FD Day 2003: Speech by Dr. Felicia B. Axelrod

Familial Dysautonomia: 
Current Treatments and Directions for the Future!

Knowing the gene was the important first step-and there has been great effort expended in trying to get the word out and expand population screening. Reports about IKBKAP being the FD gene appeared in March 2001 and within one month Dr. Slaugenhaupt had assisted the NYU and Mt. Sinai laboratories in launching carrier screening and within a few months companies like Genzyme were also able to perform the testing. Prior to identification of the FD gene, The Dysautonomia Center registered about 15 to 20 new FD cases/year.

So far in the first half of '03, there have been 7 new cases registered. Although some are older patients in whom the diagnosis had been previously missed, about 50% of these newly diagnosed cases are births that might have been avoided if prenatal screening had been offered. So obviously there still is a need for increasing public and physician awareness about the availability of gene testing.

Testing is important, but it is also important to continue basic research to understand how the FD gene functions IKBKAP is the FD gene. IKBKAP regulates the production of a protein called IKAP. FD is associated with a change in the structure of IKBKAP so that in some tissues the IKAP is not normal. Therefore we need to answer the following questions:

• Why do some nerve cells in FD patients make an abnormal type of IKAP?
• How does this abnormal IKAP interfere with nerve cell function so that the FD disease is produced?
• Can "normal" IKAP be increased in the appropriate nerve (brain) tissue?
• Would it be better or more therapeutic to correct for a product of IKAP's activity?

With the answers to these, and similar, types of questions we will be able to go forth, start clinical trials and offer definitive treatments.

Much of the initial work will have to be done in the laboratory where cells and their products will be analyzed. In fact, through research funded by the Dysautonomia Foundation and the NIH, over 1000 drugs have already been tested and results should be available this summer. The next step will be to see if these drugs will work in living tissue, such as in a mouse and that is why the Foundation is working so hard to create a mouse model. It would be important to assess whether the drug or chemical is actually effective, and is reaching the appropriate tissue. Finally one or more of these drugs can be tried in the FD patient. Sometimes one can go directly from the laboratory to the patient but it is always important to have objective measures prior to and then after start of a drug to assess effectiveness.

In the interim, while we await our definitive treatments, over the past 30 plus years, the Dysautonomia Center, which could not exist without the unfaltering support of the Dysautonomia Foundation, has been actively finding other methods to help the individual affected with FD. The Dysautonomia Treatment and Evaluation Centers at NYU Medical Center in New York and Hadassah Hospital in Israel have played critical roles in both clinical care and research.

There is no doubt, however, that the primary function of the Centers has been to develop expertise in treatment of the affected individual. This expertise has evolved through centralization of care that has led to accumulation of sufficient data to permit depth and breadth of experience.

Most physicians have never seen one affected child, and only a few have seen an occasional child during their training or in practice, and only a handful throughout the world have actually cared for more than a single case. However, the combined Center registry now includes 591 individuals known to have FD!

Dr. Channa Maayan is the Director of the Israeli Dysautonomia Center and cares for 1/3 of the world's population of FD patients.

I am the Director of the NY Dysautonomia Center and I am aided by Dena Berlin, our nurse practitioner and study coordinator, Alice Chaikin, our patient education nurse, Philip Giarraffa, our director of social services, and the newest addition to our team, my new associate Dr. Gabrielle Gold von Simson.

Dr. Max Hilz is the Associate Director of the NY Dysautonomia Center and will be the director of future clinical trials.

With such a large population it is understandable that treatment and research become intertwined and the Centers have understood their dual role and have been conducting clinical studies.

In general, clinical studies are important because they help buy time -they provide a means of helping patients until definitive therapies are found. In general we have been conducting two types of studies-studies to understand problems and assess treatment and studies to assess available treatments. Sometimes these will overlap. Today I will talk about a few of our current projects and our goals for the future.

Current Center Projects

1. Review of (non-spinal) orthopedic problems
Laplaza J, Turajane T, Axelrod FB, Burke SW. (2001) Non-spinal orthopaedic problems in familial dysautonomia. J of Ped Ortho 21:229-232
This was a retrospective review of the records and X-rays of 182 FD patients. They concentrated on-fractures joints and other non-spinal problems.

• Fractures: 60% had 1 or more (average was 1.4/patient) and there was a high incidence of femur fractures
• Joints: 11% had neuropathic (painless swelling with destruction) joint problems, especially the knee.
• Foot problems were also common (26%) and included severe pronation, equinas deformity and bunions
• Tibial torsion was also common.

Conclusion: FD patients have an increased prevalence of fractures and neuropathic joints and foot problems. The cause may be the combination of decreased sense of proprioception and pain, ataxia, and possibly osteopenia.

2. Survival and Quality of Life:
Axelrod FB, Goldberg JD, Ye XY, Maayan C. (2002) Survival in familial dysautonomia: Impact of early intervention. J Pediatr;141:518-23.
The first review of survival was in 1965. This study indicated that a child born with FD at that time had a 50% probability of surviving to age 5 years. Our own review in 1982 (based on data accumulated up to March '81) indicated that even supportive treatment was making an impact, as the 50 % probability of survival had increased to age 30 years.

In January 2001 we reviewed our statistics again and the "new data" were even better as the 50% mark had shifted to age 40 years. Neither sex nor geographic location appeared to impact on survival. What was significant was that the second group of patients, the more recent group, was younger at time of entry and had benefited from Center treatment longer.

Conclusion: The younger population now has better survival, which is believed due to the ability to access the resource of expertise emanating from centralized care.

We are not sure what has caused the improvement. Among the possibilities 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.

Finally our data indicate that not only is survival improving, but the quality of life for our patients with familial dysautonomia is also improving. The number of adult patients has increased and more of them are functioning independently. More patients are now surviving into adulthood.

Of our 551 FD patients, 226 patients (41%) survived to at least 20 years of age. Among them, almost 20% are living independently, 16% have married, 5 patients have children, 23% have driver's licenses and 89% are employed at least part time.

3. Quality of Life study of the Pediatric FD Population
Sands S, Giarraffa P, McClain C, Axelrod FB. (manuscript in preparation)
Quality of life study in the pediatric familial dysautonomia population.
Because the care of the younger FD patients impacts heavily upon parents, parental perceptions were assessed via questionnaires. Responses were obtained from71 of 81 questionnaires. The questions were designed to assess parental impressions of their child's physical function, psychosocial function and the impact on themselves. In addition the pediatric ages were divided into three discrete age subgroups: I = 4-6 y; II = 7-10 y; III = 11 - 16 y

• Physical Quality of Life indices included physical functioning, general health, bodily pain, and role limitations.
• Psychosocial Quality of Life indices included general behavior, mental health, self-esteem, and role limitations.
• Parental impact: emotional distress and time required to care for child were assessed.

Conclusions: Overall FD patients were perceived as being physically within the impaired range, especially the youngest children. However, psychosocial functions were perceived as being average. In particular the youngest children were thought to have the best self-esteem, followed by the middle group and then the oldest group. Parents reported that they felt the impact of emotional distress was greater than impact of the time required to care for their child.

4. Efficacy of chest therapy with HFCWO (vest)
Chaikin A, Berger K, Giarraffa P, Axelrod FB (2003) Assessing efficacy of high-frequency chest wall oscillation (HFCWO) in patients with familial dysautonomia. Meeting of Amer Coll of Chest Physicians, October.

Some of FD patients with chronic lung disease have problems clearing secretions because of ineffective cough, stiff chest walls and problems with being tipped (GER & labile BP). Therefore we did a prospective one-year study using HFCWO. 15 patients were enrolled and 13 completed the study (ages 11-33 years).

• Oxygen saturation: Significant improvement within 1 mo
• Pulmonary Function: Only FVC significantly improved
• Quality of Life Measures: Highly significant improvements
  

Conclusions: HFCWO is a useful adjunct in the management of FD patients with chronic lung disease. It improves pulmonary function and quality of life

5. Review of experience with growth hormone
Kamboj MK, Axelrod FB, David R, Geffner ME, Novogroder M, Oberfield SE, Turco JH, Maayan Ch, Kohn B. (2003) Growth hormone treatment in children with Familial Dysautonomia. (Manuscript submitted)

This was a retrospective review. Of 22 FD patients treated with GH, data was retrieved on 13 (ages1-15 y)

• In first 6 months of GH, growth velocity exceeded pretreatment rates in all but 1 patient.
• Normal growth rate is 7 cm/y - 10/13 FD patients achieved annualized growth rate >7 cm/yr.
• Poor responses were attributed to poor compliance, intercurrent illness, scoliosis or advancing puberty.

Conclusions: GH treatment in FD patients may increase growth velocity, at least short term. This experiential data supports a future prospective study.

6. Effect of Catapres prior to gastrostomy feeding
Hilz MJ, Brys M, Marthol, H , Franta R, Tutaj M, Axelrod FB (2002) Clonidine improves baroreflex sensitivity after gastrostomy feeding in Familial Dysautonomia. American Autonomic Meetings, October.

Because FD patients frequently experience hypertensive autonomic crises after bolus GT and it had been observed that Catapres often was able to stop this reaction, we decided to try and determine the cause.

We speculated that Catapres might be causing a change in baroreceptor sensitivity.

What are Baroreceptors? Baroreceptors are pressure receptors located in blood vessels. After they are stimulated (when the volume in the blood vessel increases) they signal the heart to slow down and the other blood vessels to relax (dilate). This results in a slowing of the heart and a decrease in blood pressure.
What is Baroreflex sensitivity (BRS)? Calculation of BRS incorporates joint analysis of BP and HR fluctuations. It is an important measure of autonomic nervous system function because it reflects sympathetic and vagal influences.

• 9 FD patients (11.6 ±3.1 y; 4 girls & 5 boys) participated
• Each came to the Center twice and had bolus gastrostomy feed; once without and once with Catapres prior
•  Data converted to determine baroreflex sensitivity (BRS)

Known:

• From previous studies by Dr. Hilz, we knew that baroreflex function is compromised in FD patients
• We also knew that after a meal, hyperemia (splanchnic pooling) can occur in any individual
• However, in response to this blood shift, some FD patients then overreact (inappropriately) with hypertensive autonomic crisis

Results:

• Catapres augments BRS and parasympathetic tone after GF.
• This cardiovascular stabilization may explain why Catapres helps avoid GF induced hypertensive crisis in some FD patients

7. Additional studies to understand autonomic function (conducted by Dr. Hilz's team)
Just in the last two years there have many journal publications covering a number of different systems but all under autonomic control and potentially affecting an FD individual's function. 

GI Tract: Catapres prior to GT bolus feed

• Hilz MJ, Brys M, Marthol, H , Franta R, Tutaj M, Axelrod FB (2002) Clonidine improves baroreflex sensitivity after gastrostomy feeding in Familial Dysautonomia. American Autonomic Meetings, October.

Brain: Cerebral blood flow during tilt, etc

• Hilz, Axelrod, Haertl, Brown, Stemper. (2002) Transcranial doppler sonography during head up tilt suggests preserved central sympathetic activation in familial dysautonomia. J Neurol Neurosurg Psychiatry
•  Hilz, Axelrod, Braeske, Stemper. (2002) Cold pressor test demonstrates residual sympathetic cardiovascular activation in familial dysautonomia. J Neurol Sci

Eye: Pupillary function

• Dutsch, Hilz, Rauhut, Solomon, Neundorfer, Axelrod (2002)
  Sympathetic pupillary dysfunction in familial dysautonomia. J Neurol Sci

Skin: Nerve endings, neurotransmitters & circulation (perfusion)

• Bickel, Axelrod, Schmetz, Marthal, Hilz. (2002) Dermal microdialysis provides evidence for hypersensitivity to noradrenaline in patients with FD. J Neurol Neurosurg Psych.
• Brown, Stemper, Welsch, Brys, Axelrod, Hilz. (2003) Orthostatic challenge reveals impaired vascular resistance control but normal venous pooling and capillary filtration in FD. Clin Sci.

Respiratory & Brain interaction: With of low O2 and high CO2

• Bernardi, Hilz, Stemper, Passino, Welsch, Axelrod. (2002) Respiratory and cerebro-vascular responses to hypoxia and hypercapnia in FD. Am J Respir Crit Care Med.

These studies are really just a small sample of the type of work being done by Dr. Hilz and his team. He has initiated much of the clinical research in the past few years and has developed a number of noninvasive means to assess neurophysiological responses for the FD population. Some of these are special techniques that cannot be performed at many other institutions. These measurements require enormous expertise, highly technical equipment, often international collaboration and the cooperation of our own FD patients. This will be extremely important in eventually assessing impact of future therapies.

Future Center Projects

• Review of experience with pacemakers
• Prospective study to increase bone density
• Prospective growth hormone study
• Prospective study of sleep physiology
• Analysis of subtypes within the FD population
• Clinical trials of indicated drugs

Dys-tinguished FD Adults:
Finally we cannot think about the future 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. Since 1993 the Dysautonomia Center has been selecting a few of these special individuals on an annual basis 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 27 individuals have been so recognized.

 
This year I have added four more individuals. This year's DYS-tinguished FD Adults are Sheli Kol-Hadany Dror (Israel), Maggie Miller (Chicago), Steven Klein (Florida), and Laura Bale (Pennsylvania).

• Sheli graduated Art College and now works as an art therapist with children and the elderly. She married Roni Dror one year ago and they are creating a wonderful life together.
• Maggie is a clerical assistant at NSSED (Northern Suburban Special Education). She is upbeat, cheerful with a good sense of humor and has come to enjoy public speaking.
• Steve is our traveler and bon vivant. He has been to Europe and learned to enjoy excellent food and now is attending a Culinary Program in West Palm Beach, Florida and plans on being a chef to the rich and famous one day.
•  Laura was a Child Care Assistant but now assists individuals with mental retardation to help improve their quality of life

Although they all have FD, there is no doubt they have their own individual personalities and are living very different types of lives. I think the things they do have in common are that they are creative (Sheli is an art therapist, Maggie likes to make jewelry, and Steve is a culinary wizard) and they are altruistic and want to help others (Maggie has talked about FD and learning disabilities to groups of high school students, parents and teachers and Laura has volunteered at the Kiwanis Association for Developmental Disabilities). None of them likes having FD. However, they are optimistic and they maintain a sense of humor and they have great advice for us all. To quote Maggie..."FD stinks". However, Maggie feels good about herself when she concentrates on what she can do. Laura advises us that "On days you feel good make the most of it", Sheli has learned that "If you want something very much you can do it." and Steve is approaching life like an adventure and advises living "life to the fullest." How wise they all are. How much we can learn from them all.

So let us concentrate on the positive and remember - Life (and happiness) is an attitude-and possible for us all!