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Hereditary Dysautonomias: Current Knowledge and Collaborations for the Future


 

National Institute of Neurological Disorders and Stroke
Hereditary Dysautonomias: Current Knowledge and Collaborations for the Future
Meeting Report
October 3-4, 2002

Written by Math Cuajungco PhD, for the National Institute of Neurological Disorders and Stroke and Office of Rare Diseases

Introduction

The hereditary dysautonomias are a large group of disorders that affect the autonomic nervous system. Taken together, inherited forms of dysautonomia are actually quite common in the population. Recently, medical scientists, NIH/NINDS representatives, and several patient support groups gathered for a workshop in order to discuss recent findings and future directions in the field. This was the first workshop on this subject, and it was instrumental in promoting interactions between basic and clinical investigators. Further, it allowed attendees to have an opportunity to meet each other, understand the similarities between the various forms of dysautonomia, and experience the unique perspective offered by patients and their families.

The subject of the first session of the workshop was familial dysautonomia (FD), the first of the hereditary dysautonomias to be well described and extensively studied. FD involves dysfunction of both the autonomic and sensory nervous systems. The neuropathological and clinical aspects of the disease, as well as a historical overview, were presented by Dr. Felicia Axelrod. She was followed by Dr. Susan Slaugenhaupt who spoke on the genetics of FD. She gave a brief chronological review of the search, and ultimate discovery, of the splicing mutation in IKBKAP that causes FD. Various clinical assessments that sensitively identify abnormal baroreflex and chemoreflex responses of the autonomic nervous system were then presented by Dr. Max Hilz, and it was shown that these standardized tests are by far the best means to further understand pathological correlates of the central and peripheral autonomic nervous system. On a similar note, Dr. William Kennedy showed that biopsies from FD patients may be a potential means of clinically measuring neuropathological alterations in neurotransmitter expression, nerve degeneration, and loss of associated tissue structures. Observations from these biopsied samples indicated that the disappearance of specific histochemical stains over time was a good indicator of disease progression. The functional significance of IKAP, the protein encoded by IKBKAP, and its role in FD pathology was discussed by Dr. Jesper Svejstrup. Recent studies in his laboratory suggest that IKAP may be involved in transcription elongation. Next, Dr. Yang Xu gave a brief overview outlining the construction of a mouse model for FD. As part of promoting research on FD, the head of the medical advisory board of the Dysautonomia Foundation, Dr. Gail Sonenshein, gave a short talk on current research endeavors currently funded by the Foundation. The session ended with a lively dialogue between presenters and attendees, with Dr. Berish Rubin serving as moderator.

The second session provided an expanded perspective on various forms of dysautonomia and dysautonomia-associated genetic polymorphisms. Dr. David Goldstein gave an introduction to the autonomic subdivisions, their functions, and the corresponding neurotransmitters utilized by these systems. He then went on to discuss dysautonomia in the context of central nervous system (CNS) disorders like familial Parkinson's disease (PD) or multiple system atrophy. Recent data suggests that, at least in familial PD, sympathetic denervation is characteristic of the disease. Dr. Sonia Peltzer provided the audience insight into what it feels like to be a parent of children suffering from familial dysautonomia (FD). Patient advocacy and the need for translational research were the main points of Dr. Peltzer's talk. Meanwhile, in keeping with the diverse theme of the session, an inherited genetic defect that causes familial amyloidotic polyneuropathy (FAP) was presented by Dr. Yukio Ando. FAP results from mutations or deletions in the transthyretin gene. The pathologic form of transthyretin protein deposits as amyloid plaques in systemic organs, dorsal root and sympathetic ganglia, as well as peripheral nerves. Dr. Ando presented current knowledge on the clinical manifestations, assessments, and treatments of FAP. Dr. Maureen Hahn then discussed the genetic defect responsible for NET deficiency, a common cause of Dysautonomia. Dr. Hahn touched on the historical aspect of the discovery of the NET gene mutation, and discussed the clinical manifestations of the disorder. There is much work currently being done in vitro to dissect the pathology caused by NET deficiency. Following this presentation, a different, but very interesting human genetic study on adrenergic receptor polymorphisms was given by Dr. Stephen Ligget. The adrenoreceptors are distinct class of receptors in the sympathetic branch of the ANS. Dr. Ligget and his colleagues identified several polymorphisms in the alpha and beta adrenoreceptor subclasses that result in specific phenotypes in vitro. Dr. Ligget concluded the talk by suggesting that several polymorphisms in the adrenergic receptors may play role as disease modifiers in some commonly observed dysautonomic syndromes, and possibly cardiac dysfunction. The final presentation of the day began with an introduction to baroreceptors, which are afferent receptors that regulate blood pressure. Dr. Italo Biaggioni described various clinical cases that exhibit complete absence of baroreceptor modulation, and linked these symptoms with other disorders like FD and multiple system atrophy. Dr. Biaggioni concluded that studying patients with autonomic failure provides a unique model of both sympathetically dependent and independent hypertension. A question and answer forum headed by Dr. Goldstein ended the session.

The third and final session focused on the intricate genetics of catecholamine metabolism. Several speakers presented discussions of the clinical symptoms resulting from baroreflex abnormalities and genetic factors that influence blood pressure regulation. Dr. David Robertson described a female patient who presented with postural orthostatic tachycardia (POTS). POTS is believed to be related to abnormalities in the interplay between the cardiovascular system and the ANS. Sufferers experience a number of symptoms such as lightheadedness, palpitations, and tremulousness during standing. Indeed, Dr. Robertson's patient was found to be suffering from dopamine-beta hydroxylase deficiency, and that elevation of dopamine was central to the clinical presentation. Next, Ms. Linda Smith gave the audience a patient's perspective on living with a form of dysautonomia. Ms. Smith suffers from NET deficiency, and is the founder and current executive director of the National Dysautonomia Research Foundation (NDRF). Ms. Smith outlined the role of NDRF in advocating awareness, patient-doctor education and governmental support. The remaining speakers continued the discussions on baroreflex control and genetic influences in baroreceptor function. Dr. Giris Jacob talked about the epidemiology and pathology involved in blood pressure regulation. Dr. Jacob presented a case of neuropathic postural tachycardia syndrome (NPTS), and concluded that NPTS patients are clearly dysautonomic. Similarly, Dr. Jens Jordan briefly outlined some clinical data, but focused mainly on current findings which indicate that genetic risk factors are seen in patients with dysautonomia. Finally, Dr. Daniel O'Connor discussed the effects of catestatin and related protein on neurotransmitter modulation. Dr. O'Connor showed that catestatin is capable of inhibiting catecholamine activity in the ANS, and their current work is aimed at elucidating genes that modify dysautonomia phenotypes. Dr. Allan Guttmacher presided over the panel discussion, which was followed by the session summary headed by Dr. Katrina Gwinn-Hardy.

The first workshop on dysautonomia successfully concluded with all attendees agreeing on several issues: (i) that it is imperative to expand clinical and basic research and put emphasis on translational research; (ii) to endorse patient advocacy and improve awareness and education; (iii) to develop resources that will aid research and treatment strategies, and possibly establish collaborative broad scale efforts in the form of multi-project applications and grants and multi-site efforts; (iv) to encourage collaborative efforts and enhance data sharing and management; (v) and to hold regular, follow-up scientific meetings.

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Agenda

Hereditary Dysautonomias
Current Knowledge and Collaborations for the Future

National Institute of Neurological Disorders and Stroke, NIH
Office of Rare Diseases, NIH

October 3 and 4, 2002
Doubletree Hotel, Rockville, Maryland, USA


Thursday, October 3

8:30 a.m.
Announcements
Katrina Gwinn-Hardy M.D., NINDS National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD

Welcome
Audrey Penn, M.D., Acting Director, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD

Stephen Groft, Pharm. D., Director, Office of Rare Diseases, NIH, Bethesda, MD

Session 1: Familial Dysautonomia-Genetics and other Factors

Chairperson Felicia B. Axelrod, M.D.

8:45 a.m.
Introduction
Familial Dysautonomia: Historical, Neuropathological, and Clinical Overview Felicia B. Axelrod, M.D., New York University School of Medicine, New York, NY

9:10 a.m.
Genetics of Familial Dysautonomia - Tissue Specific Expression of the IKBKAP Gene Mutations
Susan Slaugenhaupt, Ph.D., Harvard Medical School, Cambridge, MA

9:30 a.m.
Autonomic and Sensory Assessment and Evaluation of Familial Dysautonomia with Standardized Tests.
Max J. Hilz, M.D., Ph.D., New York University School of Medicine, and University Erlangen-Nuremberg, Germany

9:50 a.m. Break

10:10 a.m.
Future Directions for Familial Dysautonomia
Gail Sonenshein, Ph.D. (Chair, Dysautonomia Foundation Scientific Advisory Board) Boston University School of Medicine, Boston, MA

10:30 a.m.
What Is IKAP and Speculations on its Role in the Development, Maintenance and Survival of Autonomic and Sensory Neurons
Jesper Q. Svejstrup, Ph.D., Clare Hall Laboratories, UK

10:50 a.m.
Secondary Neurotransmitter Aberrations as Demonstrated by Immunoreactive Stains in Dermal Neurons
William R. Kennedy, M.D., University of Minnesota, Minneapolis, MN

11:10 a.m.
Construction of a Mouse Model to Study Mechanisms of Pathogenesis in Familial Dysautonomia
Yang Xu, Ph.D., Division of Biology, University of California, San Diego, CA

11:30 a.m.
Open Discussion and Q & A
Moderator: Berish Rubin, PhD, Fordham University, Bronx, NY (All Participate)

12:00-1:15 p.m. Break

Session 2: Inherited Dysautonomias: Familial Dysautonomia and Beyond

Chairperson David S. Goldstein, M.D., Ph.D.

1:15 p.m.
Dysautonomia in Familial Parkinson's Disease
David S. Goldstein, M.D., Ph.D., National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD

1:40 p.m.
Setting Priorities for Basic, Disease-Oriented, and Patient-Oriented Research about Inherited Dysautonomias: A Patient Advocacy Perspective
Sonia Peltzer, M.D., President, Familial Dysautonomia Hope, Newton, NC

2:00 p.m.
Familial Amyloidotic Polyneuropathy
Yukio Ando, M.D., Ph.D., Kumamoto University School of Medicine, Kumamoto, Japan

2:20 p.m.
NET Deficiency: Perspective of a Molecular Researcher
Maureen Hahn, Ph.D. Center for Molecular Neuroscience, Vanderbilt University, Nashville, TN

2:40 p.m.
Adrenoreceptor Polymorphisms Affecting Autonomic Regulation
Stephen Liggett, M.D., University of Cincinnati, Cincinnati OH

3:00 a.m. Break

3:20 p.m.
Hypertension in Autonomic Disorders: Genetic factors and Phenotyping
Italo Biaggioni, M.D., Vanderbilt University, Nashville TN

3:40 p.m.
Open Discussion and Q & A Moderator: David Goldstein, M.D., Ph.D. National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD (All Participate)

4:15 p.m. Adjourn

Friday, October 4

Session 3: Lessons from Other Dysautonomias: An Overview


Chairperson David Robertson, M.D.


8:30 a.m.
Genetic Disorders of Catecholamine Metabolism
David Robertson, M.D., Vanderbilt University, Nashville TN

8:55 a.m.
NET Deficiency: Perspective of a Patient
Linda J. Smith, Executive Director/Founder, National Dysautonomia Research Foundation, Redwing, MN

9:15 a.m.
Neuropathic Postural Tachycardia Syndrome
Giris Jacob, M.D., D.Sc., Rambam Medical Center, Haifa, Israel

9:35 a.m.
Genetic Factors in Blood Pressure Regulation
Jens Jordan, M.D., Clinical Research Center, Franz Volhard Klinik, Berlin, Germany

9:55am Break

10:15 a.m.
Genetic Determinants of Autonomic Blood Pressure Control
Daniel O'Connor, M.D., University of California, San Diego, San Diego CA

10:35 a.m.
Open Discussion and Q & A
Moderator: David Robertson M.D. Vanderbilt University School of Medicine, Nashville TN (All Participate)

11:10 a.m.
Summary of Sessions and Directions for the Future
Moderator: Alan Guttmacher, Ph.D., Deputy Director, National Human Genome Research Institute, NIH, Bethesda, MD (All Participate)

12:00 p.m. Adjourn

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Participant List

Sylvia L. Anderson, Ph.D.
Laboratory Director
Laboratory for Familial Dysautonomia Research
Biological Sciences Department
Fordham University

Yukio Ando, M.D., Ph.D.
Associate Professor
Department of Laboratory Medicine
Kumamoto University School of Medicine

Yair Anikster, M.D.
Head
Metabolic Disease Unit
Department of Pediatrics
The Chaim Sheba Medical Center

Connie Atwell, Ph.D.
Director
Division of Extramural Research
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Arie Augarten, M.D.
Pediatric Emergency Department
Sheba Medical Center

Italo Biaggioni, M.D.
Professor
Departments of Medicine and Pharmacology
Vanderbilt University Medical Center

Alyson Brenner
Parent
Dysautonomia Foundation, Inc.

David Brenner
Vice President
Dysautonomia Foundation, Inc.

Michael J. Brownstein, M.D., Ph.D.
Chief
Laboratory of Genetics
National Institute of Mental Health
National Human Genome Research Institute
National Institutes of Health

Rocco Coli
Graduate Student
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Math P. Cuajungco, Ph.D.
Research Fellow
Harvard Institute of Human Genetics
Massachusetts General Hospital

Roy Freeman, M.D.
Director, Autonomic and Peripheral Nerve Laboratory
Department of Neurology
Beth Israel Deaconess Medical Center

Nathan Gadoth, M.D.
Professor and Chairman
Department of Neurology
Meir General Hospital

William A. Gahl, M.D., Ph.D.
Clinical Director
National Human Genome Research Institute
National Institutes of Health

Sandra Gill
Harvard Institute of Human Genetics
Massachusetts General Hospital

David Goldstein, M.D., Ph.D.
Chief
Clinical Neurocardiology Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Maureen K. Hahn, Ph.D.
Instructor
Center for Molecular Neuroscience
Department of Pharmacology
Vanderbilt University School of Medicine

Henry and Ruth Halle

Melissa J. Hanson
Clinical Research Coordinator
Laboratory of Neurogenetics
National Institute on Aging
National Institutes of Health

John Hardy, Ph.D.
Laboratory Chief
Laboratory of Neurogenetics
National Institute on Aging
National Institutes of Health

Max Hilz, M.D., Ph.D.
Associate Professor
Department of Neurology
University of Erlangen-Nuremberg

Matthew Hims, Ph.D.
Research Fellow
Harvard Institute of Human Genetics
Massachusetts General Hospital

Tuula Kallinki, Ph.D.
Senior Scientist
Apoptosis Laboratory
Danish Cancer Society

Horacio C. Kaufmann, M.D.
Associate Professor
Department of Neurology
Mount Sinai School of Medicine

Erin M. Keefe
Research Assistant
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Rosanne B. Keep
Genetic Counselor
Division of Genetics
Department of Pediatrics
Albert Einstein Medical Center

William R. Kennedy, M.D.
Professor
Department of Neurology
University of Minnesota

Lauretta A. LeVoci
Graduate Student
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Marie Leyne
Research Fellow
Harvard Institute of Human Genetics
Massachusetts General Hospital

Lynn Lieberman
FD Hope

Shiloh Lieberman, D.D.S.
Board of Directors
FD Hope

Stephen B. Liggett, M.D.
Professor of Medicine and Pharmacology
Division of Pulmonary and Critical Care Medicine
Department of Internal Medicine
University of Cincinnati

Channa Maayan, M.D.
Director of Israeli Familial Dysautonomia Center
Department of Pediatrics
Hadassah Hospital Jerusalem
German Colony

Audrey S. Penn, M.D.
Acting Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Beth A. Pletcher, M.D.
Medical Geneticist
Center for Human and Molecular Genetics
University of Medicine and Dentistry of New Jersey
Medical School

Jinsong Qiu
Graduate Student
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Irma Rapaport, Ph.D.
Board of Directors
FD Hope

Jack Rapaport, Ph.D.
FD Hope

Rivkah Reichmann
Clinical Social Worker
Department of Family Services
Chai Lifeline

Quandra Scudder
Program Analyst
Neurological Disorders
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Yehonatan Sharabi, M.D.
Clinical Fellow
Clinical Neurocardiology
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Einat Shiran, M.D.
Chairperson
Israeli Familial Dysautonomia Organization
Rambam Medical Center

Suzanne Silberberg, M.D.
Board of Directors
FD Hope

Amanda A. Singleton
Research Coordinator
Neurogenetics Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Gail E. Sonenshein, Ph.D.
Professor
Department of Biochemistry
Boston University School of Medicine

Jennifer Sonenshein
President
Dysautonomia Foundation, Inc.

Giovanna Spinella, M.D.
Program Director
Neurogenetics
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Peter M. Spooner, Ph.D
Director
Arrhythmias Ischemia and SCD Research Program
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
National Institutes of Health

Julian M. Stewart, M.D., Ph.D.
Professor
Departments of Physiology and Pediatrics
Center for Pediatric Hypotension
New York Medical College

Miguel E. Weil, Ph.D.
Assistant Professor
Department of Cell Research and Immunology
Faculty of Life Sciences
Tel Aviv University

Maryon Weill
Assistant Executive Director
Dysautonomia Foundation, Inc.

Chava White
Board of Directors
FD Hope

Felicia B. Axelrod, M.D.
Professor
Departments of Pediatrics and Neurology
NYU School of Medicine

Robert Baughman, Ph.D.
Associate Director for Technology Development
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Anna Berkovitz
Instructor in Genetics
Department of Biological Sciences
Purdue University

Dan Berkovitz, J.D.
FD Hope

Michelle Berkovitz, J.D.
Board of Directors
FD Hope

Dena Berlin
Clinical Nurse Associate
Department of Pediatrics
New York University Familial Dysautonomia Center
New York University Medical Center

Greta Dornberg

Basil A. Eldadah, M.D., Ph.D.
Clinical Fellow
Clinical Neurocardiology Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Rebecca Farkas, Ph.D.
AAAS Fellow
Office of Science Policy and Planning
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Mavis Feinberg
Secretary
FD Hope

Beverly Fettman
Board Member
Dysautonomia Foundation, Inc.

Brian P. Fox
Graduate Student
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Stephen Groft, Pharm.D.
Director
Office of Rare Diseases
National Institutes of Health

Robert H. Gross, Ph.D.
Professor
Department of Biology
Dartmouth College

James Gusella, Ph.D.
Director
Molecular Neurogenetics Unit
Massachusetts General Hospital
Harvard Medical School

Alan E. Guttmacher, M.D.
Deputy Director
National Human Genome Research Institute
National Institutes of Health

Katrina Gwinn-Hardy, M.D.
Program Director
Neurological Disorders
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Kurt Hirschhorn, M.D.
Professor
Departments of Pediatrics, Human Genetics and Medicine
Mount Sinai School of Medicine

Eric J. Huang, M.D., Ph.D.
Assistant Professor
Attending Neuropathologist
Departments of Neurology and Neuropathology
University of California, San Francisco
Pathology Service

Giris Jacob, M.D., D.Sc.
Director
Jacob Recanati Autonomic Dysfunction Center
Rambam Medical Center

Jens Jordan, M.D.
Franz-Volhard Clinical Research Center
Humboldt University

Lisa Joseph
Vice President
Dysautonomia Foundation, Inc.

Mark Joseph
Parent
Dysautonomia Foundation, Inc.

Irwin J. Kopin, M.D.
Scientist Emeritus
Clinical Neurocardiology Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Jesse H. Lachter, M.D.
Senior Clinical Lecturer
Senior Attending Physician
Department of Gastroenterology
Rambam Medical Center

Laurent Landau
Vice President
Dysautonomia Foundation, Inc.

Robin Landau
Parent
Dysautonomia Foundation, Inc.

Story Landis, Ph.D.
Scientific Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Andrew M. Lauber
Case Manager
Chai Lifeline

Eliyahu Mass, D.M.D.
Department of Pediatric Dentistry
School of Medicine
Tel Aviv University

James D. Mull
Research Fellow
Harvard Institute of Human Genetics
Massachusetts General Hospital

Huda Mussaffi-Georgy, M.D.
Pediatric Pulmonology Unit
Schneider Children's Medical Center of Israel

Daniel T. O'Connor, M.D.
Professor of Medicine
Department of Nephrology
University of California, San Diego

Barry Orton, Ph.D.
Board of Directors
FD Hope

Sonia R. Peltzer, M.D.
President
FD Hope

David Robertson, M.D.
Professor of Medicine, Pharmacology, and Neurology
Clinical Research Center
Vanderbilt University

Matthew J. Rork
Graduate Student
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Lenore Roseman
Executive Director
Dysautonomia Foundation, Inc.

Berish Rubin, Ph.D.
Chairman and Professor
Biological Sciences Department
Fordham University

Donna Ruppert
Executive Director
FD Hope

Adele Schneider, M.D.
Director, Clinical Genetics
Division of Genetics
Department of Pediatrics
Albert Einstein Medical Center

Andrew B. Singleton, Ph.D.
Chief
Molecular Genetics Section
Laboratory of Neurogenetics
National Institute on Aging
National Institutes of Health

Susan A. Slaugenhaupt, Ph.D.
Assistant Professor of Neurology
Harvard Institute of Human Genetics
Massachusetts General Hospital

Ann Slaw, J.D.
FD Hope

Kenneth M. Slaw, Ph.D.
Vice-President
FD Hope

Daniel P. Smith
President
National Dysautonomia Research Foundation

Linda Smith
Executive Director and Founder
National Dysautonomia Research Foundation

Don Summers
President
The Shy-Drager Syndrome/Multiple System Atrophy Support Group

Jesper Q. Svejstrup, Ph.D.
Head of Laboratory
Cancer Research UK
London Research Institute
Clare Hall Laboratories

Gary Swergold, M.D., Ph.D.
Assistant Professor
Division of Molecular Medicine
Department of Medicine
Columbia University College of Physicians and Surgeons

Nicole R. Toto
Research Assistant
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Sabrina A. Volpi
Graduate Student
Laboratory for Familial Dysautonomia Research
Department of Biological Sciences
Fordham University

Yang Xu, Ph.D.
Assistant Professor
Department of Biology
University of California, San Diego

David Zagzag, M.D., Ph.D.
Division of Neuropathology
Department of Pathology
New York University Medical Center

Robert Zalutsky, Ph.D.
Senior Science Advisor
Office of Science Policy and Planning
National Institute of Neurological Disorders and Stroke
National Institutes of Health

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Last updated April 8, 2011