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Dr. Felicia B.
Axelrod’s Report Familial Dysautonomia: New Hope For
Our Tomorrows!
This year we
celebrated our 16th International Dysautonomia Day and it marked a very
special one. For this year we received the news we have all wanted to
hear. The FD gene has been found and we are truly indebted to the
researchers who have persisted in this endeavor! We have come a long
way in the past 10 years. 1990 was an extremely important year. It was the
official start of the Human Genome Project when scientists all over the
world collaborated for the common goal of eventually sequencing the entire
human genome. It was also the year that the Dysautonomia Foundation
enlisted the assistance of Dr. Gusella’s laboratory. (Dr. Gusella’s
laboratory was already a part of the Human Genome Project and he agreed to
dedicate part of his laboratory to finding the FD gene). Then, in the year
2000, the human genome was sequenced and in January 2001 the FD gene was
identified. With the
identification of the FD gene, general population screening is a reality
but more importantly we can start working toward development of new and
better treatments for individuals affected with FD. As Dr. Slaugenhaupt
has indicated, IKBKAP is the name of the gene, IKAP is the protein product
and two mutations can cause FD. In addition, Dr. Slaugenhaupt has
demonstrated that there is tissue-specific expression in FD. The FD
patient seems to be able to make some normal as well as abnormal IKAP in
many tissues of the body but only abnormal IKAP in neural (brain) tissue.
The most common mutation (also called the major mutation) does not seem to
cause marked changes in the amount of normal IKAP made in skin or blood
cells but practically eliminates normal IKAP in the brain. Instead an
abnormal IKAP is made which probably is not able to function to full
capacity. What is the result of
a poorly functioning IKAP? This is the major question. At present it is
suspected that IKAP may work with other proteins and help other genes
function. This would cause multiple other problems and explain the marked
variability in expression of FD. At this point basic
research and clinical research will have to work together to understand
the FD gene’s function so that we can understand the following and treat
the affected FD patient:
Basic research will
probably include a number of different approaches. In addition to the
development of animal models, such as the mouse and fruit fly, there will
be laboratory experiments to understand the chemistry of cellular action
and interactions. It will also be important to continue pathological
examinations in order to correlate the new genetic findings with
expression in patient tissues. Most of the
pathological advances occurred from 1969 to 1980. In this period, major
contributions by Dr. John Pearson suggested that FD was a
neurodevelopmental disorder—a disorder resulting from incomplete
development of a special portion of the nervous system. The affected nerve
cells were the unmyelinated and small myelinated neurons which eventually
provide sensory function (pain and temperature perception) and autonomic
function (sympathetics to help cope with stress). However, all of the
reported findings were in the peripheral nervous system and obviously this
is not the complete story, since we know that in the brain there are many
autonomic centers. In addition, the clinical manifestations and the
genetic findings indicate that the central nervous system (the brain) is
also involved in FD. The question then is whether the decreased nerve
cells in the peripheral autonomic nervous system are part of the original
problem in development, or if they are a secondary loss because the
nurturing central neurons are decreased. To help understand
more about nerve supply, i.e. which specific types are affected, this
spring Dr. Hilz and I did a study with Dr. Kennedy from the University of
Minnesota. Skin biopsies were taken from two sites (the back and calf)
from 10 FD patients. The results were as follows: • Epidermal
nerve fibers were markedly decreased in back and calf • Dermal
nerve fibers to subepidermal neural plexis were markedly decreased • Sweat
glands were decreased and those present had decreased innervation •
In the remaining subepidermal nerve fibers there was a complete
absence of Substance P and Calcitonin gene-related peptide. Normally,
using special stains, 10% of subepidermal nerve fibers will contain these
proteins. These proteins help transmit pain sensation •
However, there was positive staining for vasoactive intestinal
peptide in 9 of 10 skin biopsies from the back. This protein is not
normally seen and only is seen when there is reinervation (or new nerve
growth). Clinical research
is ongoing. One of the goals of clinical research at the Dysautonomia
Treatment and Evaluation Center is to correlate clinical symptoms and
genetic findings through studies. In general, clinical studies are
important because they help buy time—they provide a means of helping
patients until definitive therapies are found. One type of study is
prospective and requires ongoing evaluation of effect. The second type is
to analyze data in retrospect. The prospective type can be used to help us
understand the gene and the wide variability of expression or for
assessment of drug effect—either a new drug or a new use of an old drug.
The retrospective clinical study helps to evaluate interventions and
determine efficacy and impact. For the past 30
years, the Dysautonomia Center has appreciated that although the FD
patient has many different problems, there are four body systems that
continue to be especially problematic—gastrointestinal, respiratory,
cardiovascular and neurological. Of these four the gastrointestinal
problems are especially distressing and difficult to manage, especially
the dysautonomia vomiting crisis. Prospective
studies: This has included
assessment of autonomic and sensory function in our patients and Dr. Hilz
has been very helpful in this area. We have studied the FD patients’
response to breathing low oxygen and high carbon dioxide, variability in
pain and temperature sensations, and blood flow in the brain under various
provocations such as change in position. This will be extremely important
in eventually assessing impact of future therapies. Other prospective
studies have been directed to trying new drug therapies. Some drugs were
shown not to be helpful but some have been helpful. Midodrine (proamatine)
is one example of a study drug that was found to be helpful in treatment
of low blood pressure. Over the past few
years advances have also been made in our treatment of the dysautonomia
vomiting crisis. It is now appreciated that the cause of vomiting (and
nausea) is not primarily due to a problem with the gastrointestinal system
(the stomach or the intestines)—rather vomiting and nausea appear to be
caused by the brain’s excessive reaction to stress (due to infection,
visceral pain, anxiety or even the stress of arousal from sleep). In some
ways the brain is acting like it is having uncontrolled
discharges—similar to a type of seizure. In this case instead of arms or
legs reacting, the individual’s internal organs react. This is like an
autonomic seizure with nausea being the “aura.” Prevention of the
crisis relies on understanding the particular stress and either avoiding
that stress or treating it early. However, once the crisis has begun,
Valium is still the most effective drug and one that neurologists
frequently use in emergency situations to control seizures. Other
medications that modify brain activity have also been helpful—drugs that
modify response to stress (such as Catapres) and, in some selected cases,
more classical anticonvulsants (seizure medications) have been helpful. Retrospective
studies: These studies are an
excellent means of evaluating past interventions but they require three
essential factors—a critical number of participants, a sufficient amount
of time, and a dedicated statistician. As of January 2001, the Center had
over 550 registered patients, had thirty years of data, and had started to
work with a staff of statisticians led by Dr. Judith Goldberg. The areas
presently being evaluated are growth hormone therapy, medications and
treatments and survival and quality of life. The preliminary results are
as follows: Growth Hormone
Therapy: Assessment in this
area is extremely problematic since only 22 patients have been treated and
there were 20 different physicians involved. Testing, medication, and
doses vary widely. However, we are trying to obtain and interpret the
data. We also understand that we will need new growth and weight charts
for all our patients because there is a coexisting impact from our ability
to provide better nutrition through gastrostomy feedings, as well as
treatment of spine curvature. Medications and
Treatment: The medications that
we plan to review are the ones that are used widely to treat blood
pressure problems—Florinef, proamatine (midodrine), and Catapres (clonidine).
The surgical interventions that we plan to review are fundoplication, tear
duct cautery and tonsillectomy and adenoidectomy. Survival
and Quality of Life: Some
preliminary results from these data are already available. The first
review of survival was in 1965. This study indicated that 50% of children
born with FD did not survive past 5 years of life. However, our own review
in 1982 indicated that even supportive treatment was making an impact
because 50% of patients could expect to survive to at least age 30 years. As of January 2001,
the Center’s registry had more than doubled from the 1982 database and
the Israeli population had been added, so it was appropriate to review our
results again. Of the 551 patients, 273 were males and 277 were females.
Although 30.5% of patients were from the Greater NYC area (New York, New
Jersey and Connecticut), patients from other areas were included:
United States and Canada
63.5% The data from prior
to March ’81 were considered the “old data” and were compared to the
data obtained from March ’81 to January ’01, the “new data.” The
“new data” were somewhat better as overall survival improved. The 50%
mark had been shifted to age 40 years. We also learned that neither sex or
geographic location appeared to impact on survival. What was especially
significant was the length of time that a patient was followed by the
Center. For example, in the “old data,” if a patient was followed for
10 years, one could expect 65% survival, whereas in the “new data”
survival increased to 80%.
Therefore patients who entered the Center after March ’81 are receiving
benefits that markedly improve their prognosis. We are not sure what
has caused the improvement. Among the possibilities being considered are
increased expertise of Center personnel, use of particular treatments
(Valium use started in 1970 but Florinef started in 1985), fundoplication
and gastrostomy (started in 1980), and establishment of the Israeli Center
(1982). It may be one or a combination of the above. Quality of life
factors are still being assessed. At the present time 24 patients have
married, there have been a total of 15 children born to individuals with
FD (all children are healthy), and 37 patients drive. We are still
analyzing educational levels, independent living and types of employment. The finding of the FD
gene has certainly brought us closer to more definitive
treatments—either directly by gene or protein or enzyme replacement or
indirectly through medications that can induce function. In the interim we
are making progress in our supportive treatments. However, we will have to
continue to evaluate present treatments, continue proven beneficial
programs, and continue research and studies. Finally, we cannot
think about the future of FD without appreciating the fact that we have a
wonderful expanding number of adult patients. This is one of the best
testaments to the effectiveness of our advances in treatment. Not only
does their number increase each year but also their personal
accomplishments become more impressive. Among my personal
joys I must admit the FD adult population accounts for a large proportion.
Although I strongly believe that all of the FD adults are very special,
since 1993 the Dysautonomia Center has been selecting a few of these
special individuals for special mention. None of us knows what
the future has in store or what challenges we might have to face in the
future. However, what we can do is look to others who have shown us by
example that there are many facets to an individual and that there are
various ways to make the most of one’s own potential. The individuals
that I have chosen in the past, as well as the ones that have been chosen
today, have accepted FD and then gone beyond it—they have shown great
courage and have taken pride in their own accomplishments. With that inner
strength, they have developed independence and self esteem. They are an
inspiration to other individuals with FD because they are the leaders and
the pioneers and are showing the way. To date 20 individuals have been so
recognized.
Rachel Berger
Jason Gross This year I have
added three more individuals. This year’s DYS-tinguished FD Adults are
Veronica Segal, Andrew Sigman, and Lori Kaplan. All three of these
individuals have worked hard to overcome some of their problems and have
made a real effort to reach out and communicate with other FD individuals
to encourage and help. They have accomplished their goals with a great
deal of self-reliance and courage and they are excellent role models. I
believe much of their success is due to their ability to accept FD and go
beyond their anger at being affected. They concentrated instead on greater
goals—work, jobs, school, friends and family. They are an inspiration
and should be applauded. *
* * * * Now on a personal
note I would like to thank a few individuals. First of all my staff—Dena
Berlin, Alice Chaikin and Philip Giarraffa. They are essential and make
the Center run efficiently and with a level of expertise that is
incredible. I would also like to thank Lenore Roseman and Maryon Weill who
are the heart and soul of an organization that is unique. They give 150%
of themselves on a daily basis and I am sure we would not have come so far
without them. Finally I want to thank the Dysautonomia Foundation as a
whole and in particular the Board and their visionary Presidents. Over the
years some hard decisions and choices had to be made. But these
presidents, who work tirelessly without financial compensation, and
rarely, if ever, are thanked for their efforts, maintained their vision
and their optimism and made all the correct choices. These choices have
brought us to the threshold of a new era for FD—one that will challenge
us but will bear incredible rewards for our FD population. “Success is not a place at which one arrives, but rather…the spirit with which one undertakes and continues the journey.” —Alex
Noble, “In Touch with the Present” Let us continue our
journey with continued hope!
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