31 Childhood Occipital Visual Epilepsy............................................... 243

Maria Augusta Montenegro

Chapter 32 Photosensitive Occipital Lobe Epilepsy ........................................... 249

Maria Augusta Montenegro

Chapter 33 Childhood Absence Epilepsy ........................................................... 253

Stéphane Auvin

Chapter 34 Epilepsy with Myoclonic Absences.................................................. 259

Anita M. Devlin

Chapter 35 ­Lennox–Gastaut
​­ Syndrome .............................................................. 265
Jong M. Rho

Chapter 36 Epilepsy with ­­Myoclonic-Atonic

​­​­​­ Seizures (Doose
­­ Syndrome) ........ 271
A.G. Christina Bergqvist

Chapter 37 ­Landau-Kleffner
​­ Syndrome ............................................................. 277
Frank M. C. Besag

Chapter 38 Developmental/Epileptic
­ Encephalopathy with Spike-and-Wave
­ ­​­­ ​­
Activation in Sleep (D/EE-SWAS)...................................................
­ ­­ ​­ 283
Kevin Chapman

Chapter 39 Epilepsy with Eyelid Myoclonia (Jeavons Syndrome) ..................... 291

Ifrah Zawar and Elia Pestana Knight

Chapter 40 ­Anti-NMDA
​­ Receptor Encephalitis ................................................. 299
Jennifer Yang and Jennifer Graves
Contents ix

Chapter 41 Nonconvulsive Status Epilepticus.....................................................307

Sonali Sen and James J. Riviello, Jr.

Chapter 42 Febrile ­Infection-​­Related Epilepsy Syndrome (­FIRES)................... 313

Rima Nabbout and Sara Matricardi

Chapter 43 ­New-​­Onset Refractory Status Epilepticus (NORSE)........................ 317

Steven Yang and Jerry Shih

Chapter 44 ­Low-​­Grade Developmental and Epilepsy

Associated Brain Tumors.................................................................. 323
Christie Becu and Angus Wilfong

Chapter 45 Rasmussen’s Encephalitis.................................................................. 333

Maria Augusta Montenegro

Section V The Adolescent

Chapter 46 Juvenile Myoclonic Epilepsy............................................................. 341

Cornelia Drees

Chapter 47 Epilepsy with Generalized Tonic-​­

­­ Clonic Seizures Alone................. 347
Kaitlin C. James and Jesus Eric Pina-​­
­­ Garza

Chapter 48 Juvenile Absence Epilepsy................................................................ 353

Maria Augusta Montenegro

Chapter 49 ­New-​­Onset Seizure in an Adolescent Female................................... 359

Mary L. Zupanc

Chapter 50 Temporal Lobe Epilepsy................................................................... 369

June ­Yoshii-​­Contreras

Chapter 51 ­Unverricht–​­Lundborg Disease.......................................................... 375

Mayank Verma, Berge A. Minassian, and Danielle M. Andrade
x Contents

Chapter 52 Reflex Seizures ................................................................................. 383

Maria Augusta Montenegro

Chapter 53 ­Sleep-Related
​­ Hypermotor Epilepsy ................................................ 387
Kevin Chapman

Chapter 54 Psychogenic Nonepileptic Seizures .................................................. 393

Guillermo Delgado- García and Colin B. Josephson

Index ...................................................................................................................... 399

Preface
Epilepsy encompasses a wide variety of clinical syndromes characterized by het-
erogeneous etiologies, presentations, and prognoses. Accurate diagnosis is critically
important for the proper care of patients with epilepsy, especially since some forms
of epilepsy have a benign and self-limited course, while others are associated with
progressive neurocognitive decline.
Advances in neuroimaging and genetics have improved our diagnostic abilities
and our fundamental understanding of epilepsies. In addition, newer medications
have offered patients better tolerability than traditional agents, but unfortunately, no
significant improvements in overall seizure control have been afforded. Many epilep-
tic conditions remain intractable to currently available medications. However, other
nonpharmacological treatment options (such as the ketogenic diet and vagus nerve
stimulator) have provided hope for improved seizure control in these patients with
medically intractable epilepsy.
Since the publication of the first edition, there have been remarkable scientific and
clinical advances in the field of pediatric epilepsy, the most notable of which has been
our understanding of the genetic underpinnings of many disordered encountered in
clinical practice. While we are still far from transforming the therapeutic landscape
with precision therapies based on the unique neurobiology of an individual patient’s
epileptic condition, we have learned that the molecular mechanisms underlying sei-
zure genesis (and indeed, epileptogenesis) are far more complex than previously
realized. Nevertheless, with current efforts to explore and validate innovative gene
therapies and a new generation of antiseizure medications with unique and somewhat
unexpected mechanisms of action, the future remains promising.
For the physician or allied health professional in training, grasping the complexity
and nuances associated with various epileptic syndromes can be daunting. The goal
of this book remains the same – to help trainees at all levels and healthcare profes-
sionals understand the different epilepsies encountered in the clinical setting across
the pediatric age range. The intent is to provide a readily digestible reference that
introduces the novice to the remarkable and at times bewildering array of epilepsies
in neonates, infants, children, and adolescents.
The initial section forms an introduction to the fundamentals of epilepsy, and
subsequent sections include succinct case presentations and salient discussions of
the more common epilepsy syndromes affecting each age group. There are other
rarer forms of epilepsy that have not been included, such as seizures arising from
certain metabolic-genetic and neurodegenerative conditions. Suggested references
are also provided to guide the reader toward more detailed studies of a specific topic
of interest.
This book is the culmination of a group effort involving many of the leading phy-
sicians and researchers in the field of pediatric epilepsy. We believe that their indi-
vidual contributions together constitute a concise and practical reference for health

xi
xii Preface

professionals in training. Research in the field of epilepsy continues to grow at a

rapid pace, with the ultimate hope of curing many patients with refractory epilepsy.
We further hope that this book may spark the interest of residents, trainees, and other
healthcare professionals in joining the international fight against epilepsy.

Maria Augusta Montenegro, MD, PhD

Rady Children’s Hospital
University of California San Diego

Jong M. Rho, MD
Rady Children’s Hospital
University of California San Diego
Authors
Maria Augusta Montenegro is a pediatric neurologist and epileptologist currently
working at Rady Children’s Hospital/ University of California San Diego School of
Medicine. Her clinical expertise is in pediatric epilepsy, with an emphasis on epilep-
tic encephalopathy and EEG. She completed medical school, residency, and Ph.D.
at the University of Campinas (Brazil) and a postdoctorate research fellowship at
Columbia University (NY). Prior to her current position, she held an academic fac-
ulty appointment at the University of Campinas (Brazil) where she was the head of
Pediatric Neurology.

Dr. Jong M. Rho is a Professor of Neurosciences, Pediatrics and Pharmacology at

the University of California San Diego, and Division Chief of Pediatric Neurology
at the Rady Children’s Hospital San Diego. He received a bachelor’s degree in
molecular biophysics and biochemistry at Yale University, and an M.D. from the
University of Cincinnati. He has held prior faculty appointments at the University of
Washington (Seattle), the University of California at Irvine, the Barrow Neurological
Institute (Phoenix), and most recently, the University of Calgary. His main research
interests are the mechanisms underlying the antiseizure and neuroprotective effects
of metabolism-based treatments such as the ketogenic diet. His research activities
have been sponsored by research grants from the U.S. National Institutes of Health,
Canadian Institutes of Health Research, and other public and private sector sources.

xiii
Abbreviations & Acronyms
AAN American Academy of Neurology
ACMG American College of Medical Genetics and Genomics
ACTH adrenocorticotropic hormone
ADHD attention deficit hyperactivity disorder
ADME absorption, distribution, metabolism, and excretion
ADNFLE autosomal dominant nocturnal frontal lobe epilepsy
ANT anterior nucleus of the thalamus
ASM antiseizure medication
BECTS benign epilepsy with centrotemporal spikes
BIPDs bilateral independent periodic discharges
BOLD ­blood-oxygen-level-dependent
­​­­ ­​­­ ​­
CAE childhood absence epilepsy
CBT ­cognitive-behavioral
​­ therapy
CBZ carbamazepine
CEEG continuous EEG monitoring
CI confidence interval
CIV continuous intravenous
CIVASM continuous intravenous antiseizure medication
CMA chromosomal microarray analysis
CNS central nervous system
CNVs copy number variants
COVE childhood occipital visual epilepsy
CSE convulsive status epilepticus
CSTB cystatin B
CSWS continuous ­spike-and-wave
­​­­ ​­ during sleep
CYP cytochrome P450
DBS deep brain stimulation
DEE developmental and/or epileptic encephalopathy
­DEE-SWAS
​­ developmental epileptic encephalopathy with spike-and-wave
­ ­​­­ ​­
activation in sleep
DEND developmental delay, epilepsy, and neonatal diabetes
DNA deoxyribonucleic acid
DNT dysembryoplastic neuroepithelial tumor
EAF epilepsy with auditory features
ECoG electrocorticography
ED emergency department
EEG electroencephalogram
EIDEE early infantile developmental and epileptic encephalopathy
EIMFS epilepsy of infancy with migrating focal seizures
EMAS epilepsy with myoclonic-atonic
­ ​­ seizures
EME early myoclonic epilepsy
ES exome sequencing

xv
xvi Abbreviations & Acronyms

ESES electrical status epilepticus of sleep

ESET status epilepticus treatment trial
ESI electrical source imaging
ETC Electron transport chain
ER emergency room
FAME familial adult myoclonic epilepsy
FCD focal cortical dysplasia
FDA food and drug administration
­FDG-PET
​­ ­2-Deoxy-2-[18F]
­​­­ ­​­­ ​­ ­fluoro-D-glucose
­​­­ ​­ positron emission tomography
FIRES febrile ­infection-related ​­ epilepsy syndrome
FLAIR ­fluid-attenuated
​­ inversion recovery
fMRI functional magnetic resonance imaging
FSE febrile status epilepticus
GABA ­gamma-aminobutyric
​­ acid
GEFS+ genetic epilepsy with febrile seizures plus
GGE genetic generalized epilepsies
GLUT1DS glucose transporter 1 deficiency syndrome
GnRH gonadotropin-releasing
­ ​­ hormone
GS genome sequencing
GTC generalized tonic clonic
GTCA epilepsy with generalized tonic-clonic seizures alone
HH hypothalamic hamartoma
HIE ­hypoxic-ischemic ​­ encephalopathy
HR hazard ratio
HSE herpes simplex encephalitis
HSV herpes simplex virus
ICU intensive care unit
IESS infantile epileptic spasms syndrome
IGE idiopathic generalized epilepsy
ILAE International League Against Epilepsy
IVIG intravenous immunoglobulin
JAE juvenile absence epilepsy
JME juvenile myoclonic epilepsy
JS Jeavons syndrome
KD ketogenic diet
LD Lafora disease
LEAT Low-grade
­ ​­ developmental, ­epilepsy-associated
​­ brain tumor
LEV levetiracetam
LGS Lennox–Gastaut
­ ​­ syndrome
LITT laser interstitial thermal therapy
LKS ­Landau–Kleffner ​­ syndrome
LPD lateralized periodic discharges
MAD modified Atkins diet
MAE myoclonic astatic epilepsy
MAS myoclonic-atonic
­ ​­ seizures
MCD malformation of cortical development
Abbreviations & Acronyms xvii

MEG magnetoencephalography
MEI myoclonic epilepsy of infancy
MELAS mitochondrial encephalomyopathy, lactic acidosis, and stroke-like
episodes
MERRF myoclonus, epilepsy, with ragged red fibers
mFCD minimal focal cortical dysplasia
MgFUS MRI-guided
­ ​­ focused ultrasound
MgLITT MRI-guided laser interstitial thermal therapy
MGP multigene panels
MHD monohydroxy derivative
MOGHE mild malformation of cortical development with oligodendroglial
hyperplasia and epilepsy
MRI magnetic resonance imaging
MRS magnetic resonance spectroscopy
MS myoclonic
­MS-MLPA
​­ ­methylation-sensitive ​­ multiplex ­ligation-dependent
​­ probe
amplification
mtDNA mitochondrial DNA
­MTLE-HS​­ mesial temporal lobe epilepsy with hippocampal sclerosis
mTOR mammalian target of rapamycin
MTS mesial temporal sclerosis
nAChR neuronal nicotinic acetylcholine receptor
NCS nonconvulsive seizures
NCSE nonconvulsive status epilepticus
NDDs neurodevelopmental disorders
nDNA nuclear DNA
NGS next-generation
­ ​­ sequencing
NICU neonatal intensive care unit
NLSTEPSS North London Status Epilepticus Surveillance Study
NMDA ­N-methyl-D-aspartate
­​­­ ­​­­ ​­
NMDAR N-methyl-D-aspartate
­ ­​­­ ­​­­ ​­ receptor
NORSE ­new-onset ​­ refractory status epilepticus
NREM nonrapid eye movement
OCP oral contraceptives
OSA obstructive sleep apnea
PCR polymerase chain reaction
PDMS patient data management system
PHACE posterior fossa anomalies, hemangioma, arterial anomalies, cardiac
anomalies, and eye anomalies
PICU pediatric intensive care unit
PLEDs periodic lateralizing epileptiform discharges
PME progressive myoclonus epilepsy
PNES psychogenic nonepileptic seizures
POLE photosensitive occipital lobe epilepsy
POLG polymerase gamma
ppm parts per million
xviii Abbreviations & Acronyms

PPR photoparoxysmal response

PWS ­port-wine ​­ stain
REM rapid eye movement
RFTC radiofrequency thermocoagulation
RNS responsive neurostimulation
RSE refractory status epilepticus
SE status epilepticus
sEEG ­stereo-EEG ​­
SeLEAS self-limited epilepsy with autonomic seizures
SeLECTS self-limited epilepsy with centrotemporal spikes
SeLIE ­self-limited
​­ (familial)
­ infantile epilepsy
SHE ­sleep-related​­ hypermotor epilepsy
SISCOM subtraction ictal SPECT co-registered to MRI
SMAP sulfamoyolacetylphenol
SMEI severe myoclonic epilepsy of infancy
SPECT single photon emission computed tomography
SRSE super refractory status epilepticus
SSEPs somatosensory evoked potentials
SUDEP sudden unexpected death in epilepsy
SWI ­spike–wave ​­ index
SWS ­Sturge–Weber ​­ syndrome
TIRDA temporal intermittent rhythmic delta
TLE temporal lobe epilepsy
TMS transcutaneous magnetic stimulation
TSC tuberous sclerosis complex
UDP uridine diphosphate
UGT glucuronosyltransferase
ULD Unverricht–Lundborg
­ ​­ disease
VAP valproic acid (VPA)
Vd volume of distribution
VNS vagus nerve stimulation
VZV varicella zoster virus
WNV west Nile virus
Contributors
Samiya Ahmad Kevin Chapman
Baylor College of Medicine University of Arizona College of
Houston, Texas Medicine
Phoenix, Arizona
Danielle M. Andrade
University of Texas Southwestern Nitish Chourasia
Medical Center The University of Tennessee Health
Dallas, Texas Science Center
Memphis, Tennessee
Juan Ignacio Appendino
Hospital Italiano de Buenos Aires Harry T. Chugani
Buenos Aires, Argentina NYU School of Medicine
New York, New York
Juan Pablo Appendino
University of Calgary Dave F. Clarke
Calgary, Canada The University of Texas at Austin
Austin, Texas
Stéphane Auvin
Université ­Paris-​­Cité & Institut Danielle deCampo
Universitaire de France (­IUF) Children’s Hospital of Philadelphia
Paris, France Philadelphia, Pennsylvania

Melissa ­Barker-​­Haliski Guillermo ­Delgado-​­García

University of Washington University of Calgary
Seattle, Washington Calgary, Canada

Christie Becu Anita M. Devlin

Barrow Neurological Institute at Newcastle University
Phoenix Children’s Hospital Newcastle upon Tyne, United Kingdom
Phoenix, Arizona
Cornelia Drees
A. G. Christina Bergqvist University of Colorado
University of Pennsylvania Aurora, Colorado
Philadelphia, Pennsylvania
Aliya Frederick
Frank M. C. Besag UC San Diego School of Medicine
Neurodevelopmental Team San Diego, California
London, England
Daniel A. Freedman
Michaela Castello The University of Texas at Austin
UC San Diego School of Medicine Austin, Texas
San Diego, California

xix
xx Contributors

Andrew J. Gienapp Eric H. Kossoff

The University of Tennessee The Johns Hopkins Hospital
Memphis, Tennessee Baltimore, Maryland

Jeffrey J. Gold Linda Laux

UC San Diego School of Medicine Northwestern University
San Diego, California Chicago, Illinois

Jennifer Graves Aimee F. Luat

Rady Children’s Pediatric MS Center Central Michigan University
San Diego, California Mount Pleasant, Michigan
and
Marilisa M. Guerreiro Wayne State University
University of Campinas Detroit, Michigan
Campinas, Brazil
Eric Marsh
Ajay Gupta Children’s Hospital of Philadelphia and
Neurological Institute Cleveland Clinic University of Pennsylvania
Cleveland, Ohio Philadelphia, Pennsylvania

Shaun A. Hussain Sara Matricardi

UCLA Mattel Children’s Hospital and Children’s Hospital “G. Salesi”
David Geffen School of Medicine Ancona, Italy
Los Angeles, California
Berge A. Minassian
Ann Hyslop University of Texas Southwestern
Stanford University Medical Center
Stanford, California Dallas, Texas

Kaitlin C. James Kenneth A. Myers

Monroe Carell Jr Children’s Hospital at Montreal Children’s Hospital - McGill
Vanderbilt University Health Centre
Nashville, Tennessee Montreal, Canada

Colin B. Josephson Rima Nabbout

University of Calgary University of Paris cite
Calgary, Canada Paris, France

Olivia ­Kim-McManus
​­ ­Yu-tze
​­ Ng
UC San Diego School of Medicine The Children’s Hospital of San Antonio
San Diego, California and Baylor College of Medicine
Houston, Texas
Joerg Klepper
Children’s Hospital Aschaffenburg Douglas R. Nordli, Jr.
Aschaffenburg, Germany University of Chicago Medicine
Chicago, Illinois
Contributors xxi

Douglas R. Nordli, III Morris H. Scantlebury

Mayo Clinic University of Calgary
Jacksonville, Florida Calgary, Canada

James W. Owens Sonali Sen

University of Washington Baylor College of Medicine
Seattle, Washington Houston, Texas

Heather Pekeles Jerry Shih

McGill University Health UC San Diego School of Medicine
Center San Diego, California
Montreal, Canada
Sabrina ­Tavella-Burka
​­
Elia Pestana Knight Cleveland Clinic
Cleveland Clinic Cleveland, Ohio
Cleveland, Ohio
Mayank Verma
Jesus Eric Pina-Garza
­ ​­ University of Texas Southwestern
Centennial Children’s Hospital Medical Center
Nashville, Tennessee Dallas, Texas

Annapurna Poduri James W. Wheless

Boston Children’s Hospital The University of Tennessee
Boston, Massachusetts Memphis, Tennessee

Reega Purohit Angus Wilfong

Northwestern University Feinberg Barrow Neurological Institute at
School of Medicine Phoenix Children’s Hospital
Chicago, Illinois Phoenix, Arizona

James J. Riviello, Jr. Korwyn Williams

Baylor College of Medicine Phoenix Children’s Hospital
Houston, Texas Phoenix, Arizona

Russell P. Saneto Kimberly Wiltrout

University of Washington Harvard Medical School
Seattle, Washington Boston, Massachusetts

Harvey B. Sarnat Jennifer Yang

University of Calgary UC San Diego
Calgary, Canada San Diego, California

Shifteh S. Sattar Steven Yang

UC San Diego School of Medicine UC San Diego School of Medicine
San Diego, California San Diego, California
xxii Contributors

June Yoshii-Contreras
­ ​­ Mary L. Zupanc
UC San Diego School of Medicine UC Irvine
San Diego, California Orange County, California

Ifrah Zawar
UVA Health
Charlottesville, Virginia
Section I
The Basics
 1 A Pediatric Epilepsy
Primer
James W. Owens
University of Washington

CONTENTS
Pediatric Epilepsy Is Common...................................................................................4
.
Pediatric Epilepsy Encompasses a Wide Range of Disorders....................................4
Pediatric Epilepsy Viewed from a Developmental Context ....................................... 8
A Wide Range of Treatment Options Are Available .................................................. 9
Pediatric Epilepsy Is Not Just about Seizures .......................................................... 10
Summary .................................................................................................................. 11
Suggested References............................................................................................... 11

Epilepsy is a common, and often misunderstood, chronic medical condition of child-

hood. As frequently encountered as childhood asthma, seizures (inclusive of febrile
seizures) occur in up to 5% of all children in the United States and 1% of children are
diagnosed with epilepsy. Appropriate diagnosis and management are crucial given
the potential for life-long consequences to the developing brain.
Not all seizures need to be treated, as there are differences in the management of
true epileptic conditions vs. reactive or isolated seizures. An example of the former
would be recognizing the clinical phenotype of infantile spasms, a particularly dev-
astating type of developmental brain disorder. An illustration of the latter would be
refraining from the use of antiseizure medications (ASMs) for children with febrile
seizures, even if recurrent. This common form of acute provoked seizure does not
reflect an enduring epileptic condition, and, typically, daily preventative treatment
is not warranted. Furthermore, there are many paroxysmal disorders affecting chil-
dren, such as parasomnias and behavioral problems, which are frequently mistaken
for epileptic phenomena.
The epilepsies of childhood differ significantly both from each other as well as
from those encountered in adulthood; the pediatric brain is not just a smaller adult
brain. The key, then, is to understand what epilepsy is and what it is not, and to
appreciate the unique ­age-dependent
­​­­ – ​­and ­syndrome-dependent
­​­­ – nature
​­ of epileptic
conditions to guide proper diagnosis and management. In this introductory chapter,
a few key points regarding pediatric epilepsy will be highlighted and expanded upon
in the remainder of this book.

DOI: 10.1201/9781003296478-2 3
4 Handbook of Pediatric Epilepsy Case Studies, Second Edition

PEDIATRIC EPILEPSY IS COMMON

Within the first two decades of life, approximately 5% of children will have experi-
enced some form of seizure. A significant majority of these seizures will be acutely
provoked events, often in the context of a febrile illness, and not spontaneous recur-
rent seizures (SRSs) which are the hallmark of epilepsy. Among all children who
have a single unprovoked seizure, only about 40% of them will ever have a second.
This rate of recurrence varies greatly depending on such factors as what type of
seizure occurred and whether there is other evidence of neurological dysfunction.
For example, a patient who, at baseline, has an abnormal neurological examination,
abnormal electroencephalogram (EEG), and abnormal brain MRI may have a risk of
recurrence of approximately 90%. Of course, this does not indicate when a subse-
quent seizure might actually occur.
Approximately 20% of patients experiencing a seizure of some type will later
develop epilepsy: by 20 years of age, approximately 1% of the population will have
been diagnosed with this condition. Published studies of incidence vary greatly,
which may be partly due to the inclusion of single unprovoked seizures as well as
acute symptomatic seizures in some studies. With respect to age-specific incidence,
it seems clear that the onset of epilepsy most frequently occurs at the two extremes
of the lifespan. That is, several studies have shown that the incidence of epilepsy is
high in the first year of life, lowest in middle age, and rises again in the elderly. In a
population of patients aged 70 years or more, the incidence is as high as 3%. As one
might imagine, the causes, types, and outcomes differ significantly between these
two populations, although there is certainly some overlap.

PEDIATRIC EPILEPSY ENCOMPASSES A

WIDE RANGE OF DISORDERS
Imagine sitting in the waiting room of a pediatric epilepsy clinic and observing the
variety of patients awaiting their turn to be evaluated. A 6-year-old child, initially
referred for “staring spells”, is now here for a follow-up appointment with well-
controlled childhood absence epilepsy. In a wheelchair, you see a 13-year-old child
with spastic quadriparetic cerebral palsy and poorly controlled structural focal-onset
epilepsy. She is here to have the settings on her vagus nerve stimulator (VNS) adjusted
with the hope that her focal seizures, some of which spread to both hemispheres,
might become less frequent. An 8-month-old infant has been worked into the schedule
with continued clusters of infantile spasms despite completing a trial of adrenocorti-
cotropic hormone (ACTH). A new patient is here for a second opinion about whether
his brief stereotyped events of generalized shaking with partial loss of awareness are
epileptic in nature. Finally, there is an 8-year-old for a 6-month postoperative follow-
up visit after a focal neocortical resection to remove an area of cortical dysplasia and
who happily remains seizure free. As different as these patients may be in age, clinical
phenomenology, and response to therapy, they all have epilepsy. Clearly, this is a het-
erogeneous collection of distinct disorders, which may more appropriately be referred
to as “epilepsies”. To understand this clinical spectrum, one must be familiar both
with what unifies these conditions as well as what makes each distinct.
A Pediatric Epilepsy Primer 5

The traditional definition of epilepsy is deceptively simple: having two or more

unprovoked seizures separated by more than 24 hours. A couple of recent modifi-
cations have become increasingly accepted as meeting criteria for the diagnosis of
epilepsy, specifically one unprovoked (or reflex) seizure and a probability of further
seizures similar to the general recurrence risk (at least 60%) after two unprovoked
seizures occurring over the next 10 years, or the diagnosis of an epilepsy syndrome.
Each component of these definitions is important to bear in mind. Seizures are par-
oxysms of abnormally hyperexcitable and hypersynchronous cortical activity, which
results in a change in sensation, motor function, behavior, or sensorium. If the sei-
zure occurs immediately following a precipitating event, then it is referred to as an
acutely provoked/reactive seizure or acute symptomatic seizure.
As mentioned above, a common example of such an event would be a febrile
seizure: 2%– 4% of all children between the ages of 6 months and 5 years’ experi-
ence a generalized tonic– clonic seizure lasting less than 15 minutes in association
with a fever not caused by a central nervous system (CNS) infection. In this case, the
acute provoking event – the fever – is immediately followed by the seizure. Other
examples of acute symptomatic seizures would include those which occur at the time
of trauma, in the context of hyponatremia, or in association with a withdrawal syn-
drome (e.g., alcohol).
In contrast, with epilepsy, there is no immediate provoking event for the sei-
zure. At times, the seizure may arise from an old injury such as from a prior stroke.
Because the precipitating event precedes the seizure by weeks to years, such an event
is considered unprovoked and is often referred to as a “remote symptomatic seizure”,
or structural/metabolic in origin. Finally, in order to meet the traditional definition of
epilepsy, two or more unprovoked seizures must be separated by more than 24 hours.
The reason for this is that rapidly recurrent seizures occurring close together carry
the same epidemiological risk of eventual recurrence as a single seizure.
As stated above, another definition of epilepsy has been added: a single unpro-
voked seizure with a recurrence risk of at least 60%. The threshold of 60% reflects
the risk of seizure recurrence after two unprovoked seizures. Findings on EEG, MRI,
and neurological examination as well as other factors such as family history and the
presence of a defined epilepsy syndrome determine the likelihood of recurrence.
For example, if a patient has a single absence seizure, then one would not need to
see a second in order to make the diagnosis of childhood absence epilepsy as this
syndrome is known to be associated with frequent seizures.
If a patient has two or more unprovoked seizures (or a risk of recurrence of greater
than 60%), then they may justifiably be labeled as having epilepsy. Given the broad
nature of this definition, many different types of clinical phenotypes fall under
the cover of this one large umbrella. It is a bit like stating that one lives in North
America – helpful information but not very specific! Nowhere is this more evident
than in pediatric epilepsies in which cause, clinical phenomenology, and outcome
vary greatly.
Like the epilepsies which arise in adulthood, children may suffer from seizures as
a consequence of trauma, CNS infections, strokes, and other brain insults. A particu-
lar example of this would be children who suffer injuries in utero or during the pro-
cess of birth. Largely unique to childhood are seizures that arise from developmental
6 Handbook of Pediatric Epilepsy Case Studies, Second Edition

brain malformations such as disorders of neuronal migration leading to focal cortical

dysplasia. It is interesting to note, however, that although the abnormally formed cor-
tex is present from birth, an epileptic disorder may not develop for many years. The
reasons for this remain unclear.
To bring some semblance of order to this landscape, the epilepsies have histori-
cally been categorized or classified based on electroclinical features. Clinically,
this is accomplished using a schema developed by the International League Against
Epilepsy (ILAE), which utilizes etiology and seizure type. If the patient’s epilepsy
arises from an evident cause, such as a remote symptomatic seizure due to an old
brain injury, then the epilepsy is referred to as structural (Figure 1.1). In general, the
abnormal area of brain will be evident on MRI or other imaging modalities. Another
example of a structural epilepsy would be one arising from a focal cortical dysplasia.
However, some epilepsies are caused, not by a clear anatomic abnormality, but are
instead inherited – either as a single mutation or, more commonly, as a collection of
interacting mutations on different genes. Predictably, epileptologists refer to such
epilepsies as genetic. Several common epilepsies of childhood, such as childhood
absence epilepsy and self-limited epilepsy with centrotemporal spikes, are consid-
ered genetic.
Other etiological categories of epilepsy include infectious, metabolic, and immune
mediated. Finally, some epilepsies occur in patients without an evident cause: the
brain MRI is normal, there is no clear heritability, and no aspect of the workup
reveals a potential etiology. These epilepsies were once labeled “cryptogenic”
­ –​
literally meaning that the cause is hidden – but now are more straightforwardly
referred to as “unknown” or “idiopathic” (equated with a likely genetic cause). One
of the primary goals for the epilepsy research community is to abolish the need for
this category by increasing our understanding of what causes epilepsy as well as
expanding our repertoire of tools available for diagnosis.
In addition to etiology, the present classification scheme utilizes seizure type as
a criterion. Seizures that arise from a particular region of the brain are labeled focal
while seizures that involve both hemispheres from the onset are referred to as gener-
alized. It should be noted that seizures may begin focally and then spread to involve
the other hemisphere. Such a seizure is said to have evolved from focal to bilateral
tonic– clonic expression (what were formerly called “secondarily generalized sei-
zures”). Although not utilized in the classification scheme, focal seizures are further
divided into those with loss of awareness and those without loss of awareness. They
are also categorized as having motor onset (like clonic jerking on one side of the
body) or nonmotor onset (like a visceral sensation or visual phenomenon). Putting
the etiologic and phenomenological criteria together yields the appropriate classi-
fication. For example, epilepsies may be “structural focal” (a clear anatomic cause
affecting just one part of the brain), “genetic generalized” (an inherited epilepsy pro-
ducing seizures which affect both hemispheres at the outset-like childhood absence
epilepsy), or any other combination of terms. As will become clear in the chapters to
follow, utilizing this scheme is helpful in determining an appropriate evaluation and
management strategy.
Another peculiarity of pediatric epilepsy is the concept of an epilepsy syndrome:
a constellation of a particular type of seizure (or seizures), EEG features, and other
A Pediatric Epilepsy Primer 7

F­ IGURE 1.1 MRI images and EEG data from a teenager with structural focal epilepsy. This
­15-year-old
­​­­ ​­ ­ ​­
right-handed boy had ­left-sided
​­ hemiplegic cerebral palsy and ­startle-induced
​­
focal impaired awareness (previously referred to as complex partial) seizures. Panels A and
B are representative T1-weighted postcontrast MRI images (axial and coronal planes, respec-
tively) demonstrating the damage caused by an in utero right middle cerebral artery territory
infarction (the left side of the image corresponds to the right side of the brain). Panel C shows
the patient’s EEG immediately prior to and following an auditory startle as well as several
seconds into his typical electrographic ictal discharge. Note the high-amplitude slow activ-
ity with superimposed faster frequencies in the leads labeled Fp2–F4, F4– C4, and C4–P4
indicating that the seizure is arising from the right frontocentral region (by convention, EEG
leads with even numbers are on the right and those with odd numbers are on the left; Fp,
frontal polar; F, frontal; C, central; and P, parietal). The patient underwent definitive surgical
resection and became seizure free.
8 Handbook of Pediatric Epilepsy Case Studies, Second Edition

clinical phenomena – often associated with a particular age of onset. For example,
West syndrome represents the combination of epileptic spasms (a particular type of
seizure), an interictal EEG pattern called hypsarrhythmia, and developmental arrest
or regression with a peak age of onset between 3 and 7 months of age. Although
still clinically diverse, epilepsy syndromes seem to represent a more homogeneous
clinical population than is afforded by the ILAE classification scheme. For example,
childhood absence and juvenile myoclonic epilepsy are both categorized as genetic
generalized epilepsies, but they differ significantly in their age of onset, predominant
seizure type, and rate of remission.

PEDIATRIC EPILEPSY VIEWED FROM A

DEVELOPMENTAL CONTEXT
The CNS is unique in that its development extends from early embryonic life,
throughout childhood, and even into early adulthood. This has implications both
for the causes and the consequences of pediatric epilepsy as well as its treatment.
An important determinant of the effects of a developmental insult is the ontogenetic
stage at which it occurs. For example, failure of the anterior neuropore to close in
the fourth embryonic week would cause anencephaly while an insult in the second
trimester might cause a focal cortical dysplasia. For reasons that remain incom-
pletely understood, the immature nervous system seems to be uniquely susceptible to
developing seizures. Another way to state this is that the “seizure threshold” of the
developing nervous system seems to be lower than that of the adult nervous system.
At least part of this susceptibility may be secondary to the ongoing ontogenetic pro-
cesses of the immature brain.
One possible contributor to the decreased seizure threshold of the immature
nervous system is a physiologic imbalance of excitation and inhibition. In general,
excitatory synaptic connections develop before inhibitory ones. Further, very early
in development, it appears that inhibitory neurotransmission is actually depolariz-
ing and therefore, possibly excitatory. This appears to be due to the developmen-
tal expression of a particular type of cation chloride cotransporter, which produces
a more positive (depolarized) chloride reversal potential than what is found in the
mature nervous system. This is a potentially clinically relevant physiological phe-
nomenon since most first-line ASMs used to treat neonatal seizures – barbiturates
and benzodiazepines – act by increasing inhibition. Maturation of the GABAergic
system also involves expression of different receptor isoforms and unique modula-
tory neuropeptides (such as somatostatin). Overall, relatively late emergence of func-
tional inhibition may increase the propensity of the CNS toward excessive excitation,
which increases the likelihood of seizures.
The process of synaptogenesis involves abundant synapse formation followed
by activity-dependent pruning of ineffective, aberrant, or unnecessary connections.
Such developmental plasticity requires the developing nervous system to be uniquely
responsive to environmental effects. Because of this, insults can have pervasive and
persistent effects. Excessive activity during critical periods of development may
strengthen neuronal pathways, which subsequently form a seizure focus or pathways
of seizure propagation. Indeed, this may be one important component of the process
A Pediatric Epilepsy Primer 9

of developmental epileptogenesis. Relative immaturity of cortical connections is also

important for the clinical appearance of seizures. For example, neonates, who physi-
ologically lack extensive well-formed intercortical and interhemispheric connectiv-
ity, do not exhibit generalized seizures.
Formation of the cerebral cortex is an intricate and remarkable process which
begins with cells becoming neurons near the ventricles followed by migration of
these new neurons to their appropriate location in the cortex. Interestingly, this pro-
cess proceeds in an “inside-out” fashion – with the most recently generated neurons
migrating through cells forming the more inner cortical layers. This choreographed
relocation of cells involves glial cells, called radial glia, upon which the neurons
migrate, as well as morphological cues to guide their entrance to and exit from this
pathway. As might be expected, given the inherent complexity of this process, not all
cells successfully reach their designated location.
Such “heterotopic” neurons are likely of little consequence if found in isolation as
they are a common incidental finding in the brains of normal individuals without epi-
lepsy. However, in some patients, a collection of neurons fails to completely migrate
and may become a focal cortical dysplasia. The extent of dysplastic cortex can range
from quite restricted to very extensive. For reasons that are incompletely understood,
such foci of abnormally formed cortex are often highly epileptogenic and are com-
monly found in children with structural focal epilepsy.
In addition to the developmental causes of epilepsy, clinicians caring for children
with epilepsy must always be mindful of the potential developmental consequences
of our treatments. ASMs, in general, act by increasing inhibition or decreasing exci-
tation; some have dual and opposing actions, such as felbamate. Such therapeutic
manipulations interact with the ongoing process of synaptogenesis and may alter
cognitive processes. This is one important reason to be judicious in the use of medi-
cal therapy since it can carry its own set of potential morbidities.

A WIDE RANGE OF TREATMENT OPTIONS ARE AVAILABLE

Once the diagnosis of epilepsy has been made, consideration turns to appropriate
treatment. Some forms of childhood epilepsy may not require any intervention other
than education and reassurance. For example, self-limited epilepsy with centro-
temporal spikes is a common genetic focal epilepsy of childhood, which sponta-
neously resolves by the age of 16 years, and was previously referred to as Benign
Rolandic Epilepsy and Benign Epilepsy with Centro-Temporal Spikes (BECTS).
Approximately 60% of patients with this condition experience very few seizures.
When seizures do occur under such circumstances, an abortive therapeutic option –
such as a rectally administered form of diazepam – is often prescribed in lieu of daily
medical therapy.
For those children with SRS, which are sufficiently frequent and/or severe to
require intervention, there are many different medications from which to choose.
Factors such as type of epilepsy, age of the patient, and comorbidities are important
considerations in deciding which medication to use. Perhaps, the single most impor-
tant factor in medication choice is the specific side-effect profile of the drug and its
suitability for a particular patient.
10 Handbook of Pediatric Epilepsy Case Studies, Second Edition

Overall, approximately 60% of patients will become seizure free with one of the
first two ASMs prescribed. Unfortunately, for those whose epilepsy does not respond,
the chance of treatment success with subsequent medication trials becomes progres-
sively less. For this reason, patients who do not respond to one of the first two or three
medications are referred to as “pharmaco-resistant”,
­­ ​­ “drug-resistant”,
­­ ​­ “medically
­
refractory”, and “medically intractable”. Fortunately, there is an ever-increasing
range of options for patients with medically intractable epilepsy. One possibility is
the use of the ketogenic diet: a high-fat and low-carbohydrate therapy which results
in increased ketone body production by the liver and produces improved seizure
control through as yet undefined mechanisms.
For certain carefully selected patients, the best option is epilepsy surgery: e.g.,
neurosurgical removal of the epileptogenic zone in the cortex. Examples of such
procedures range from focal neocortical resection for patients with an area of corti-
cal dysplasia, to removal of the anterior temporal lobe in patients with temporal lobe
epilepsy, and to hemispherectomy in patients with hemimegaloencephaly. Epilepsy
surgery candidates undergo an extensive presurgical evaluation that includes neuro-
imaging, EEG monitoring, and detailed neuropsychological studies, as well as other
ancillary tests. Given the irreversible nature of surgical intervention, it is vital to
determine whether potential functional deficits might result from the proposed resec-
tion. Still, for excellent candidates, the chance of becoming seizure-free following
surgery is as high as 65%–70% depending principally on location of the focus and
whether or not there exist clear imaging findings related to that focus. At times,
surgical procedures are conducted with a goal of decreasing seizure frequency or
for palliation. This may involve, for example, partial resection of a lesion, if the pres-
ence of eloquent cortex prevents complete removal, or corpus callosotomy to prevent
generalization of seizure activity from one hemisphere to the other.
Another surgical option used to decrease seizure frequency is implantation of a
VNS device. This device consists of a generator implanted subcutaneously over the
pectoral muscle and is connected via leads wrapped around the left vagus nerve. The
VNS has an adjustable stimulation cycle, which delivers pulses of defined intensity
and duration to the vagus nerve. For unknown reasons, such stimulation significantly
decreases seizure frequency in approximately 50% of patients.
Although unlikely to make a patient seizure free, the VNS may significantly
improve seizure control. A unique responsive neurostimulator (RNS), which detects
seizure activity and utilizes cortical stimulation to abort focal seizures, is now in
routine use in adult epilepsy and is being used with greater frequency in children.
Deep brain stimulation of targets in the thalamus is similarly being employed to
treat severe pharmacoresistant epilepsy. As the range of therapeutic interventions
for medically intractable epilepsy expands, it becomes ever more vital to refer such
patients to a comprehensive epilepsy center where the possible use of such therapies
can be considered.

PEDIATRIC EPILEPSY IS NOT JUST ABOUT SEIZURES

While seizures are surely the most dramatic aspect of epileptic disorders, they are
far from the only clinical manifestation. Compared to children with other chronic
A Pediatric Epilepsy Primer 11

medical conditions, patients with epilepsy have a lower rate of successful educational
completion, employment, marriage, and other important ­quality-of-life ­​­­ ​­ measures.
Rates of affective disorders and behavioral problems are also much higher than in
the general population. Interestingly, this remains true even for patients with epilepsy
that readily comes under medical control, as well as patients who undergo successful
epilepsy surgery.
Certainly, many patients with epilepsy do extremely well, yet it remains trou-
bling that there are those who do not. For some, frequent seizures can result in an
encephalopathy that interferes with psychosocial function. Also, as ASMs generally
work by increasing inhibition or decreasing excitation, cognitive dysfunction is not
an infrequent side effect. Also, there are psychiatric problems such as depression
and anxiety, and attentional deficits. Still, another aspect of this multifactorial phe-
nomenon is the fact that epilepsy reflects, at some level, neuronal dysfunction. It is
therefore perhaps not surprising that patients with epilepsy also may have difficulties
with other cortically and subcortically mediated processes. This possibility is further
suggested by the finding that neurobehavioral problems in children with epilepsy
precede the diagnosis of epilepsy approximately 25% of the time. Regardless of the
underlying pathophysiology, it is crucial that we consider such comorbidities in car-
ing for our patients with epilepsy.

SUMMARY
Given the relatively high incidence of epilepsy, all physicians who work with chil-
dren, regardless of specialty, will encounter patients afflicted with this heterogeneous
disorder (more accurately termed, “epilepsies”). Appropriate care of these patients
is crucial given the potential developmental consequences of both the underlying
epileptogenic process, as well as those of the treatments we employ. The therapeutic
armamentarium available to neurologists and epileptologists continues to expand as
does our understanding of the basic neurobiology of these conditions. Yet, as we
work with our patients to make them seizure free, we must also be continually cog-
nizant of the wide-ranging effects of the epilepsies and avoid focusing solely on the
seizures themselves.

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 2 Epilepsy Genetics Primer
Kimberly Wiltrout
Boston Children’s Hospital

Annapurna Poduri
Boston Children’s Hospital

CONTENTS
Epilepsy Genetics Principles.................................................................................... 13
Utility of Genetic Testing ......................................................................................... 15
Genetic Testing Methods ......................................................................................... 15
Choosing Genetic Tests for Patients with Epilepsies ............................................... 18
Interpretation of the Genetic Testing Results ........................................................... 19
The Importance of Pre- and Posttest Genetic Counseling .......................................20
Conclusions ..............................................................................................................20
Suggested References...............................................................................................20

Genetics has long been recognized as having an important causal role in epilepsy.
From the first gene discoveries of familial epilepsies in the 1990s to now, there has
been rapid growth in the identification of monogenic causes of epilepsy as well as in
the delineation of the principles underlying the genetics of epilepsy. In this chapter,
we will highlight the advances in clinical practice that have come from the growth
of epilepsy genetics and will review the principles that guide a rational approach to
genetic testing in epilepsy.

EPILEPSY GENETICS PRINCIPLES

Genetic epilepsies are defined as epilepsies with a known or presumed genetic etiol-
ogy. Generally, people with presumed genetic epilepsy lack an acquired cause, such
as trauma or infection, although newer studies are beginning to examine the role
of genetic susceptibility to developing epilepsy after events such as traumatic brain
injury and stroke.
In the past 30 years, there has been a veritable boom in the identification of genetic
causes of epilepsy (Figure 2.1). Like other diseases, the genetic variants associated
with epilepsy include single nucleotide variants (one base pair), small insertions
and deletions that may or may not lead to a shift in the reading frame of the gene,
copy number abnormalities ranging from microdeletions/microduplications to larger
structural variation in the form of monosomies and trisomies, and genomic rear-
rangements that include inversions, translocations, and ring chromosomes. Copy
number variants (CNVs) are a type of genomic rearrangement that have 1 Kb or larger

DOI: 10.1201/9781003296478-3 13
14 Handbook of Pediatric Epilepsy Case Studies, Second Edition

­ IGURE 2.1 Timeline of epilepsy gene discoveries during the past 25 years. (Created by
F
Alfred George and reprinted with permission from Poduri et al., 2021, How We Got to Where
We’re Going, Elements in Genetics of Epilepsy.)

differences in copy number compared to the reference genome. CNVs mainly consist
of microdeletions and microduplications. Other less common types of genetic varia-
tion associated with epilepsy include trinucleotide repeat expansions and genomic
imprinting, which is an epigenetic phenomenon.
Familial segregation and twin studies provided the first evidence for genetic causes
of familial epilepsy. De novo variants are variants that are considered new in an
individual and are detectable in the individual but not detected in their parents when
DNA is assayed, typically from peripheral blood leukocytes or buccal samples. De
novo variants have been demonstrated to play an important role in causing epilepsy,
particularly in the case of developmental and epileptic encephalopathies (DEEs).
De novo variants most often arise during meiosis during the formation of the
oocyte or spermatocyte, and so are present starting from the individual’s zygote stage
and should be detectable in a blood sample. A de novo variant may also occur in the
postzygotic stage, with the implication that it is present in only a fraction of cells
and may potentially be restricted to only the brain or only certain neuron popula-
tions in the brain. These mosaic variants may not be detectable with the routine
DNA analysis of blood leukocytes. This phenomenon of somatic mosaicism has been
demonstrated to be a mechanism for focal cortical dysplasia, hemimegalencephaly,
and other brain malformations that have an association with epilepsy. Genetic testing
may only be successful at identifying the causative variant if performed on the brain
tissue removed during epilepsy surgery. Rarely, mosaicism has occurred in a par-
ent’s oocytes or spermatocytes, meaning that multiple eggs or sperm may have the
Epilepsy Genetics Primer 15

variant but the rest of the parent’s cells do not, resulting in “negative” testing from
DNA assayed in leukocytes and an apparently de novo testing result but a slightly
higher (1%–10%) risk of recurrence in offspring compared to a truly de novo variant
in which only one oocyte or spermatocyte had the variant DNA.
For most familial epilepsies and de novo epilepsies identified during the initial
periods of gene discovery, the genetic causes have been monogenic, meaning the
causal variant is in a single gene and follows basic inheritance patterns of autoso-
mal dominant, autosomal recessive, X-linked, etc. However, for many of the com-
mon, more drug-responsive forms of epilepsy, such as genetic generalized epilepsies
(GGEs), efforts to identify monogenic causes have not been as successful, and there
is likely a multifactorial etiology that involves risk incurred from multiple gene vari-
ants, called “polygenic risk,” and possibly epigenetic factors. The understanding of
these polygenic and epigenetic risk factors is still in its infancy, and their clinical
applicability has not yet been established.

UTILITY OF GENETIC TESTING

Identification of the genetic cause of epilepsy has a multitude of benefits, including
both clinical and personal benefits for the patient/family. From a clinical stand-
point, identification of a genetic etiology ends the diagnostic odyssey, provid-
ing clarity of the diagnosis and stopping the cycle of invasive tests. A diagnostic
genetic test may also provide prognostic value and lead to targeted diagnostics to
screen for known comorbidities, such as with TSC1/TSC2-,­ ​­ MECP2-,​­ and WDR45-
related disorders, to name a few. Identification of the genetic etiology of epilepsy
may also guide antiseizure medication (ASM) or other treatment choices and may
affect clinical trial eligibility (Table 2.1). For those with drug-resistant epilepsy,
growing evidence supporting genetic testing may also inform predictions of surgi-
cal candidacy and surgical outcomes, particularly in focal epilepsy without M RI-
­identified lesions.
Beyond the clinical utility, genetic testing is also of personal utility. Although a
more formal assessment of the psychosocial impact of genetic testing is needed, there
is general agreement about the importance of psychosocial factors. Several papers
have described that a positive genetic result may alleviate parental guilt, provide
a sense of closure, and facilitate processing of the diagnosis and prognosis. It may
increase the family’s understanding of the diagnosis and enable communication of
the diagnosis to family members, schools, other healthcare providers, and other care-
takers to increase understanding and potentially improve access to services. It also
opens doors to family support networks. Lastly, it provides important information for
recurrence risk determination and family planning.

GENETIC TESTING METHODS

Multiple techniques are used in the genetic evaluation of epilepsy, although not all
techniques have the same clinical utility. The range of tests available continues to
evolve and improve diagnostic yield. No single technology currently available can
screen for all possible genetic mechanisms of epilepsy. The ordering clinician must
16 Handbook of Pediatric Epilepsy Case Studies, Second Edition

­TABLE 2.1
Genetic Epilepsies and Syndromes with Epilepsy as a Prominent Feature in
Which Genetic Etiology Influences Treatment and Trial Eligibility
Gene Treatment
ALDH7A1 Pyridoxine
CAD Uridine
CHRNA4, CHRNB2, and CHRNA2 Potential precision therapy: transdermal nicotine
CLN2 Cerliponase alfa to delay motor impairment
DEPDC5, NPRL2, and NPRL3 Potential precision therapy: mTOR inhibitors
GRIN1, GRIN2A, GRIN2B, and GRIN2D Potential precision therapy: memantine, dextromethorphan
for ­gain-of-function
­​­­ ​­ variants
KCNQ2 Sodium channel-blocking ASMs generally helpful. Potential
precision therapy: ezogabine (in trial currently)
KCNT1 and KCNT2 Potential precision therapy: quinidine for ­gain-of-function
­​­­ ​­
variants
MECP2 Symptomatic treatments and trials ongoing
PNPO Pyridoxal ­5-phosphate
​­
PRRT2 Carbamazepine helpful
SCN1A Avoid sodium ­channel-blocking
​­ ASMs (generally)
­
Potential precision therapy: fenfluramine and stiripentol
SCN2A Sodium channel blocking ASM for ­gain-of-function
­​­­ ​­
variants. Generally, avoid sodium channel blocking ASM
for ­loss-of-function
­​­­ ​­ variants
SCN8A Sodium channel blocking ASM for ­gain-of-function
­​­­ ​­ variants
Potential precision therapy: Trials ongoing
SLC2A1 Ketogenic diet
TSC1 and TSC2 Vigabatrin for infantile spasms
Precision therapy: mTOR inhibitors
CDKL5 Ganaxolone
UBE3A Potential precision therapy: trials ongoing

consider the phenotype of the individual and decide the test most likely to target the
genes associated with the phenotype:

• Karyotype
Karyotypes are images of a person’s chromosomes isolated from an indi-
vidual cell and arranged in pairs in numerical order based on size and band-
ing patterns to look for abnormalities in chromosome number or structure.
Historically, karyotypes have been used for identification of chromosomal aber-
rations in those with dysmorphic features or congenital anomalies (e.g., trisomy
21). However, chromosomal microarray analysis (CMA) has largely replaced
the karyotype as the preferred modality in these situations due to greater resolu-
tion. Karyotype remains useful in epilepsy genetics evaluation if there is sus-
picion of a complex chromosomal rearrangement, such as a ring chromosome.
Epilepsy Genetics Primer 17

• Chromosomal Microarray Analysis

CMA evaluates for CNVs (i.e., deletions and duplications). Laboratory
technologies vary in the size of deletions and duplications that they can
detect, to a minimum reporting threshold of 25 Kb. CMA is also able to
detect regions of homozygosity, which may be due to parental consan-
guinity or uniparental disomy. The yield of testing with CMA is higher in
individuals with epilepsy cooccurring with dysmorphic features or neuro-
developmental disorders (NDDs) such as developmental delay and autism
spectrum disorder. CNVs are also more prevalent in the GGEs.
• Single Gene Testing with Sanger Sequencing
Targeted testing for a variant in a single gene can be performed by poly-
merase chain reaction (PCR) and Sanger sequencing. Although, historically,
this has been a mainstay of genetic testing, particularly for disorders such as
Dravet syndrome, in which variants in a single gene are predominantly the
explanation for the disorder, and more recently, gene panels have replaced
single gene testing. Even in Dravet syndrome, where SCN1A variants are
the predominant cause of the phenotype, there remains some genetic hetero-
geneity, in which other genes may cause a similar phenotype, particularly
early in the course of the disorder. This genetic heterogeneity contributes
to the higher yield of gene panels and exome sequencing over single gene
testing. There are also reports of missed identification of variants due to
errors in the Sanger sequencing technique. Single gene testing with Sanger
sequencing remains useful to validate previously identified single nucleo-
tide variants and for family segregation analysis.
• Next Generation Sequencing (NGS)
NGS technologies allow for sequencing of the DNA and RNA at a faster
and more cost-effective rate than Sanger sequencing. NGS includes three
testing techniques: multigene panels, whole exome sequencing, and whole
genome sequencing.
• Gene Panels
Multigene panels (MGP) feature sequencing of the coding regions and
surrounding splice sites, and depending on the panel, CNV analysis for tar-
geted genes specific to a group of disorders, such as infantile-onset epilepsy.
The panels may include several to hundreds of known epilepsy genes. The
obvious limitation of MGP is that only genes in the panel will be tested.
Several studies have found that the more genes included in the panel, the
higher the diagnostic yield of the panel.
• Exome Sequencing
Exome sequencing (ES) evaluates for sequence changes within the entire
coding regions of approximately 20,000 genes and intronic regions near
the exons. With the exception of splice sites immediately flanking an exon,
intra- and intergenic noncoding regions are not included in the analysis.
More recently, some laboratories are also able to detect CNV within the
exons. ES may be analyzed for the patient alone or the patient and parent
data may be analyzed together as a “duo” or “trio.” Analysis of trio-based
exome increases the diagnostic yield, as it improves the ability to classify
18 Handbook of Pediatric Epilepsy Case Studies, Second Edition

any variants identified during testing. Exome sequencing allows for the
option of reanalysis in the future if negative.
• Genome Sequencing
Genome sequencing (GS) includes sequencing of the entire human
genome, including the coding sequences, as well as the noncoding regions,
and can detect SNVs, insertions/deletions, CNVs, and structural variants.
GS has the potential to yield more variants of uncertain significance (VUS)
than other methods, making a trio-based approach a key component of vari-
ant interpretation. GS is a more expensive testing method that is not often
covered by insurance, but, as has been experienced with the other testing
methods, the costs are expected to decline over time. As analysis methods
develop, we anticipate more detection of noncoding variants in the regions
of known genes and novel genes.
• Other
In specific cases, additional targeted genetic testing may be required,
guided by epilepsy-related phenotypes that suggest specific syndromes or
genes.

Detection of Repeat Expansion Disorders. If disorders with tandem repeats as a

causative mechanism of disease are suspected, targeted testing for the expansion
triplet repeat within the gene should be considered. Examples of these disorders
include Fragile X Syndrome (CGG repeats in the FMR1 gene), ARX-related​­ infan-
tile epileptic-dyskinetic encephalopathy, Unverricht Lundborg Disease, and Familial
Adult Myoclonic Epilepsy (FAME). Technologies utilizing long-read NGS platforms
may improve the yield for identifying tandem repeat disorders using GS in the future.
Methylation Studies. If Angelman syndrome or Prader–Willi syndrome is sus-
pected, methylation studies of 15q11.2-q13 chromosome region via methylation-
­sensitive multiplex ­ligation-dependent
​­ probe amplification (MS-MLPA)
­­ ​­ should be
considered to detect deletions, uniparental disomy, and imprinting defects.

CHOOSING GENETIC TESTS FOR PATIENTS WITH EPILEPSIES

Just as there is not one test that will screen for all possible mechanisms of genetic
variation in epilepsy, there is not a single algorithm for genetic testing in epilepsy.
Similar to other diagnostic tests in medicine, there are pros and cons for each testing
strategy that must be considered. The first step in genetic testing is to determine the
phenotype of the individual, as this both inform the expected diagnostic yield of the
genetic test and will also play a role in the interpretation of any results (Table 2.2).
Detailed phenotype information should be provided to the testing lab to aid in their
interpretation of any variants identified.
In general, for epilepsy, diagnostic yields for ES and GS are higher than those
of MGP and CMA. As such, ES or epilepsy-focused MGP is generally considered
the initial methodology of choice for most epilepsies. DEE and the presence of epi-
lepsy with other neurodevelopmental comorbidities, such as intellectual disability or
autism, increases the diagnostic yield for all of the testing techniques, and supports
the continued testing with an alternative technique if the first test is negative. ES and
Epilepsy Genetics Primer 19

­TABLE 2.2
Diagnostic Yield of Genetic Testing Techniques in Epilepsy
Diagnostic Yield

Total Epilepsy Epilepsy + Other

Test Cohort (%) DEEs (%) NDDs (%) Focal Epilepsy (%)
CMA 9 9
Multigene Panel 19 24 7
Exome 24 29 27 8
Sequencing
Genome 48
Sequencing

Source: Percentages obtained from Sheidley et al. (2022).

GS provide the additional benefit of opportunity for reanalysis after an initial nega-
tive test. The yield of CMA is higher in those with epilepsy and dysmorphic features
or other systemic abnormalities, supporting the use of CMA earlier in the diagnostic
testing algorithm for these individuals.

INTERPRETATION OF THE GENETIC TESTING RESULTS

The work of epilepsy genetics does not end with receiving a genetic testing result.
Any identified variant must be interpreted in the context of the patient’s phenotype
and what is known (or not known) about the structure and function of the gene,
as well as previously identified variants in the gene. The interpretation of variants
is guided by the American College of Medical Genetics and Genomics (ACMG)
standard terminology, which includes five categories: pathogenic, likely pathogenic,
uncertain significance, likely benign, and benign.
When receiving a genetic test result from the laboratory, the first step is deter-
mining if the clinical features are fully explained by the detected genetic variant.
For some genes, the associated disorder, prognosis, and therapeutic implications
depend on the functional consequence of the variant. This requires obtaining data on
whether the variant has ­loss-of-function
­​­­ ​­ or ­gain-of-function
­​­­ ​­ properties, which may
be reported in the literature or may require contacting a research group studying the
gene and inquiring about the possibility of performing functional testing.
If the detected variant is of uncertain significance, there are several steps that may
be taken to aid in interpretation. First, if parents have not been tested for the vari-
ant, parental testing may be helpful, as an unaffected parent with the same variant is
often, although not always, a hint that it is not the cause of the epilepsy. If other fam-
ily members are affected and available for testing, performing a familial segregation
analysis of the variant and disorder can also be helpful. In addition, gaining a deeper
understanding of the phenotype may aid interpretation of the variant. The clinician
may reach out to the laboratory or use GeneMatcher to identify other clinicians and
20 Handbook of Pediatric Epilepsy Case Studies, Second Edition

researchers to combine individuals with variants in the gene and evaluate for any
potential ­gene–disease
​­ relationships.
If no genetic cause is identified, there may still be a genetic cause, but it has not yet
been identified by the methods used in testing. If one is still suspicious of a genetic
cause, a new technique may be employed to detect different types of variants, or if
some time has passed, a benefit from improvement in technology. Reanalysis of ES
or GS data after an appropriate time interval has also been shown to be successful
at identifying causative genetic variants, as the scientific knowledge of gene variants
continues to grow.

THE IMPORTANCE OF PRE- AND POSTTEST

GENETIC COUNSELING
Prior to sending genetic testing, genetic counseling should be provided to individuals
and families to review the reasons for testing, any anticipated results, and limitations
of the tests. A discussion of potential results, including the meaning of ACMG variant
interpretation classifications (pathogenic, likely pathogenic, variant of uncertain signif-
icance), and additional testing that may be undertaken for negative or uncertain results.
It is also important to review the possible outcomes from positive results, including the
impact (or potential lack of impact) on therapies and candidacy for trials.
For ES and GS, counseling must be provided on the possibility of identification
of actionable secondary findings, which mostly include variants in cancer predispo-
sition genes and cardiac arrhythmia genes. Individuals and parents may opt not to
receive these secondary findings and should be counseled regarding this decision
prior to testing. Nonclinical implications for genetic testing also need to be weighed
by families prior to testing, and these include costs of the test, the effect on insurance,
and potential implications for family dynamics.

CONCLUSIONS
Genetic testing has an established role in the evaluation of familial epilepsy and
drug-resistant and early-onset epilepsy, and the understanding of the role of genet-
ics in more common, non-drug-resistant epilepsy continues to grow. The pace of
new discoveries in the genomics of epilepsy continues to be rapid. Genetic testing is
becoming routine in the care of patients with epilepsy, presenting a challenge even to
the well-informed neurologist, who must triage individuals who might benefit from
testing, determine the appropriate and available tests, partner with genetic counsel-
ors or geneticists to consent patients and families, and interpret and explain findings,
as well as implement the findings into a treatment plan that includes expanding prog-
nostic and therapeutic implications.

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​­
Epilepsy Genetics Primer 23

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Another Random Scribd Document
with Unrelated Content
 Joseph Rose, son of William B. Horton and Mary Rose, born in
Sheshequin, when his father was but sixteen years old; married Anna
Lorinda Shores, daughter of Caleb Shores and Anna Horton, and born
on Shores' Hill, 31 July, 1821. They live in Waverly, N. Y., and have
two children, Sophia and Melinda; Sophia married Smith Barnum—
reside in Litchfield; Melinda remains unmarried.
Joseph R. Horton possesses more than ordinary intellectual
capacity, and is highly respected and esteemed. He was a faithful
Union soldier in the war of the Rebellion, and lost a leg in the
service.
 Third Generation.—Caleb I.
I. Barnabas, son of Caleb Horton I. and Abigail Hallock, born at
Cutchogue, L. I., Sept., 1666; married about 1686, Sarah Hines.
Children, all born at Cutchogue:
1. Caleb, born 1687; married Phebe Terry. 2. Barnabas. 3. Penelope. 4.
Bethia.

II. Jonathan, son of Caleb I. and Abigail Hallock, born at

Cutchogue, about 1668; married about 1693, perhaps, Bethia
Conklin.
Children, born at Cutchogue:
1. Jonathan, born 1694; married Elizabeth Goldsmith. 2. Barnabas.

IV. David, son of Caleb Horton I. and Abigail Hallock, born at

Cutchogue, about 1672; married Mary Horton, daughter of Capt.
Jonathan Horton I.
Children, all born at Cutchogue:
1. David, born in 1697; married Eliza Sweazy. 2. Silas, born in 1700. 3. John.
4. Adam. 5. Patience. 6. Mary. 7. Abigail. 8. Lydia. 9. Phebe, born 1715;
married Constant King, son of Capt. John King, a mariner, of Southold.

V. Mary, daughter of Caleb Horton I. and Abigail Hallock, born at

Cutchogue; married 31 Nov., 1682, Nathaniel Terry, son of Richard
Terry I.
Children, all born at Cutchogue:
1. Phebe. 2. Uriah, and others, names not known.
 Fourth Generation.—Caleb I.
I. Caleb, son of Barnabas Horton and Sarah Hines (Caleb I.), born
in Southold 22 Dec., 1687; married 10 Dec., 1714, Phebe Terry,
daughter of Nathaniel, son of Richard Terry I., and born in Southold,
in 1689. They moved to Roxbury, now Chester, N. J., in 1748, and
settled there. They were both members of the Southold Church, and
liberal supporters of the Gospel. On their tombstone in Chester
Cemetery we find "Caleb Horton, of Southold, L. I., N. Y., died 6
Aug., 1772, having lived almost 85 years with an unblemished
character. Phebe, wife of Caleb Horton, died 24 Dec., 1767, having
finished a life of 78 years, 58 of which she was the wife of Caleb
Horton.
"'Martha's care she had at heart,
And also chosen Mary's better part.'"
Children all born in Southold:
1. Caleb, born 1715; married Sarah Benjamin. 2. Hannah, born 1717;
married Samuel Sweazy, son of Joseph Sweazy. 3. Nathaniel, born 13 Oct.,
1719; married Mehetabel Wells. 4. Nathan, born about 1720; married
Mehetabel Case. 5. Phebe, born about 1722; married Henry Tuthill. 6. Elijah,
born 19 June, 1724; married Lydia Sweazy. 7. Richard, born about 1726;
married Elizabeth Harrison. 8. Sarah, born about 1735; married Stephen
Sweazy. 9. Mary, born about 1831; married Richard Terry. 10. Rachel, born
about 1733; married 23 Aug., 1753, Jonathan Racket. 11. Rhoda, born about
1728; married Robert Robinson; died in Chester, 30 June, 1771, aged 43 years
and 5 days.

II. Barnabas, son of Barnabas Horton and Sarah Hines, born in

Southold, about 1690; married Mary Sweazy and moved to Goshen,
Orange Co., N. Y., about 1732.
Children, probably all born in Southold:
 1. Barnabas, born in 1772; married Abigail Parshall. 2. David, born 1724;
married Mary Warner. 3. Matthias, born 1726; married. 4. Elihu, born 1720;
died young. 5. Silas, born 1730; married Experience Vail. 6. Mary, married
Charles Seely.

I. Jonathan, son of Jonathan Horton and Bethia Conklin (Caleb I.),

born at Cutchogue, L. I., about 1694; married in 1720, to Elizabeth
Goldsmith, daughter John Goldsmith, and born at Southold, 3 Nov.,
1701. They were both members of the Southold Church.
Children, all born at Cutchogue:
1. Israel, born in 1728; married Sarah Lee. 2. Jonathan, born in 1730;
married Bethia Horton. 3. Barnabas, born in 1732; married, perhaps, Mary
Tuthill. 4. Zaccheus, born in 1734; married widow Elizabeth Case. 5. Bethia,
born in 1736. 6. Elizabeth, born in 1739; married David Tuthill, probably a son
of Henry Tuthill and Phebe Youngs, and born in Southold about 1735.

II. Barnabas, son of Jonathan Horton and Bethia Conklin, born at

Cutchogue, in 1695; married about 1721, to Sally Clark.
Children, all born at Cutchogue:
1. Jonathan, born 1722. 2. Bethia. 3. Calvin.

I. David, son of David Horton and Mary Horton (Caleb I.), born at
Cutchogue, in 1697; married about 1720, perhaps, to Eliza Sweazy,
daughter of Richard Sweazy.
Children, all born at Cutchogue:
1. Richard, born in 1720; married, probably, Mehitabel Jayne. 2. Mary, born
in 1724. 3. Abigail. 4. John.
 Fifth Generation.—Caleb I.
I. Caleb, son of Caleb Horton and Phebe Terry (Barnabas, Caleb
I.), born in Southold in 1715; married in April, 1737, to Sarah
Benjamin, born in 1717. They moved to Chester, N. J., about 1748.
Children, all born in Southold, except Sally and Mary, who were
born in Chester:
1. Caleb, born in 1738. 2. Richard. 3. Stephen. 4. Justin. 5. Patty. 6. Sally. 7.
Mary, married Richard Terry.

III. Nathaniel, son of Caleb Horton and Phebe Terry, born in

Southold, 13 Oct., 1819; married Mehetabel Wells about 1740. They
moved to Chester, N. J., in 1748. "She died 10 Dec., 1801. He died
24 Jan., 1804, having lived about 85 years, with an unblemished
character."—From tombstone, Chester Cemetery.
Children, 1. and 2. born in Southold, the rest in Chester:
1. Dea. Nathaniel, born in 1741; married Rebecca Robinson. 2. Benjamin,
born 1743. 3. David, born 2 Sept., 1750; married Olive Skellinger. 4. Daniel,
married Martha Terry. 5. Polly, married Caleb Terry. 6. Mehetabel, married
Edward Lewis.

IV. Nathan, son of Caleb Horton and Phebe Terry, born in Southold
about 1725; married about 1749, to Mehetabel Case, of Southold.
They moved to Chester, N. J., soon after marriage. He was a soldier
and a captain in the Revolutionary war.
Children, all born in Chester, or Black River, Morris Co., N. J.:
1. Israel, born 1750; died young. 2. Jemima, married Houston, or Hughson;
lived at Mount Highest, N. J. 3. David, no record. 4. Nathan, born 25 Feb.,
1757; married Elizabeth Eagles. 5. Bethia, married Caleb Terry, of Black River.
6. Sarah, married Daniel Sweazy. 7. Zephaniah, born 13 Nov., 1760; married
 Jane McCurry. 8. Phineas, born 17 Feb., 1774; married 1. Bethia Luce; 2.
Esther Horton.

VI. Elijah, son of Caleb Horton and Phebe Terry, born in Southold,
19 June, 1724; married Lydia Sweazy, daughter of Joseph Sweazy,
and born in Southold about 1731. They moved to Roxbury, now
Chester, N. J., in 1748. He died 7 Oct., 1799. She died 18 March,
1723. He was a Justice of the Peace, of fair reputation, and much
respected.
Children, all born in Chester:
1. Barnabas, born 27 Sept., 1749; married Elizabeth Coleman, or Corwin. 2.
Elijah, born 19 Dec., 1756; married Lydia Sweazy. 3. Silas, born 17 July, 1746:
married 1. Susan Corwin; 2. Mary Kelsey; 3. Esther Horton.

VII. Richard, son of Caleb Horton and Phebe Terry, born in

Southold about 1727; married Elizabeth Harrison, and moved to
Chester, N. J., about 1750; and thence to Radnor, Delaware Co., Pa.
They were Quakers, and attended the Radnor Meeting, but the early
records of Radnor Meeting cannot be found. The dates are mostly
given by estimate. He remained in Chester only a short time.
Children, all born in Radnor:
1. Samuel, born about 1752; settled in Huntington Co., Pa. 2. Nathan, born
1754; settled in Huntington Co., Pa. 3. Josiah, born 1756. 4. Jesse. 5. John,
married Elizabeth Thomas. 6. Thomas. 7. Septimus, died in Baltimore, about
1850.

I. Barnabas, son of Barnabas Horton and Mary Sweazy (Barnabas,

Caleb I.), born in 1720; married in 1740, to Abigail Parshall, born in
Goshen about 1721.
Children, born in Goshen:
1. Barnabas, born about 1743; married 8 Nov., 1767, to Abigail Dickerson. 2.
Abigail, born about 1748; married Henry Youngs. 3. Sarah, born about 1752;
married 23 July, 1775, Henry Conklin. 4. Anna, born about 1754; married 12
 Oct., 1774, Ichabod Cleveland. 5. Lydia, born about 1756; married 5 Feb.,
1775, Thomas Webb.

II. David, son of Barnabas Horton and Mary Sweazy, born about
1724; married 31 May, 1744, Mary Warner. They settled in the town
of Goshen about 1760. He was a warm Whig, was one of the signers
of the Pledge of Independence for the Colonies in 1775.
Children:
1. David, born about 1745; married 29 Oct., 1773, Theodosia Allen. 6.
Dorothy, born 3 April, 1756; married Eli Corwin.

III. Mathias, son of Barnabas Horton and Mary Sweazy, born about
1726; married about 1750, and had Mathias, born in Goshen in
1751, and others, names not known.

IV. Elihu, son of Barnabas Horton and Mary Sweazy, born about
1728; married Colman, and had one child, which died young. He was
a true patriot, and signed the Pledge of Independence in 1775.

V. Silas, son of Barnabas Horton and Mary Sweazy, born in

Southold, about 1730; married about 1755, Experience Vail, daughter
of Jeremiah Vail, Esq., and Mary, and born in Goshen, N. Y., about
1732.
Children, probably, all born in Goshen:
1. Silas, born 24 August, 1756; married Mary Danes. 2. Benjamin, married
24 Sept., 1786, Anna Goldsmith. 3. Gamaliel, or Samuel, married Mehetabel
Hulse. 4. Mathias, married Sarah Rumsey. 5. Elihu. 6. Barnabas, married
Milicent Howell. 7. Nellie, married —— Stringham. 8. Mary, married John L.
Hommedinn. 9. Lucretia, married Henry Youngs. 10. Hannah, married Isaiah
Vail, Jr. 11. Abigail, born 3 Sept., 1773; married Capt. Daniel Stringham.

I. Lieut. Israel, son of Jonathan Horton and Elizabeth Goldsmith

(Jonathan, Caleb I.), born at Cutchogue, about 1728; married in
1755, to Sarah Lee, daughter of Rev. John Lee, of Lyme, Conn., born
about 1730. The Rev. John Lee had two sons who were preachers.
 Israel and his family moved from Cutchogue to Goshen Township
in 1762. He was a farmer. In the Autumn of 1771, he went to
Newburgh with a load of grain. On the way home, he was taken
sick, succeeded in getting home, but died in a day or two after.
About 1782, his widow married Parshall Terry, formerly of Southold.
He was a widower, was living with his family in Wyoming Valley in
1778. He and his family were in the famed Forty Fort the night after
the Indian battle and massacre. The next morning they fled to the
mountains and after suffering great hardships, crossing the "big
swamp," afterwards known as "Swamp Dismal," or the "Shades of
Death," they reached Stroudsburg, Pa., in safety. Leaving his family
here, he hastened to Orange Co., N. Y., for assistance. During his
absence his wife was taken sick with "camp distemper" (malignant
dysentery), and died leaving a large family of children, the youngest
but three years old.
He took his family to Little Britain, Orange Co., N. Y., and as
above-stated, married the widow Horton. The two families, all told,
numbering twenty-two persons. The house in which they lived being
an old-fashioned double log-house, they hired a school-master and
made one part of it a school-house, thus evincing a laudable
determination to have the education of their household properly
cared for. The writer obtained these facts in 1828, from Benjamin
Horton, son of Israel, who was one of the pupils. But this
arrangement was not of long continuance, for in 1786, Sarah, the
mother and step-mother died, and was buried by her first husband
in Warwick Cemetery.
Israel Horton had children as follows, the first four born in
Southold, the rest in Goshen, Orange Co.:
1. Israel, born 23 Sept., 1756; married Anna Van Devort. 2. Jason, born 18
Dec., 1758; married Mary Terry. 3. Jeremiah, born 12 Nov., 1760; married Mary
Goldsmith. 4. Eunice, born Dec., 1761; married George Howell. 5. John, born
30 July, 1763; married Deborah Terry. 6. Joseph Lee, born 27 April, 1765;
married Hannah Todd. 7. Sarah, born in 1767; died young. 8. Mary, born 6
Dec., 1768; married John Clark. 9. Samuel, born in 1770; died of small-pox;
unmarried. 10. Benjamin, born 7 Feb., 1772; married Hannah Vance.
 Israel Horton and his wife were pious people, active members of
the Southold Church, and after removing to Orange County they
became members of the Presbyterian Church of Warwick. Their
children were trained up to love and fear the Lord and keep his
commandments. He was a soldier in the old French war, and, in
1758, bearing the commission of Lieutenant, he had charge of Fort
Stanwix, N. Y., and remained there until the close of the war.

II. Jonathan, son of Jonathan Horton and Elizabeth Goldsmith, born

at Cutchogue, L. I., about 1730; married Bethia Horton about 1752,
and moved to Orange Co., N. Y. He was a zealous Whig, and early
espoused the cause of the colonies against the mother country. He
was one of the signers for the Pledge for Independence, in 1775.—
Vide "History of Orange County," page 499.
Children, probably born in Orange County:
1. John, born 1753, went to Wyoming Valley; married Mary De La Montayne. 2.
Caleb, went to New Jersey; married a Jayne. 3. Benjamin.

III. Zaccheus, son of Jonathan Horton and Elizabeth Goldsmith,

born at Cutchogue, 1734; married widow Elizabeth Case; moved to
Orange County; lived at Cornwall, where he signed the Pledge for
Independence. He was probably married twice. He had a son,
Zaccheus, who also signed the Pledge, and after the war was over
he probably settled at Penfield, Monroe Co., N. Y., and was
appointed Postmaster, at the first town meeting of that town, in
1811. Some of his posterity are living in that part of the country yet,
and some are buried in East Palmyra Cemetery, Wayne Co., N. Y.
 Sixth Generation.—Caleb I.
I. Dea. Nathaniel, son of Nathaniel Horton and Mehitabel Wells
(Caleb, Barnabas, Caleb I.), born in Southold, about 1741; married
in 1761, to Rebecca Robinson, born 21 June, 1742; died, 14 Dec.,
1819. He died 13 Aug., 1824; moved to Chester, N. J., with his
father's family, in 1748.
Children, all born at Chester:
1. Huldah, born 14 Jan., 1762; married Joel Coe; died 13 Dec., 1803. 2.
Rebecca, born 31 Dec., 1763; married Benj. Fordyce; died in 1840. 3. Jonah,
born in 1765; married Jane Dalrymple; died in Lockport, N. Y. 4. Susan, born in
1767; married 30 March, 1798, to Robert McCollam; died in Calais, N. Y. 5.
Polly, born in 1769; married David Lewis. 6. Nathaniel. 7. Hiram. 8. Mehitabel,
all three died in childhood. 9. Elisha, born about 1777; married Mary Horton;
died in Scipio, N. Y. 10. Nathaniel, born 1778; married Eunice Horton, daughter
of Daniel Horton and Martha Terry. 11. Esther, born about 1782.

Dea. Nathaniel Horton was one of the excellent of the earth, loved
by all.

II. Benjamin, son of Nathaniel Horton and Mehitabel Wells, born in

Southold, in 1743; married 1767; moved to Brutus, N. Y., and settled
there; died in Brutus.
Children:
 1. Benjamin, born 1778, had William, Wines and Omar. 2. David, born 1780,
had Spencer, who lives in Lansing, Mich., and others. 3. Rhoda, born 1782.

III. David, son of Nathaniel Horton and Mehitabel Wells, born in

Chester, 2 Sept., 1750; married Olive Skellinger, born 28 March,
1761.
Children, all born in Chester:
1. Edward, born 17 March, 1777; married Charlotte Seward. 2. Mehitabel. 3.
Daniel.

David Horton was a soldier in the Revolution—served to the close

of the war—drew a pension to the close of his life. He was a man of
integrity and sound Christian character.

IV. Daniel, son of Nathaniel Horton and Mehitabel Wells, born in

Chester, in 1751; married Martha Terry, daughter of Richard Terry
and Mary Horton, and born in Chester, in 1757; died 9 Feb., 1842.
He died 27 Nov., 1835.
Children, born in Chester:
1. Stephen, died young. 2. Eunice, born 1782; married Col. Nathaniel
Horton. 3. Daniel, married Esther Terry. 4. Lydia, married William Skellinger. 5.
Esther, married Phineas Horton, being his 3d wife.

Daniel Horton was a Justice of the Peace for many years, of fair
reputation and much respected.

II. Jemima, daughter of Capt. Nathan Horton and Mehitabel Case

(Caleb, Barnabas, Caleb I.), born in Chester, about 1752; married
about 1770, Robert Hughson. They lived at a place called Mount
Highest, N. J.
Children, probably all born at Mount Highest:
1. John. 2. Elizabeth. 3. Nathan. 4. Jacob. 5. Sarah. 6. Samuel. 7. Phineas. 8.
Robert. 9. Daniel. 10. Julia. 11. Lydia.
 Jemima Hughson died 3 Oct., 1842. Her husband survived her six
years. The children nearly all had families. Phineas had Elizabeth,
Emeline, Theodore, Sarah, Mary, John and Lura; Julia married a
Leek; Lydia married a Messler.

IV. Col. Nathan, son of Capt. Nathan Horton and Mehitabel Case,
born in Chester, N. J., 25 Feb., 1757; married in New York City, 10
July, 1783, to Elizabeth Eagles, daughter of John Eagles and Hannah
——, and born in the city of New York, 1 Dec., 1766. They moved to
North Carolina about 1785, and settled on New River, then Wilkes,
now Watauga Co., N. C.
Children, probably, all born at New River, except—
1. Hannah, born at Chester, 15 Dec., 1784; and died at Hagerstown, Md.,
while on the way to North Carolina. 2. William, born 15 August, 1786; married
Milley Dula. 3. James, born 28 Feb., 1789; married Sydnia Webb. 4. David
Eagles, born 4 May, 1792; married Sarah Dula. 5. Phineas, born 9 Jan., 1795;
married Sarah Councill. 6. Sarah, born 19 Sept., 1797; died of croup when
young. 7. John, born 11 June, 1800; died of croup when young. 8. Elizabeth,
born 15 Sept., 1803; married Zephaniah Horton, Jr., of Yancey Co. 9. Jonathan,
born 26 Feb., 1806; married Malinda Hartzag.

Col. Nathan Horton was a soldier in the Revolutionary War, and

was on guard at the hanging of Major Andre. The gun which he then
carried has been carefully preserved, and is now in the possession of
his grandsons, who live near Elkville, Wilkes Co., N. C.
The Colonel was a farmer, a prominent man and for many years a
Colonel of a regiment of militia of his county. He represented the
county of Ashe in the Legislature in 1800–1–2. He was one of the
first settlers in the county, and became wealthy in lands and other
property. He died at his residence on New River, 22 July, 1824, and
there his wife also died, 19 May, 1854.

V. Bethia, daughter of Capt. Nathan Horton and Mehitabel Case,

born in Chester, N. J., about 1759; married Caleb Terry, of Chester.
Children, probably, all born in Chester:
 1. Nathaniel, married Coleman. 2. Nathan, married Van Doren. 3. Richard,
married Smith. 4. Julia, married Caleb Horton. 5. Deborah, married Thomas
Stoute. 6. Jemima, died young. 7. Esther, married 1. Daniel Horton, son of
David Horton; married 2. Nathan Hughson, son of Robert Hughson.

VI. Sarah, daughter of Capt. Nathan Horton and Mehitabel Case,

born in Chester, N. J., about 1761; married Daniel Sweazy.
Children, probably, all born in Chester:
1. Benjamin, married Margaret Wiley. 2. James, married Effie Swackhammer.
3. Isaac, married an English lady, name not given. 4. Sarah, married Low Sliker.
5. Mehitabel, married John Sliker. 6. Mary, never married.

VII. Zephaniah, son of Capt. Nathan Horton and Mehitabel Case,

born in Chester, N. J., 13 Nov., 1760; went to North Carolina when a
young man, soon returned to Chester, and 25 March, 1788, married
Jane McCurry, daughter of Malcolm McCurry, Esq., of Chester, and
soon afterwards moved to Wilkes Co., N. C., and thence in 1793, to
Burke Co., and thence to Tennessee, where he remained only a short
time, and then returned to North Carolina, and settled in Buncomb,
now Yancey Co., where he lived, and where, 5 April, 1844, he died.
He was a magistrate for many years, and also represented Buncomb
Co. in the Legislature, in 1810–1812, and 1815.
On the day he was seventy years old he had his funeral sermon
preached by Rev. Goodson McDaniel, of the Holston Conference. His
wife died at her residence, 13 August, 1857. Her father was born on
the Island of Ila, Highlands, Scotland. He was kidnapped when a
small boy and brought to New Jersey, where he obtained a good
education, became a lawyer, and practiced law at Morristown, N. J.
Children, 1. and 2. were born in Wilkes Co.; 3. born in Burke Co.,
and the rest in Buncomb Co., N. C.:
1. Nathan, born 24 Jan., 1789. 2. Rachel, born 31 May, 1791; died 29 Oct.,
1800. 3. Sarah, born 30 June, 1794. 4. Malcolm, born 8 April, 1797. 5.
Elizabeth, born 15 Nov., 1799. 6. Zephaniah, born 26 Nov., 1802. 7. Jane M.,
born 18 March, 1806. 8. Phebe D., born 30 Oct., 1810.
 VIII. Phineas, son of Capt. Nathan Horton and Mehitabel Case,
born in Chester, N. J., 17 Feb., 1774; married 1. 19 Oct., 1797, to
Bethia Luce (Lewis), she died 20 August, 1809. He married 2. the
widow Esther Horton, daughter of Daniel Horton, and widow of Silas
Horton.
Children, all born in Chester, 1, 2, 3, 4, by first wife; 5 and 6 by 2d
wife:
1. Sarah, born 27 March, 1799; married Jeremiah Wilcox. 2. Nathan, born 27
Dec., 1801; married Julia Horton. 3. Elias, born 6 Feb., 1803; married Melinda
Lewis. 4. Mary, born 6 Feb., 1806; married Daniel Skellinger. 5. Martha Esther,
born 7 June, 1819. 6. Daniel, born 3 August, 1820; married Lydia C. Horton.

Phineas Horton died 8 Feb., 1857. Esther is still (1874) living,

resides at the homestead with her son Daniel.

I. Barnabas, son of Barnabas Horton and Abigail Parshall

(Barnabas, Barnabas, Caleb I.), born in Goshen, N. Y., about 1747;
married 1. 8 Nov., 1767, to Abigail Dickerson, she died about 1777, he
married 2. Rachel Bostwick.
Children, all born in Goshen, exact order of births not known:
1. David. 2. Isaac. 3. Selah. 4. Richard. 5. Barnabas, married Mehitabel
Youngs. 6. Mary. 7. Betsey. 8. Henry. 9. Benjamin, born 12 April, 1788. 10.
Abigail, married William Brewster.

I. Samuel, son of Richard Horton and Elizabeth Harrison (Caleb,

Barnabas, Caleb I.), born in Radnor, Delaware Co., Pa., about 1752.
He moved to Huntingdon Co., Pa., married and raised a large family,
but no family record has been found. He was a blacksmith, and had
the reputation of being a first-class workman.

II. Nathan, son of Richard Horton and Elizabeth Harrison, born in

Radnor about 1754. He settled in Huntingdon Co., Pa., and was a
blacksmith by occupation, a very skillful workman, and a man of
good character and standing. He married Rebecca Priest, and lived in
West Chester for a short time before he went to Huntingdon.
 Children:
1. William, born in West Chester, Pa., about 1789. 2. Henry, born in West
Chester, 25 Jan., 1791; married Elizabeth White. 3. Mary, born in West Chester,
25 Jan., 1791; (twins). The rest viz.: 4. Catherine. 5. Rebecca. 6. Deborah. 7.
John. 8. Elizabeth. 9. Nathan Priest, were all born in Huntingdon.

V. John, son of Richard Horton and Elizabeth Harrison, born in

Radnor in 1762; married Elizabeth Thomas.
Children, all born in Newtown, Chester Co., Pa.:
1. Jesse, born in 1786; married about 1819, Mary Steel. 2. Jacob, born in
1791; married about 1813, Sarah Winans. 3. John, born 1798; married about
1828, Jane Lindsley. 4. Elizabeth, born 27 Nov., 1800; married Samuel Black.

I. Lieut. John, son of Jonathan Horton and Bethia Horton

(Jonathan, Jonathan, Caleb I.), born in Southold, L. I., 1753; went in
early life to Chester, N. J., and thence to Wyoming Valley, where
about 1782, he married Mary De La Montagnye, daughter of John De
La Montagnye. He was a soldier in the Revolutionary War, and was a
Lieutenant at the battle of Wyoming, July, 1778. He and his wife
both died in Wyoming.
Children, all born in Wyoming:
1. Sarah, born about 1784; married John Hannas; settled in Hanover, Pa. 2.
Mary, born about 1786; married John Shalls; settled in Kingston, Pa. 3. Ann,
born about 1788; died unmarried. 4. John, born about 1790; married ——
Wickizer. 5. Miller, born 2 Feb., 1792; married Elizabeth Waller. 6. Josiah, born
1795; went south; died in Georgia. 7. Jesse, born 1797; married 1. ——
Headly; 2. Widow Cook. 8. Lewis Mulison, born 1799; married Priscilla Crisman.
9. Abigail, born 1803; died in Kingston, in 1808.

I. Silas, son of Silas Horton and Experience Vail (Barnabas,

Barnabas, Caleb I.), born in Goshen, 24 Aug., 1756; married about
1777, Mary Danes. Settled in Wallkill, Orange Co., N. Y. He died 25
Dec., 1816.
 Silas, though young, like his father, was truly patriotic, and signed
the Pledge of Independence for the Colonies in 1775.
Children, probably all born in Wallkill:
1. Silas Danes, born in July, 1778. 2. Barnabas, born 1780; died in 1867. 3.
Hiram, born 1782; died in 1840. 4. Nelly, married Timothy Wheat. 5. Molly,
married Israel Moore; had Alfred and William; she married 2. Daniel Slawson,
and had six children. 6. Mehala, married William Wheat.

This family were all dead in 1873, except Mehala.

IV. Matthias, son of Silas Horton and Experience Vail, born in

Goshen, in 1765; married about 1800, Sarah Rumsey, born in Goshen,
about 1765.
Children, probably all born in Goshen:
1. John, born in 1801. 2. James, born 1803. 3. Hector, born 26 Jan., 1805. 4.
Gabriel, born 9 Aug., 1806; married Eliza Corwin; dead. 5. Dolly (Dorothy),
born 1809; married John Coleman. 6. Matthias, born 26 Jan., 1812; married
Eveline Williams. 7. Julia, born 1814; married Hector Tuthill.

Matthias Horton died 1815; his wife in 1842.

V. Elihu, son of Silas Horton and Experience Vail, born 1758;

married, about 1779, Hannah Coleman. He was a zealous Whig in
Revolutionary times, and signed the Pledge of Independence for the
Colonies in 1775.
Children, probably born in Goshen:
1. Ira, born 1780; married Sarah Vanduzen. 2. Gabriel H., married Margaret
Faulkner.

VI. Barnabas, son of Silas Horton and Experience Vail, born in

Goshen, 30 June, 1770 (Mrs. Lee says 3 Jan.); married in 1794,
Milicent Howell, of Southampton, L. I., born 18 Sept., 1770; died 13
Jan., 1849. He died 24 Oct., 1823, both in Minnisink.
Children:
 1. Parmenas Howell, born in Wallkill, 13 Dec., 1795; married Fanny Cash. 2.
Anna, born in Wallkill, N. Y., 21 Jan., 1798; married Simon W. Stoddard; died 30
Sept., 1843. 3. Harvey, born in Goshen, 1 Feb., 1800; married Mary Bennet. 4.
Horace, born in Minnisink, 6 Oct., 1803; left at 18; never heard of afterwards.
5. Gabriel, born 9 Aug., 1806, in Minnisink; died 18 Dec., 1847. 6. Milicent
Ellen, born 10 July, 1809; married Charles Lee. 7. Hampton Howell, born in
Minnisink, 16 May, 1811; died 6 Jan., 1825.

XI. Abigail, daughter of Silas Horton and Experience Vail, born in

Goshen, in 1773; married in Goshen, in 1794, Capt. Daniel Stringham,
born in Wallkill, N. Y., in 1765. They moved to the State of Indiana in
1816. He died in 1841. She died in 1842.
Children, all born in Middletown, N. Y.:
1. John D. Stringham, born in 1795; died in 1814. 2. Silas Horton Stringham,
born 7 Nov., 1797. 3. Charles S., born 1799; died 1818. 4. Lewis, born 1801;
died 1816. 5. William M., born 1803; died 1805. 6. Margaret, born 1805;
married Z. C. Hovey in 1837; died 1874. 7. Jane, born 1808; married Randolph
Widding; is now a widow in Terre Haute, Ind. 8. William M., born 1808; died
1816. 9. Hannah, born 1811; married John Gilkey; now a widow,
Crawfordsville, Ind. 10. Mary, born 1814; died 1816.

X. Hannah, daughter of Silas Horton and Experience Vail, born in

Goshen, about 1770; married in 1790, Isaiah Vail, Jr. Settled in
Goshen.
Children, probably all born in Goshen:
1. Lebbeus Lathrop, born 27 Oct., 1791; married Sally Moore; had 10
children. 2. Julia, married Whitehead Halstead; had 5 children. 3. Dolly, died in
infancy. 4. Oliver Horton, married Eunice Moore; had 5 children. 5. Nathaniel,
died unmarried. 6. William Morris, married Harriet Edwards; had 10 children. 7.
James Williamson, married 1. Lindamira Jackson, had 2 children; married 2.
Rebecca Sherman, grand-daughter of the Hon. Roger Sherman, of Connecticut,
of the Continental Congress; had 5 children.

I. Israel, Jr., first son of Lieut. Israel Horton and Sarah Lee
(Jonathan, Jonathan, Caleb I.), born in Cutchogue, Southold, 23
Sept., 1756. He died at Phelps, Ontario Co., N. Y., 22 July, 1813. She
died Jan., 1842. He moved with his father from Southold to Goshen,
N. Y., in 1762. At the death of his father he was about 15 years old,
and he being the oldest of the family, remained with his mother, and
assisted in taking care of the family. On the 23 Feb., 1780, he
married Anna Van Devort; she was the daughter of Thomas Van
Devort, and was born in Orange Co., N. Y., 29 Nov., 1763. He
removed from Orange County to Owego, N. Y., about 1801 or 1802,
and in 1816 from Owego to Phelps, Ontario Co., N. Y., where he
settled permanently, and spent the remainder of his days. They were
pious people and members of the Methodist Episcopal Church.
Children:
1. Jason, born in Orange Co., N. Y., 23 Feb., 1781; married Sally Miller, of
Geneva. 2. William Lee, born in Orange County, New York, 21 October, 1781. 3.
Sarah, born in Orange County, New York, 9 April, 1784; married in Phelps,
1813, Samuel Minnis. 4. Phebe, born in Orange Co., N. Y., 6 March, 1786;
married Frederick Schenick, of Spencer, N. Y. 5. John, born in Orange Co., N. Y.,
26 Feb., 1788; married Rachel Hiler. 6. Thomas Van Devort, born in Orange
Co., N. Y., 6 April, 1790; died 21 July, 1811. 7. Benjamin, born in Orange Co., N.
Y., 9 Sept., 1792; died 22 Sept., 1834. 8. Arietta, born in Orange Co., N. Y., 28
Nov., 1794; married Isaac Butler. 9. Peter Davis, born in Orange Co., N. Y., 11
Dec., 1796; married Hannah Couch. 10. Isaac T., born in Orange Co., N. Y., 28
Feb., 1799; married Esther Clark. 11. Eleanor, born in Owego, N. Y., 27 Dec.,
1802; married Thomas Van Devort. 12. Cornelius, born in Owego, N. Y., 13
Aug., 1804; died unmarried. 13. Joseph Lee, born in Owego, N. Y., 9 July,
1807; married widow Elizabeth Hatfield.

II. Jason, son of Lieut. Israel Horton and Sarah Lee, born at
Cutchogue, Southold, L. I., 18 Dec., 1758; married in 1783, to Mary
Terry, daughter of Uriah Terry and Abigail Cleveland, and born in
Southold, L. I., in 1760. He was a clothier by trade, served his
apprenticeship in Chester, and then settled for a short time at
Boskenridge,—it is now Basking Ridge,—New Jersey, and then
moved to Somerville, New Jersey, where he settled permanently and
where he died. He was one of the most pious and exemplary men
that ever lived, a zealous, active, intelligent Presbyterian. He was a
very strict observer of the Sabbath, and violation of it by his
neighbors always gave him great displeasure. Observing one of his
neighbors frequently chopping firewood on the Sabbath, he went
one Saturday afternoon and took his neighbor a load of wood
prepared for the fire, telling him it was to save him the trouble of
chopping his firewood on the Sabbath. His neighbor took it kindly,
and was careful afterwards to see that his fuel was all ready
beforehand for the Sabbath. It was a common remark of one of the
most reckless men of Somerville, that "If all professors of religion
would live like Old Jason Horton, he would believe there was some
reality in religion."
Jason Horton never failed to exert a strong influence for the
Christian religion as long as he lived. And his wife also was a true
help-meet for him in this regard, possessing genuine piety and
Christian activity. She died at Somerville, on Sabbath morning at 5
o'clock, 22 Aug., 1841.
Children:
1. Uriah, born in Sugar Loaf, Orange Co., N. Y., in 1784; married Elizabeth
Fairchild. 2. Sarah, born 20 Jan., 1788; married William Guest. 3. Elizabeth,
married 1. John Denniston; 2. Adam Huyler. 4. Mary, born in 1793. 5. Abigail,
born in Somerville, 6 March, 1795. 6. Eunice, born in 1797. 7. Fanny, born in
1799. 8. Israel, born in 1801; died young.

These children were all members of the Presbyterian Church,

except Elizabeth, who is a member of the M. E. Church.

III. Jeremiah, son of Lieut. Israel Horton and Sarah Lee, born at
Cutchogue, L. I., 24 Oct., 1759. He lived with his grandfather Lee on
Long Island, until he was sixteen years old, and then came to
Orange Co. On the 16th of Jan., 1783, he married Mary Goldsmith.
One of his hips was injured by sciatic rheumatism in early life,
causing him to be a cripple all his days. He was a stone-mason and
farmer, and notwithstanding he was lame, he still performed a great
amount of manual labor. He was a man of good judgment, and a
Justice of the Peace for many years, and was a man greatly beloved
and respected in the community. He and his wife were both
members of the Presbyterian Church. They settled in Blooming
Grove, about a mile and a quarter south of the present village of
Washingtonville, and he built, mostly with his own hands, the
venerable old stone mansion now occupied by the widow and family
of his only son Benjamin G. Horton. Jeremiah Horton died 17 Sept.,
1841. His wife died 10 June, 1833.
Children, all born in Blooming Grove:
1. Julia, died young. 2. Fanny, died young. 3. Eunice, born 2 March, 1791. 4.
Susan, born 17 Oct., 1793. 5. Mary, born 23 Oct., 1795. 6. Sarah, born 15
March, 1797. 7. Lydia, 24 April, 1799. 8. Eliza, died young. 9. Amy, born 17
Nov., 1803. 10. Benjamin G., born 28 August, 1807.

IV. Eunice, daughter of Lieut. Israel Horton and Sarah Lee, born at
Southold in 1761; married George Howell. They moved from Orange
Co., in early life, and settled at Peach Orchard, Seneca Co., N. Y.
Children:
1. Benjamin. 2. William. 3. Jeremiah. 4. George. 5. Samuel. 6. Lucinda. 7.
Anna. 8. Jemima. 9. Mehitabel. 10. Sally. 11. Hannah. 12. Eliza.

V. Maj. John, son of Lieut. Israel Horton and Sarah Lee, born in
Goshen, 30 July, 1763. He married in Little Britain, Orange Co., N. Y.,
9 April, 1785, Deborah Terry, daughter of Parshall Terry and Deborah
Clark, born in Little Britain, Orange Co., N. Y., on the 25 day of May,
1766. She was one of the inmates of the famed Forty Fort the night
after the Indian battle and massacre of Wyoming. She was the
tender and affectionate mother of eleven children, and raised them
all to maturity. They moved to Wyoming Valley in 1787, and in 1792
moved to Terrytown, Pa., where he bought land and settled
permanently, and where he died on the 28th day of April, 1848,
aged almost 85 years, and where she died on the 25th day of May,
1844, aged 78 years.
Major Horton built the first framed dwelling-house on the west
side of the river in the township of then Wyalusing, now Terry. He
was the owner of the first two-horse wagon ever brought into
Terrytown, and that wagon not only cheerfully bore the burdens he
put upon it, but also those of several of the neighbors. He also
owned the first fanning mill ever brought into the place. He built the
first frame barn that was ever built in the township. It was built in
1805, and is still in a good state of preservation, and is owned by
Edmund Horton.
The framed house mentioned above, built by Major Horton in
1806, accidentally took fire on the 23 Sept., 1861, and was burned
up. Major Horton was a wagoner in the Revolutionary War, towards
the close of the war, and was stationed in Mamakating Hollow, and
afterwards on the Neversink Creek, not far from the present Port
Jervis. He was Major of a battalion of militia in Wyalusing, frequently
held township offices, and was one of the leading men of the place.
He was not a public professor of Christianity, but his life in the main
was in harmony with its teachings, and he loved, and was
successful, in promoting good order in society. He was universally
esteemed, and at his funeral a larger concourse of people were
gathered than had ever before been witnessed in this part of the
country on a funeral occasion. Deborah, his wife, was a woman
distinguished for her eminent piety, unwearied industry, and good
economy; she knew well how to guide the house. Their children
were all born at Terrytown, except Ebenezer, who was born in Little
Britain, N. Y., and Anna and Lydia, who were born in Wyoming
Valley.
Children:
1. Ebenezer, born 9 Jan., 1786; married Mary Terry. 2. Anna, born 21 Oct.,
1788; died August, 1813; unmarried. 3. Lydia, born 14 March, 1791; married
John P. Stalford. 4. John, born 23 March, 1793; married 1. Nancy Miller; 2.
Lydia Molther; 3. Amanda Cross. 5. Eunice, born 14 Jan., 1796; married
Thomas Ingham. 6. Sallie, born 29 May, 1798; married John Morrow. 7. Betsey,
born 27 Dec., 1800; married Francis Baillet. 8. Francis, born 7 June, 1803; died
unmarried. 9. George F., born 2 Jan., 1806; married Abigail Terry. 10. Edmund,
born 9 August, 1808; married Martha A. Robinson. 11. Harry Morgan, born 24
Sept., 1811; unmarried.

VI. Joseph Lee, son of Lieut. Israel Horton and Sarah Lee, born in
Goshen, N. Y., 27 April, 1765; married in Sugar Loaf, N. Y., 27 Feb.,
1791, to Hannah Todd, daughter of Joseph Todd, of Sugar Loaf, and
born there on the 31 Aug., 1771. He died in Palmyra, 10 July, 1831.
She died at the same place on 9 Aug., 1827.
He moved from Goshen, N. Y., soon after he was married, to
Owego, N. Y., where he remained until 1803, and he then removed
to Palmyra, N. Y., and took up land and settled about four miles
north of the village, where Mrs. Sarah Durfee, one of his daughters,
now resides.
Joseph L. Horton and his wife were very pious people, both
worthy members of the Baptist Church, beloved and respected in the
community. He was a farmer and shoemaker. He had feeble health
for several years before his death, wasting away gradually by
consumption. He was a very patient and industrious man, and
towards the close of his life, suffering from the ravages of disease,
and much enfeebled, he would still work at his occupation, making
sometimes one shoe in a day, and at others only half a one,
according as he had strength and breath. His end was peace.
Children:
1. Samuel Todd, born at Owego, N. Y., 27 July, 1792. 2. Catharine, born at
Owego, N. Y., 21 May, 1794; married Geo. Spinner; he died without issue. 3.
Henry Wisner, born at Owego, N. Y., 31 May, 1797. 4. Sarah Parshall, born at
Owego, N. Y., 28 May, 1799. 5. James Parshall, born at Owego, N. Y., 5 April,
1801. 6. Millie Ann, born at Palmyra, N. Y., 20 July, 1803; died 7 Oct., 1818. 7.
Lewis Beers, born at Palmyra, N. Y., 24 May, 1806. 8. Anna, born at Palmyra, N.
Y., 5 July, 1808. 9. Durfee Delano, born at Palmyra, N. Y., 25 July, 1813. 10.
Wilson Osborn, born at Palmyra, N. Y., 26 April, 1815.

VII. Mary, daughter of Lieut. Israel Horton and Sarah Lee, born
near Goshen, N. Y., about 1767; married John Clark. Settled in
Spencer, N. Y.
Children:
John, Benjamin, Ann, Sally, and others.
 VIII. Samuel, son of Lieut. Israel Horton and Sarah Lee, born in the
township of Goshen, N. Y., in the year 1770. He was a master builder
in the city of New York, when quite a young man. He was said to
possess a mind peculiarly adapted to mechanical pursuits, and he
engaged in them before his majority. When about 23 years of age,
he took the small-pox, in New York, went home to his father's, in
Orange County, where he died in a few days.

IX. Benjamin, youngest child of Lieut. Israel Horton and Sarah Lee,
was born at Sugar Loaf, N. Y., 7 Feb., 1772. He was married in
Belvale, Orange Co., N. Y., 29 Jan., 1795, by the Rev. Mr. Stevens, to
Hannah Vance. She was born in Belvale, N. Y., 28 March, 1777. He
bought a farm and settled there, but by indorsing for a friend, he
lost his farm and all that he had. He then, about 1822, removed to
New York, and entered largely into the business of a master builder.
In 1834 he moved to Milan, Ohio, where, on the 18th Feb., 1856, he
died, of congestion of the lungs. His wife died at the same place, 25
June, 1860. He and his wife were both members of the M. E.
Church.
Children:
1. Margaret Vance, born 9 Dec., 1796. 2. Milton, born 7 April, 1799. 3. Julia
Ann E., born 12 May, 1800; died of consumption, in Ohio, 27 Nov., 1839;
unmarried. 4. Samuel, born 28 July, 1802; died 21 Nov., 1841, of epilepsy and
consumption; unmarried. 5. Nicholas Townsend, born in Belvale, 20 Jan., 1805;
married Sarah Van Orden. 6. Sarah Jane, born in Belvale, 2 May, 1807; married
Matthew Mead, and settled in Philadelphia, Pa. 7. Eliza, born in Belvale, 19
March, 1809; died of lock-jaw, 18 July, 1815. 8. Hannah Maria, born in Belvale,
7 May, 1811; married James Galloway Horton. 9. Catharine D., born in Belvale,
13 Aug., 1813; married Enoch Nichols. 10. Elizabeth R., born in Belvale, 3 Oct.,
1815; married Smith Conley. 11. Eunice, born in Belvale, 6 Oct., 1817; died 8
Oct., 1826, of dysentery. 12. Eloise, born in Belvale, 19 May, 1822; died 2 Oct.,
1843, of consumption; unmarried.

I. Elijah, son of Elijah Horton and Lydia Sweazy (Caleb, Barnabas,

Caleb I.), born in Chester, N. J., 19 Dec., 1756; married 19 Dec.,
1780, Mary ——, born in Roxbury, N. J., April, 1752; died 17 Dec.,
1790, leaving two children, Anna and Betsy, who married and settled
in Canada. He married 2. about 1793, Mehitabel Ruth Coleman, of
Goshen, N. Y., and had:
1. Elijah, born 15 Dec., 1794; married Sarah Oberton. 2. Ephraim Coleman,
born 1796; died young.

Elijah Horton was a man of correct moral deportment, and a

valuable citizen. He died 29 August, 1799; buried in Chester
Cemetery.

II. Barnabas, son of Elijah Horton and Elizabeth Sweazy, born in

Chester, 27 Sept., 1759; married 1783, Elizabeth Coleman. He died 6
Dec., 1800. She died 26 Jan., 1831. Both buried in Chester
Cemetery.
Children, born at Chester:
1. Elizabeth, born 1784; married Nathan Corwin; died 5 May, 1806. 2. Ruth,
married Lodwick Horton, of Goshen, N. Y. 3. Patty Coleman, born 23 Sept.,
1802; married John W. Thorp.

III. Silas, son of Elijah Horton and Lydia Sweazy, born in Chester,
17 July, 1764; married 1. Susan Corwin, who died 9 July, 1790,
leaving Lydia Corwin Horton, who married Isaac H. Corwin, and died
in 1816, childless. He married 2. Mary Kelsey, born in Goshen, 26
Jan., 1770; died 21 Dec., 1803, without issue. He married 3. Esther
Horton, daughter of Dea. Nathaniel Horton, and had
Mary, born 8 Sept., 1811; died 8 Oct., 1811.

On the tombstone of Silas, we find: "Filled the measure of his

days with usefulness, and departed this life 10 Dec., 1842. He was a
consistent member of the Congregational Church for 55 years, and
the loss caused by his death can only be estimated by those who
knew him. One of his last bequests was $3,200, secured by bond
and mortgage, and the interest to be appropriated annually to the
support of the elected Congregational minister of the first
Congregational Church of Chester."
Esther, his 3d wife, died 5 Feb., 1852, aged 70.

Jonathan Bani, son of Barnabas Horton and Mary Tuthill (Jonathan,

Jonathan, Caleb I.), born at Southold, 14 March, 1794; married 1.
20 May, 1815, by Rev. L. Thompson, to Deborah Osborn. She died in
1833, leaving children, as follows, all born in Southold:
1. Emily, born 11 March, 1816; married Gilbert Miller; she died in 1857. 2.
Edwin, born 1 Sept., 1817; died 6 July, 1818. 3. Joseph Osborn, born 24 Aug.,
1819; died in New York, in 1858. 4. Edmund Bani, born 5 October, 1821. 5.
Jerusha Conklin, born 14 June, 1824; married Orrin Case; died in 1874. 6.
Deborah, born 7 Sept., 1828; married Charles Van Devort. 7. Catherine
Conover, born 25 Dec., 1830; married Jonas Gulick.

Jonathan Bani married 2. in 1838, Jerusha Edwards, she died, and

he married 3. Jerusha Peorney, she died, and he married 4. Hannah
Blonvette, she died in 1870; he died in New York, 19 Feb., 1871, and
was buried at Cutchogue, L. I. Mr. Horton was emphatically a servant
of God. We here re-produce a portion of his obituary, which
appeared in the Presbyterian, of Philadelphia, shortly after his
decease:
"Mr. Horton has been for forty years the indefatigable and
successful Tract Missionary of the Seventh Ward, New York City.
When he first assumed the important task of laboring for the
spiritual interests of this portion of the city, it was known as one
of the most wicked and wretched wards. The 'Sailor Boarding-
houses' of olden times, with their numerous 'land-sharks,' and
temptations to sinful indulgence, swarmed here.... In process of
time, the greater part of this territory was occupied by dwellings
of opulent merchants. Then after another period of years, a new
generation found the older inhabitants of the Seventh Ward
crowded out, and their former homes became filled with a
population of the dregs of old country emigrants, or gave place
to shops and manufactories. Mr. Horton adapted himself and
modified his work to meet these successive changes, and calling
to his help a faithful band of distributors, teachers and visitors,
made a Christian influence to be felt, increasing its power by
every available means. A great multitude of conversions from
year to year were the result of his faithful labors. Admonished
by the approach of old age, he resigned his position as
missionary, made all arrangements as to his worldly affairs,
wrote farewell letters, and quietly looked forward to the close of
his earthly career."
 Seventh Generation.—Caleb I.
I. Huldah, daughter of Dea. Nathaniel Horton and Rebecca
Robinson (Nathaniel, Caleb, Barnabas, Caleb I.), born in Chester, N.
J., 14 Jan., 1762; married in 1781, to Joel Coe, of Middletown, Conn.
Moved to Scipio, Cayuga Co., N. Y., where they settled. He died 23
Sept., 1846, aged 88 years, 4 months. She died 13 Dec., 1803. After
her death he married Widow Hepzibah Smith.
Children, probably, all born in Scipio:
1. Mary C., born 8 Sept., 1782; married David Bennet; had Joel Coe, Mary
Jane, Charles David, Emily, Nathaniel Curtis, and Rachel. 2. Joseph, born 12
Nov., 1784; married 1st 12 Jan., 1816, Pallas Wales, she died 4 Feb., 1822; he
married 2d Sophia Harwood; he died in Ohio, 17 Oct., 1854. 3. Rachel, born 9
July, 1786; married 22 April, 1813, Benjamin Olney; he died 1st Sunday in
April, 1850; she died 1st Sunday in April, 1874. 4. Nathaniel, born 6 Sept.,
1788; married Mary Taylor White; he died in Oregon, 10 Oct., 1868. 5. Joel,
born 8 March, 1791; died 21 May, 1791. 6. Huldah Horton, born 5 July, 1793;
married Walter Bennet, of Portage, N. Y. 7. Joel, born 7 June, 1795; married
Sophronia Roberts; he died in Louisiana, in June, 1834. 8. Curtis, born 25
August, 1797; married Hannah Clark; died 10 April, 1871, at Spring Post, N. Y.
9. Alma, born 25 Sept., 1802; married William Harwood; had Joel, William, and
Alma; she died in Michigan, Jan., 1836.

A genealogy of the Coe family was published about twenty years

ago. Many eminent men belong to that family.

II. Rebecca, daughter of Dea. Nathaniel Horton and Rebecca

Robinson, born in Chester, 19 Dec., 1763; married Benjamin Fordyce.
He died 13 March, 1819. She died 17 Nov., 1840, in Scipio, N. Y.
Children:
1. John, born 2 March, 1791; died 21 Jan., 1868. 2. Eunice, born 4 July,
1792; died 20 Nov., 1861. 3. Benjamin, born 11 June, 1797; died 10 Dec.,
 1870. 4. Nathaniel Horton, born 4 Jan., 1799. 5. Rebecca, born 27 July, 1805;
died 7 July, 1829.

Mrs. Fordyce was a very pious woman, a member of the

Presbyterian Church, and highly esteemed.

III. Jonah, son of Dea. Nathaniel Horton and Rebecca Robinson,

born in Chester, 1765; married 1. about 1789, to Jane Dalrymple. She
died about 1795; married 2. in 1796, Hannah Bryant.
Children, probably all born in Chester:
1. Phebe, born 1790. 2. Huldah, born about 1792; married John King. 3.
Nathaniel, born about 1794.

By 2d wife:
4. Elisha, born about 1798; died without issue. 5. Barnabas, born about
1800; married Ruth Cramer. 6. Archibald, born about 1802; married Matilda
Smith. 7. Joanna, born about 1804; married David Horton Lewis. 8. Celestia,
born about 1807; married John Cooper Horton. 9. Lydia, born about 1809;
married Daniel Horton; no issue.

Jonah Horton died in Lockport, N. Y.

IV. Susan, daughter of Dea. Nathaniel Horton and Rebecca

Robinson, born in Chester, about 1767; married Robert McCollum, 30
March, 1788. Died in Calais, N. Y.
Children:
1. Joel. 2. Rebecca. 3. Isaiah. 4. Susan. 5. Robert L. 6. Hiram. 7. Esther. 8.
Nathaniel. 9. Anna. 10. Mehitabel. 11. Polly. All now (1872), dead, excepting
Hiram, Anna, and Esther.

IX. Elisha, son of Dea. Nathaniel Horton and Rebecca Robinson,

born in Chester, in 1777; married about 1800, to Polly, daughter of
Caleb Horton and Sarah Benjamin. She was his second cousin, and
born in Chester, about 1779. They moved to Scipio, N. Y., in 1797,
and settled there, and there they died.
 Children, probably, all born in Chester:
1. Isaiah, born 27 July, 1796; married Charlotte Chatfield. 2. Aaron,
unmarried. 3. Phebe, married Stephen Robinson. 4. Esther, married Warren R.
Atwood.

X. Col. Nathaniel, son of Dea. Nathaniel Horton and Rebecca

Robinson, born in Chester, 15 Sept., 1778; married about 1801, to
Eunice Horton, daughter of Daniel Horton and Martha Terry. He died
in Chester, 17 Dec., 1856. She died 7 June, 1857; both buried in
Chester Cemetery. He was an honorable and popular man, a Colonel
in the militia, and much esteemed as an officer and citizen.
Children, all born in Chester:
1. Julia, born 1802; married Nathan Horton. 2. Ann Eliza, born 1804; married
Levi Vanosdell. 3. Martha, born 1806; married Isaac Oakford. 4. Lydia, born
1809; married Charles Dobbins.

XI. Hiram, son of Dea. Nathaniel Horton and Rebecca Robinson,

born in Chester, 16 Feb., 1780; married in 1808, Mary Rose, born 29
Feb., 1778. He died 22 May, 1852. She died 8 March, 1855; both
buried in Chester Cemetery.
Children, all born in Chester:
1. Rebecca, born 29 Dec., 1809; married David Schuyler De Camp. 2.
Stephen Overton, born 21 July, 1811; married Dency Cooper. 3. Elizabeth
Celina, born 1813; married 1. Silas Olney; 2. Capt. Lemon. 4. Mary Rose, born
8 April, 1818; married Alfred Horton.

Hiram Horton possessed fine social qualities, was well skilled in

music, and always led the singing in the Congregational Church until
prevented by the infirmities incident to old age.
"With the most limited opportunities for early education, he
became a great and profound thinker. He was an upright and
conscientious man, and largely shared the esteem of all who
knew him. He was a most sincere and ardent Universalist, living
the life of the Christian, and dying in the full and perfect
 triumph of Gospel faith and hope. He and his wife were, for
many years, members of the Congregational Church of Chester;
but about thirty years before his death, he and his wife
embraced Universalism, and avowed it openly ever afterwards.
Nevertheless, they continued to support the church and worship
within its walls, and we hazard nothing in saying that there was
no man in Chester, nor in all the region round about it, who was
more generally and highly respected for manly and Christian
character than Hiram Horton. Some time before his death he
had requested that a minister of the Universalist denomination
should attend his funeral services; but the pastor of the church,
the Rev. Luke I. Stoutenberg, and others, refused to let them
into the church, notwithstanding that the salary of that preacher
was paid in part by the 'Horton Fund,' and the church itself had
been built mainly by the Hortons. His funeral had to be attended
in the Presbyterian Church, the Presbyterians generously
offering them the use of their church."—Obituary of Hiram
Horton.

XIII. Aaron, son of Dea. Nathaniel Horton and Rebecca Robinson,

born in Chester, about 1788; married Nancy Cramer, and had children,
viz.:
1. Silas, born about 1812. 2. Lydia. 3. Aaron Decatur. 4. Huldah. 5. Nathaniel
Charles.

Nancy Cramer Horton died, and he married the widow Maria Craig,
and she died without children by him. He married next the widow,
Pamela Smith; she died leaving no children by him. He married, for his
fourth wife, Jane Hawk, and by her he had one son, viz.: William.

I. Edward, son of David Horton and Olive Skellinger (Nathaniel,

Caleb, Barnabas, Caleb I.), born in Chester, N. J., 17 March, 1777,
married in Jan., 1798, Charlotte Seward, cousin of the late Gov.
William H. Seward, of New York, and born in Chester, 19 August,
1775. They moved to Cayuga Co., N. Y., in 1804, and settled in the
town of Brutus.
Children, all born in Randolph, Morris Co., N. J.:
1. James, born 24 Dec., 1798; married Jane Putnam. 2. John, born 29 Oct.,
1801; married Paulina Carrier. 3. David, born 4 July, 1804. 4. Daniel, born 17
March, 1808. 5. Horace, born 2 July, 1810.

Edward Horton died 6 Feb., 1835. His wife died 10 Sept., 1872, at
the remarkable age of 97 years and 21 days. In her funeral
procession were four generations of her descendants. They were
both buried in Brutus, N. Y.

II. Mehitabel, daughter of David Horton and Olive Skellinger; born

in Chester, N. J., 15 Jan., 1780; married Daniel Horton Miller; moved
to Michigan; died in Calhoun Co.
Children, probably, all born in Chester:
1. Olive, born 31 Dec., 1797; died 1st Sept., 1819. 2. David, born 30 Dec.
1799. 3. Phebe Ann, born 27 Jan., 1803; married Root. 4. Charles, born 13
Sept., 1809; died 23 Sept., 1828. 5. Esther, born 10 March, 1803; married
Hackett. 6. Mary C., born 8 Sept., 1823; married Hicks; died 27 April, 1863.

I. Silas Danes, son of Silas Horton and Mary Danes (Silas,

Barnabas, arnabas, Caleb I.), born in Goshen, Orange Co., N. Y., in
July, 1778. Moved to Wallkill, with his father, when young; married
Mary McClean, 1796:
Children, probably, born in Wallkill:
1. Fanny, born 1797. 2. Abbey, born 1799. 3. Warren, died 3 Oct., 1862. 4.
Betsey. 5. Caroline. 6. Nelson, married Sarah Shons. 7. James M., died in 1816.
8. Jane, died in 1838. 9. William Harrison. 10. Lewis, died young. 11. Judson,
died in 1859. 12. Alfred, died 27 July, 1873. 13. Emiline, died May 1861. 14.
Mary Ann. 15. Smith. 16. Verdine, resides in Jersey City.

Of the above children, the first to ninth, inclusive, were by his 1st
wife, she died 30 Jan., 1814. In 1815, he married 2. Mary Calender,
and she had the 10, 11, 12, and 13 of the above children, and died
in Sept., 1826, and in August, 1827, he married 3. Ann Purdy, by
whom he had the three last children.
Silas Danes Horton was a farmer, upright, honest, and a man of
more than ordinary mental capacity. He was a deacon of the Old
School Baptist Church at the time of his death, and for many years
before. He wrote frequently on religious subjects, and many of his
articles appeared in the "Signs of the Times" a religious paper edited
and published by the Rev. G. Beebee, of Middletown, N. Y.
Dea. Horton was one of the pillars of the church, greatly esteemed
by his fellow-citizens, and his death, which occurred 21 Sept., 1850,
was deeply lamented.

II. Barnabas, son of Silas Horton and Mary Danes, born in Wallkill,
in 1780; married about 1804, Jerusha Wheat; she died and he
married 2.
Children, born in Wallkill, and all by his first wife:
1. Loton, married Adeline Horton. 2. Harrison, married Prudence Warner. 3.
Anna, married Alanson Beeks. 4. Milicent, married Chauncey Horton, son of
Gilbert, son of Frederick. 5. Alfred M., married Adaline Wheat, they were
double cousins; had Silas Danes, and others. 6. Gabriel C., married 1. Mary Ann
Slawon; 2. Elizabeth Thompson; he had Loton, by his 1st wife, and Horace and
Gilbert, by 2d wife.

Barnabas Horton died in 1867.

I. Jason, son of Israel Horton and Anna Van Devort (Israel,

Jonathan, Jonathan, Caleb I.), born in Goshen, Orange Co., N. Y., 23
Feb., 1781; married in Lansing, Tompkins Co., N. Y., 9 Oct., 1805,
Sally Miller; she was born in Lansing, in 1787.
Children:
1. Ursula, born in Lansing, N. Y., 15 July, 1806; died in Williamston, Mich.,
Feb., 1868; unmarried. 2. Ann, born in Lansing, N. Y., 11 Aug., 1808; married
Daniel Sutton. 3. Phebe, born in Phelps, N. Y., 11 May, 1811; married David
Beeman. 4. Joseph, born in Phelps, N. Y., 25 Sept., 1812; died at Constantine,
 St. Joseph Co., Mich., 16 Sept., 1866. 5. Israel, born in Lansing, N. Y., 29 Jan.,
1815. 6. Mary Ann, born in Lansing, N. Y., 20 Feb., 1817, married —— Smith. 7.
Minor Thomas, born in Phelps, 2 June, 1816. 8. Eleanor, born in Lansing, N. Y.,
22 Nov., 1821; married Samuel Barker, in Phelps, where she now lives.

He died in Lansing, N. Y., 16 Sept., 1821. After his death his widow
married a Taylor; she died in Watkins, N. Y., 19 Dec., 1861.

II. William Lee, son of Israel Horton and Anna Van Devort, born in
Orange Co., N. Y., 21 Oct., 1782; married Eunice Tracey, of Spencer,
N. Y.
Children:
1. James Parshall. 2. Lydia Ann, married Shepherd. 3. Caroline, married
Harmer. 4. Charlotte, J., married Raymond. 5. Sarah R., married Nichols. 6.
Clark, married, had sons, Henry N. and Elliott.

He moved with his father to Phelps, N. Y., in early life.

III. Sarah, daughter of Israel Horton and Anna Van Devort, born in
Orange Co., N. Y., 9 April, 1784; married in Phelps, in 1813, to Samuel
Minnis. She died 8 May, 1864, in Wyalusing, Bradford Co., Pa.; she
was a quiet Christian woman, much esteemed by all who knew her.
Her husband died in comparatively early life, leaving her with a
family of children, and not much of this world's goods to help herself
with. But by industry and care she managed to raise and educate
her children. She was living with one of them, viz., Maria Homet, of
Wyalusing, Pa., at the time of her death. In her early life she was
very active—often rode on horseback—and at one time she made a
trip on horseback and alone, from Phelps to Wyalusing, about three
hundred miles circular.
Children, born at Phelps:
1. William. 2. and 3. (twins) Maria, married Edward Homet; Rachael, married
Stephen Spoor. 4. Ellen, married Jacob Hicks. 5. Willard, born in 1823; died
young.
 IV. Phebe, daughter of Israel Horton and Anna Van Devort, born in
Orange Co., N. Y., 6 March, 1786; married about 1806, to Frederick
Schenick, of Owego, N. Y., and went to Canada; nothing further is
known of her.

V. John, son of Israel Horton and Anna Van Devort, born in Orange
Co., N. Y., 26 Feb., 1788; married in Phelps, about 1810, to Rachael
Hiler. He died at Phelps, 9 Sept., 1859. She is still living.
Children, born in Phelps:
1. John M., born 30 Dec., 1819; married Mary Martin Boardman. 2. Samuel
Minnis, born 29 Oct., 1836; married Sylvia Ann Cole. 3. S. Van Rensalaer, born
11 Aug., 1829; married Rowena S. Rafter. 4. Peter Davis, born 17 April, 1826;
married Mary S. Aiken. 5. William P., born 26 Dec., 1821; married Phebe Ann
Brink. 6. Eunice, married Edgar P. Lake. 7. Ella S., married Gross. 8. Sarah,
unmarried.

VIII. Arietta, daughter of Israel Horton and Anna Van Devort, born
in Orange Co., N. Y., 28 Nov., 1794; married about 1818, to Isaac
Butler, of Phelps. She died 2 June, 1842.
Children:
1. Maria, married Eggleston. 2. Nancy, married Parshall. 3. Elizabeth, married
Parshall. 4. Sarah Ann, married Service. 5. Mahala, married Van Scoy. 6.
Amanda, married Larkin. 7. Elihu. 8. Samuel.

IX. Peter Davis, son of Israel Horton and Anna Van Devort, born in
Orange Co., N. Y., 11 Dec., 1796; married at Nelson, O., 5 May, 1830,
by Rev. Ezra Booth, to Hannah Couch, daughter of Samuel Couch and
Hannah Ferris, and born in Lee, Berkshire Co., Mass., 23 July, 1802.
He was a minister of the M. E. Church, a pious man, and an
acceptable preacher, standing fair among his brethren, and in the
community. Hannah Couch Horton died at Hubbard, Trumble Co., O.,
22 Feb., 1845, leaving three children, viz.:
1. Joseph Dempster. 2. Thirza Ann. 3. Marcus C.