The Newsletter of Fabry Support & Information Group • Issue 11 August 2002
Greetings and Hello to All
Hello and I hope you all are doing well. It is time for our eleventh newsletter and I am happy to report the march toward treatment for all is still on and gaining steam. As in the past this journey is both frustrating and encouraging. We have seen personal gains as well as some tragedies along the way. In reality this is a reflection of life in general but I am glad to say overall the news becomes more encouraging all the time. You’ll see what I mean in a moment.
In many regards news on treatment and the companies involved has quieted down since our last issue. It would seem most related legal issues have been decided and clinical trials are still ongoing with much of the resulting data yet to be presented. This is not to say nothing has been happening by any means. There is still new information being presented, understanding and awareness continues to grow. There are more patients in trials and receiving treatment. It helps me every day I hear of another patient receiving benefit as a result of treatment. This is basically a continuation of the story we have heard before.
Now for what is I believe most exciting for us all and what I have dedicated the bulk of my greeting to... It has been announced that the FDA will hold an Advisory Committee meeting to review the two Enzyme Replacement Therapy drugs currently being considered for treating Fabry disease. There is a detailed article on this later in the newsletter and I encourage you all to read and consider this issue. Why is this so important? Thus far, where the FDA is concerned, we have been relegated to a role of trial participants. This is a vital role but one we have little control in. Now we have the opportunity to go beyond that, to become our own advocates with names, faces, lives to share and most importantly voices.
This meeting is essentially designed to allow independent experts the opportunity to hear information relevant to the decision making process and then provide a recommendation to the FDA for consideration. In this venue the public is allowed to make their views heard as well. To my knowledge this is the only opportunity we will have to provide direct input that may be taken into consideration in the decision making process. Many of you have shared your thoughts and feelings with us here at FSIG in the past and we have tried to convey them on your behalf. Well here is your chance to be directly heard. The more of us that speak up the greater impact we will have. We no longer have to silently wait.
In late December 2000 approval was expected but did not come. The FDA cited the need for additional data to answer a number of questions. A trial was designed and initiated to address many remaining questions. Yes patients are receiving care and treatment but at the same time this trial is less than perfect in design. As a result the trial duration has been extended. Does this mean we have to wait even longer for an answer on approval. If so it could be two or more years. I certainly hope this is not the case. I believe it is fair to ask whether completion of this trial is required. Is it appropriate to ask so much of these patients? At what point is sufficient efficacy and safety established? Some safety questions have been raised and I have been assured these issues are manageable and of little concern for the majority of patients. We have to question if this warrants denial of availability.
As most of you know there are two companies vying for approval, Genzyme Corp. and Transkaryotic Therapies, Inc. FSIG does not endorse the product of one company over another in this contest but instead supports access to treatment. We want what is in the best interest of a small patient population and have tried to see that as many patients as possible can receive therapy. If you have a specific message in relation to one product or another, again this is where that can be expressed. Both products are available overseas and I believe it is most important to receive treatment. A competitive situation should not be allowed to get in the way of patient care and at times that has seemed to be the case.
With nearly a year of treatment availability in Europe why are American patients unable to receive the same benefits? This is the only treatment option available to Fabry sufferers. While we wait patients are losing their lives, irreversible organ damage is occurring. How much longer must this continue? Write to the FDA, ask to be heard, let them know they can provide the one hope we have for our futures and the future of our children. Let the decision makers know you support access to treatment and that you support their role in making treatment available. We have seen great benefit in Fabry patients supporting each other. We need your help and we know you can make a difference for us all.
Jack Johnson
A Story of Friends
A story tells that two friends were walking through the desert. During some point of the journey, they had an argument, and one friend slapped the other one in the face. The one who got slapped was hurt, but without saying anything, he wrote in the sand: Today my best friend slapped me in the face.
They kept on walking, until they found an oasis, where they decided to take a bath. The one who had been slapped got stuck in the mire and started drowning, but his friend saved him. After he recovered from the near drowning, he wrote on a stone: Today my best friend saved my life.
The friend, who had slapped and saved his best friend, asked him, "After I hurt you, you wrote in the sand, and now, you write on a stone, why?"
The other friend replied: "When someone hurts us, we should write it down in sand, where the winds of forgiveness can erase it away, but when someone does something good for us, we must engrave it in stone where no wind can ever erase it.
We need to learn to write our hurts in the sand and to carve our blessings in stone.
--Unknown
Letter to the Editor
Well I must confess I don’t have a letter to the editor to share or reply to, but I am hoping we will for the next newsletter. We are looking into ways to improve the newsletter and provide content relevant to your interest. To do this we are hoping to hear from you. Feel free to let us know what is on your mind, what we are doing right and wrong. This is the best way for us to know what you want and where we need to make changes.
Although I don’t have any letters to respond to I would like to report we have received suggestions and requests for specific topic for past issues. In most cases I believe we have been able to address these concerns and hopefully our efforts met those expectations. We have received a number of positive comments from varied sources such as, good letter, thanks for the information, keep up the good work, etc. Our last newsletter was the biggest and provided the most positive feedback.
Also as a result of past newsletters we have also received some negative comments. Some having to do with items out of our control such as publications provided by others and a couple for which we are responsible. One of these had to do with the number of press releases, of which there were many last year. What are your thoughts on the balance of content provided in most newsletters?
One other item I would like to comment on is you may have noticed I have done a lot of writing in this and the last issue. You can probably tell English was not my best subject so if you would like to submit an article or a tribute to a loved one we would be happy to consider it for inclusion. Also if you have a question for a physician we will do our best to see that it is answered. Thank you for your thoughts.
Jack Johnson
* FDA Advisory Committee Meetings on Fabry Treatments *
A meeting of the Endocrinologic and Metabolic Drugs Advisory Committee will be held to discuss issues related to safety and efficacy of biologic licensing applications for Fabrazyme and Replagal. These are the two Enzyme Replacement Therapy drugs developed for the treatment of Fabry disease by Genzyme Corp. and Transkaryotic Therapies Inc. (TKT) respectively. Genzyme’s application will be discussed on September 26th and TKT’s application will be discussed on September 27th. At these meetings both companies will be presenting information to support their desire to receive FDA marketing approval. A number of meetings have already been held between these companies and the FDA but this one is different. It is very different for a number of reasons.
One purpose of an Advisory Committee meeting is to gain insight from independent medical professionals who can advise or make recommendations to the FDA based on the information presented. At many of these meetings in the past the FDA has gone with the recommendation of the committee. This could speed the process of FDA approval resulting in sooner drug availability. What may be the most exciting aspect of this meeting for those of us affected by Fabry is the opportunity to address the FDA directly. Yes, we will have an audience with those responsible for making decisions about Enzyme Replacement Therapy for Fabry disease. Those who will be deciding issues so critically important to our future and the future of our children.
In past discussions with FDA employees we have been told that patient input is very important, but where decision making is involved our avenues for such input are very limited. This is one of those avenues where we may be able to have an impact. Nothing is guaranteed but the potential is there.
The Fabry Support & Information Group plans to address the committee and convey your desire for treatment availability. We also greatly encourage your participation in this process. There are two ways you may express your views. You may do this in writing by submitting a letter or in person. Information concerning this meeting can be found on the internet at http://www.fda.gov/cber/advisory/advisory.html and http://www.fda.gov/cder/coe.htm. Links from this page can tell you what you need to know such as meeting time, location and who to contact if you would like to submit information or address the committee. Basically here is what you will find.
ENDOCRINOLOGIC AND METABOLIC DRUGS ADVISORY COMMITTEE DATE AND TIME: September 26, and 27, 8:00 a.m. LOCATION: Hilton, The Ballroom, 8727 Colesville Rd., Silver Spring, MD. CONTACT: Kathleen Reedy or LaNise Giles, Center for Drug Evaluation and Research
Phone 301-827-7001
Fax 301-827-6776
E-mail reedyk@cder.fda.gov
Mail 5600 Fisher Lane, Rockville MD 20857 On September 26, the committee will discuss the safety and efficacy of biologic licensing application BL 103979, FABRAZYME (agalsidase beta, Genzyme Corp.) for the treatment of Fabry disease. On September 27, the committee will discuss the safety and efficacy of biologic licensing application BL 103977, REPLAGAL (agalsidase alfa, Transkaryotic Therapies) for the treatment of Fabry disease.
(Anyone wishing to speak or submit written information should contact one of the above persons before September 17th.)
Updated information including questions for discussion, presentation materials and confirmed speakers should be posted on the FDA web site 48 hours prior to the meetings so be sure to check back. Also check the FSIG web site Discussion Page for additional up to date information. http://www.fabry.org
Similar information can also be heard by calling the FDA Advisory Committees & Information Line at 800-741-8138. Each Advisory Committee notice of meeting is identified by a 5 digit number. When prompted enter 12536 to access the Endocrinologic and Metabolic Drugs Advisory Committee message.
Oral presentations from the public will be scheduled between approximately 11 am to 12 noon each day. This leaves a very limited amount of time so anyone wishing to speak should keep it concise and to the point. Remember the FDA’s job is safety and efficacy, in other words does the drug work. This is what they will be most concerned with. Due to the nature of Fabry disease, trial test results may not show much measurable benefit from treatment in the short term. It is also important to convey the impact treatment has on your day to day well being and quality of life. These are issues that we can most adequately address and this is an excellent opportunity to do so.
One more way you can help in this process is to contact your congressional representatives making them aware of this meeting, let them know Fabry patients have no other treatment options, approval has already been delayed for too long and post marketing studies can be conducted to address any remaining issues. Request that your representative or more likely their FDA liaison attend so proper understanding of this important issue can be gained. You may of course express your preference concerning an approved drug but the most important thing is that FDA approval needs to happen soon. Information about contacting your representatives can be found at the following web sites:
Thank you so much for your consideration and action on this very important issue. We all have an opportunity to play a part and make a difference. Hopefully a difference that will finally bring treatment to those in need and a difference that could save lives.
Jack Johnson
Nick and his Dragon
This incredible story was written as part of a eulogy for Warren (Nick) Nichols. It was written by his son and stands as a tribute to the wonderful man Nick became. It is a testament that he was able to be more than the Dragon wanted him to be. I knew Nick and his wife Becky. Nick’s loss is deeply felt but his smile and sense of humor will never leave those who knew him. Jack
There once was a beautiful young boy out playing in the sunshine all alone. The birds sung to him and made him smile while the trees amazed him and gave him shelter. He grew curious about all the things around him and went deep into a nearby forest to see more. As he progressed the sunshine slowly disappeared and the boy grew cold. Soon there stood before him a ferocious and hideous looking dragon that blocked this path. The boy looked at the dragon and asked him why he blocked his way. Angered that the boy was not fearful and did not run away, the dragon roared, "You don't know who I am? I'm your dragon. I'm here to teach you about Anger and Hate, and then I'm going to take your life." The little boy laughed and said, "Sorry mister scary dragon, but I'm just a boy. I already know of Anger, Hate and even death but they are of no use to me. I only like to Love and Laugh, and you can't have my life, I've much to do. This made the dragon even angrier and the dragon howled. "Little boy, those things you cherish, Love and Laughter are weak. They cannot survive against Anger and Hate. But if you will not surrender your life to me now, I have plenty of time to teach you this lesson. The dragon blew flames around the boy burning his hands and feet and then disappeared.
The burns were painful and they were deep, beyond the skin and beyond the body. Even worse, no one but the boy could see them. It was a pain that would never seem to go away, and a pain that seemed no one else could believe. Even the few that would believe could never really understand.
From that point on the boy’s life could have been very different. He could have learned Anger and Hate at that moment, but he didn't. His capacity to love and laugh only grew stronger. All those that met him could sense those things and it made them want to be around him more. He grew into a man, and was first blessed with a beautiful and strong wife and then later was blessed with two boys. In time they would all three learn that it was them that was blessed, all three to have learned to Love and Laugh from him.
The boy, now a man, didn't see the dragon for many years, but the pain in his hands and feet grew stronger, always testing his belief in Love and Laughter. The man grew more powerful through these things and soon began walking through the woods alone searching for the dragon in order to force the dragon to stop the pain. He couldn't find the dragon anywhere. He also tried to search for natural and medical cures, but none offered the slightest relief.
He decided to fight back. As a creative man he used the hands that the dragon tried to cripple to create beautiful artwork that always made others smile. As a caring man he began to teach others how to draw. Without fear and without knowing, he had crossed a dangerous line with dragon. Now the dragon, unable to control his fury, returned.
The man, uneasy, said, "Why are you here?" The dragon smiled, "You know why I'm here. I'm your dragon. I'm here to teach you about Anger and Hate and then I'm going to take your life.
The man didn't laugh this time; he felt fear because now it wasn't only about him. His wife and his two boys were in danger. "No! This won't happen. You'll never hurt them!" the man screamed. The dragon released a sigh, "Now you begin to see what it means to feel Anger and Hate." With tears pouring down his face the man argued, "No, now only stronger is my power to Love and never will I give up the joy of Laughter." The man ran full speed at the dragon and, at the moment of impact when anyone who could have witnessed it would have expected a horrific explosion or a great battle, there was only silence. There was the man lying there alone. The dragon couldn't be seen, but the poison that was once the dragon, now surged through the man's body.
The dragon was inside him and trying to take his life. His kidneys failed and his heart was weakened. His doctors thought the end was near and the man's boys and wife were stricken with grief. But the man held on, he knew that his life could not end yet, there was still much to do, but his physical suffering had only just begun.
For 10 years the man lived on, always holding on to, and sharing, his power to Love and to Laugh with all those around him, especially his family. At times, the dragon rose up from the depths of the man’s soul and took a piece from his body, always believing that it would be enough to teach the man about Anger and Hate. Every time, the man not only refused to die, but refused to accept those negative energies.
After many years of suffering the dragon was gathering himself to make his final attempt to teach his lesson. The dragon echoed in the man's head, "You have protected your family from me by containing me inside yourself, but now you are too weak. I will take your life, and what you did not learn your family will.
The man knew that the dragon was right, he was now going to die, but about those other things the dragon was wrong. He taught them well. "His wife and the boys would be fine", and hearing his wife confirm those words, he drew in his last breath, crushed the dragon and closed his eyes.
He was exactly right about how things would end up. His boys still needed practice, but even in losing their father they did not Hate and soon were not Angry. His wife would suffer for a time and miss him greatly, but her Love for him was so great, she knew when it had been time for his suffering to end. They had loved each other in ways most could never imagine, and if ever she needed to remember the good man her husband was she need only look at her two boys, Loving and Laughing, like their father always had.
Written by Casey Nichols
Coping with Fabry’s Disease: Denial vs. Acceptance
Written by Dr. Barbara A. Wehmann. As a trained psychologist and a female afflicted with many of the manifestations of Fabry disease, Barb is uniquely qualified to share her insight. She has been very supportive of FSIG in her role as Web Site Discussion Page monitor and presents weekly topics to encourage sharing and information exchange.
Introduction
Thirty million Americans have a chronic disease, an illness that cannot be cured. Like many other diseases, Fabry’s may be diagnosed at any time in your life from the prenatal period to well into adulthood. Though chronic diseases differ, those with such illnesses and their loved ones are united by feelings such as shock, disbelief, denial, anger, fear, anxiety, depression, loneliness, and despair.
Learning to live with a chronic disease is a process of continual complexities and changes, as well as physical and emotional challenges. Changes may be minor, or they may be profound, but they eventually will have to be accepted. Coming to terms with all of the issues related to Fabry’s is an intensely personal journey. Your struggle to cope may get harder before it gets easier, but it will get easier in time. Coping with Fabry’s requires doing what so many chronically ill people do each day; live with their disease the best they can. Your success in accepting Fabry’s, meeting the continual challenges, and adapting to the ongoing changes will determine how happy and satisfying the rest of your life will be despite the fact that Fabry’s is one part of it.
It is important for those dealing with Fabry’s to continue to improve coping strategies instead of putting off any progress toward adaptation until the enzyme replacement treatment is available to them, and then expecting that their life will become normal. Optimism for the future is very important. However, no one yet knows either the ultimate impact on those with various symptoms and stages of progression, or the long-term effects of the treatment on anyone who has Fabry’s.
In many ways, learning to live with a chronic illness is similar to the process of grieving. This article will focus on two stages involved in the grief process, denial and acceptance. Both positive and dysfunctional denial will be discussed. In the next article, suggestions will be given for moving forward towards adjustment and acceptance. For detailed information about the complete grief process of denial, anger, bargaining, depression, and acceptance, please see the short version of the article, “Learning You Have Fabry’s Disease: Reactions and Feelings” in the Issue 2 newsletter from 1997, or the long version of the article on the Fabry Support and Information Group (FSIG) website under “Additional Online Information.”
The Importance Of The Grief Process
When first diagnosed you may have been relieved to end the uncertainty of your symptoms in spite of the fact that the full implications of your diagnosis might not have been understood. Alternately, you may have felt little or no relief at a diagnosis and been overwhelmed by sadness, perhaps even finding yourself crying quite often. There is no set response style since people respond to a diagnosis, as well as continued diminished health, in different ways. For example, some may choose not to talk about things even with family and friends, while others want to talk to as many people as possible.
Whatever the initial reaction to a new diagnosis or symptom, health complication, or negative lifestyle change, if you have the cognitive maturity to understand both what has happened and what may occur, resulting feelings can be remarkably similar to intense grief. Your attention eventually will shift to the things that have been or may be lost. The process of acknowledging and coming to terms with our losses is known as grieving, the emotional suffering felt after a loss of some kind.
Grief is usually thought of as something experienced during times of death. However, when you are diagnosed with Fabry’s, or when your health continues to diminish, major loss is experienced. This traumatic stress has an effect very similar to grieving. When Fabry’s is involved, you grieve because of what you have lost, or may lose, including health, normal routines, future opportunities, and all the things you might no longer be able to do. You may experience additional losses as time passes such as being unable to work, or being avoided by some family members or friends. The type of loss may change over time, but any loss that is personally significant may cause you to re-experience the grieving process. It is important to remember that the grief process is normal, predictable, and even necessary when any personally significant loss occurs. Grieving may eventually lead to the replacement of overwhelming emotions with more manageable feelings and is the process that enables you to finally acknowledge and come to terms with loss.
Denial
A diagnosis of Fabry’s represents a significant life change. At first, you may deny the diagnosis and think, “Not me.” or “This can’t happen to me.” Those are common reactions in the early stages of any chronic illness. Even when you have known about the disease for quite some time, when you experience a new symptom, health complication, or negative lifestyle change, you also may face
denial. You are not ready to deal with the loss of your health and any changes so you deny the problem. It is important to remember that both the person with Fabry’s, as well as loved ones, may go through the process of denial. The amount of time that reactions such as denial take are determined by factors such as one’s age at onset of symptoms, personality factors, prior exposure to crisis situations, nature and severity of the illness, extent of social support network, and available resources.
Denial is like mental numbness. We are not quite ready to grasp the full implications of what has happened so we dismiss it, rationalize it, minimize it, or question the truth. Some completely deny that they have Fabry’s, choosing to struggle through daily routines until they are unable to function any longer. Others may admit they have the disease yet deny limitations, or the seriousness of the illness. You may tell yourself things such as, “So what if I have Fabry’s. It’s no big deal.” “I won’t be sick until I’m much older.” “I’ve felt tired lately, but it’s not because of Fabry’s.” “Now the doctor is telling me it’s causing heart problems. Those can’t be my test results.” Some may deny the disease in their actions as well. For example, they may continue to be active in outside heat even when this causes more pain.
Because Fabry’s often has invisible symptoms, it is at times easy to deny. In fact, these invisible symptoms can make it an extremely difficult disease for others to grasp and understand. Overall, denial usually does not last long when you have the disease because sooner or later, the limitations imposed by Fabry’s can no longer be ignored. It is not easy to admit to yourself that you are suffering from a chronic illness, but it is an important milestone if you are to end up adapting to new circumstances.
Positive Denial
Although denial has a negative connotation, it is a normal defense mechanism and can play a positive part in coping with Fabry‘s for both you and your loved ones. It is perfectly normal that you should sometimes find it difficult to admit having a disease, various symptoms, complications, or limitations. Denial provides a respite because for a short time, it permits you to set worries aside and function. It gives you time to deal with things such as a problem or fear, and come to terms with bad news little by little. Denial can be an initially positive coping strategy as long as it does not interfere with proper treatment, self-care, or relationships.
Dysfunctional Denial
Even though denial initially can play a positive part in coping, it will eventually cause problems if it turns into a pervasive condition. When you continue to deny your feelings and the grieving process, you postpone the maturation of your emotions and hinder progress toward a happier future. You may superficially accept the diagnosis, but remain unwilling to learn about Fabry’s, or think about the need for adjustments. It is detrimental when your emotional or physical status is denied for too long. It could even end up with you refusing to accept help that is necessary. For example, when someone refuses to use equipment that could improve mobility it could result in being isolated. Coping with Fabry’s becomes more difficult if you persist in denying that you are ill and go on stubbornly trying to do everything you were once capable of doing. For example, if you believe that you are a fully productive employee, yet you are not, denial can be detrimental. Denial even can take a dangerously defiant form. For example, someone in denial may ignore his or her doctors’ advice that could help keep the disease under control. Denial may cause symptoms to be under-reported, or attributed to some other less serious cause.
Statements like, “There’s nothing wrong with me.” or “The doctor made a mistake.” arise from the wish to take control over your life again. However, if this attitude becomes pervasive, it blocks the process of coming to terms with and adapting to the illness. While it is not uncommon to be resistant to limitations, it is far better to define a new more personally adaptive lifestyle. The difficulty can be keeping denial in balance while working towards adaptive responses.
When the person with Fabry’s continually engages in dangerous and self-destructive behaviors, perhaps as a result of denial, someone may need to intervene. Speaking with the person in a straightforward and honest way about concerns may be necessary. Pervasive denial can become extremely difficult to watch, yet even a loved one cannot force important changes.
Adjustment
Fabry’s is not going to go away regardless of how much anger, sadness, denial, etc. there is. People who have the disease eventually must accept their situation if their life is going to be happy and fulfilling. Each person will adapt or adjust to Fabry’s differently and at his or her own pace. Adjustment is a process of a succession of situations requiring specific solutions and not necessarily an orderly process. There will be emotional and physical ups and downs in living with the disease. Feelings that are overpowering today may not be perceived that way tomorrow. Your medical condition is unpredictable and emotions may change with your condition. Not only will you need to learn to deal effectively with emotional responses, it is important to remember that some family members will also find adjustment difficult.
How well you cope with Fabry’s will determine, in great part, the quality of your life. Of the three primary factors which measure your ability to cope: your attitude, the social context of your life, and the quality of resources available to you, your attitude becomes the foundation upon which the others build. Undoubtedly, some people adjust better than others to the fact that they have a chronic illness.
Conclusion
Denial and acceptance are normal steps after being diagnosed and as the disease progresses causing more changes in your health and lifestyle. While long-term pervasive denial likely will be detrimental to physical and emotional health, temporary denial can be a beneficial coping mechanism in moving towards acceptance of Fabry’s as a part of your life. When you begin to accept Fabry’s, you open yourself up to see possibilities and opportunities in your life, perhaps much different than those you had hoped for or expected. When denial continues, you close yourself off to those possibilities and opportunities. Accepting illness is a process, a personal journey. The process is not easy, does not happen all at once, and it is not something you do once and never again. In addition, it does not mean that you are ever happy about having Fabry’s. Acceptance means that you have made room for Fabry’s in your life and that it is just one aspect of an otherwise happy and fulfilling life.
Fabry Disease: Diagnosis & Inheritance
Erin O’Rourke, MS, CGC
I was at work and called home to check on my 13 year old son, Peter – he was home sick again, unable to go to school because of what he describes as burning pains in his legs and feet. He sounded very upset when he got on the phone and asked me where his Dad’s rifle was – he said that he wanted to kill himself because he couldn’t stand the pain anymore. Alarmed, I asked to speak to the sitter, made arrangements to leave work and went home.
Peter was diagnosed with anhidrosis two years ago and we have had to learn how to deal with that, but since then he has been complaining more and more often of the pains in his legs. Our doctor could not explain the painful episodes that seem to happen most often after Peter had been very active.
I was frightened and so worried about my son. Later that same night I went online - I entered anhidrosis and foot pain and hit search – that was the first time I had ever heard of Fabry disease….
Fabry disease is a genetic disease caused by the deficiency of an enzyme called alpha galactosidase A (a-gal A). The enzyme is important for the breakdown and removal of glycolipids. A deficiency of a-gal A causes progressive accumulation of globotriaosylceramide (GL3) in the lysosomes of many cell types. A variety of organs including heart, kidney and skin, can be affected because the GL3 accumulates in cells throughout the body. Some of the symptoms of FD such as the neuropathic pain and burning in the extremities, hypohidrosis, angiokeratoma and the eye findings (Fabry cataracts) typically present in childhood while the cardiac, cerebrovascular and renal complications usually occur in adulthood.
In most cells of our body we have 46 chromosomes that are organized into 23 pairs according to their size and shape. One member of each pair comes from our mother and the other from our father. Along the chromosomes there are genes that tell our body to make specific substances like the a gal A enzyme that is important in Fabry disease.
Females have 2 X chromosomes (XX) and males have 1 X chromosome and 1 Y chromosome (XY). Children who inherit an X chromosome from each parent are female and children that inherit an X from their mother and a Y from their father are male.
The a gal A gene is located on the X chromosome so Fabry disease is passed through families in an x linked inheritance pattern. Males with a changed a gal A gene on their X chromosome have Fabry disease. Females with a changed a gal A gene on one of their X chromosomes are carriers of Fabry disease. More than half of Fabry disease carriers have some disease symptoms.
When a male in the family has Fabry disease the x linked inheritance pattern looks like this
Affected fathers pass the changed a gal A gene to all of their daughters and none of their sons
When a female in the family is a carrier the inheritance pattern looks like this
Females who carry a changed a gal A gene have a 1 in 2 or 50% chance of passing the gene to each son or daughter
Some individuals with Fabry disease have no family history of the disease. These are called sporadic cases caused by “new” mutations. The rate of new mutations is unknown. A recent survey of 67 families with Fabry disease in the United Kingdom reports that 20 of the affected males had no family history of the disease (MacDermot 2001).
A diagnosis of Fabry disease can provide some relief as an explanation for the affected person’s health problems and issues. Since Fabry disease is usually an inherited disease, the diagnosis has implications for other family members as well. In addition to the immediate issues for the affected person it is important to consider who else in the family is at risk?
A detailed family history and drawing a pedigree is essential for understanding who in the family is at risk for being a carrier and the chance of having affected children. The detailed family history should include questions about whether anyone in the family has had a slit lamp eye exam, unusual skin findings, problems tolerating heat and or cold, heart disease, kidney problems (dialysis or transplant), stroke at a young age, seizures, chronic pain, infertility, and depression.
There are two laboratory tests used in the diagnosis of Fabry disease, measurement of the a-gal A activity or enzyme activity and sequencing of the a-gal A gene or DNA testing.
Males with Fabry disease have low or absent a-gal A activity. Female carriers of Fabry may have low or normal a-gal A activity and therefore enzyme activity is not reliable for determining female carrier status.
More than 200 changes or mutations have been found in the a-gal A gene. Since most of the mutations are unique in each family, it is necessary to look at or sequence the entire a-gal A gene to identify the Fabry disease mutation that is present. Once the mutation has been identified in an affected family member, looking at a particular area of the gene or targeted sequencing can be done for other at risk individuals in the family. Identification of the mutation in the a-gal A gene is diagnostic for Fabry disease but does not predict the severity of the disease.
In the scenario described above, the 13year old boy, Peter, had a blood sample taken that was tested for a-gal A activity. The a-gal A activity in the sample was zero which confirmed the diagnosis of Fabry disease. Another blood sample from Peter was sent for sequencing of the a-gal A gene and the I303N mutation was identified.
Peter’s parents were understandably concerned about whether any of their other children were at risk for the disease. So the next step is to determine whether Peter’s Fabry disease is inherited or the result of a “new” mutation. Since Peter’s Dad is 44 and has no symptoms of FD, a blood sample was taken from Peter’s Mom to see whether she carries the I303N mutation. If she is a carrier, each child has a 1 in 2 chance of inheriting the mutation, if she does not have the mutation and Peter’s father is unaffected, Peter’s brothers and sisters would not be at an increased risk for Fabry disease.
The laboratory results showed the following;
Peter’s Mom was found to carry the I303N mutation. Peter’s parents decided to pursue testing for their other children. The laboratory results showed the following;
Peter’s brother had normal a-gal A activity and was not affected with Fabry
Peter’s sister, Sarah had normal a-gal A activity and was a carrier for the I303N mutation
Peter’s sister, Suzie, had normal a-gal A activity and was not a carrier of the mutation
Family testing for this genetic disease is important for several reasons; early diagnosis allows for closer medical monitoring and early intervention especially with the prospect of enzyme replacement therapy, some individuals will learn that they are not at risk for Fabry disease and the results may provide peace of mind, and testing of the nuclear family (Peter, his parents and his brothers and sisters) provides information that makes testing for extended family members easier (for example, since we know the mutation that Peter’s mother has, it would be quite easy to test her sisters or their children for the same mutation).
Sometimes coping with the information from genetic tests may be difficult - sometimes people feel sad, angry, confused or anxious. Genetic conditions may affect family members in different ways. Sharing medical information in a family and addressing feelings is sometimes difficult and may change the way that family members relate to each other. Resources like the FSIG and this newsletter can help individuals and families obtain additional information and make connections with people facing similar issues. Most laboratories that offer genetic testing have genetic counselors available who can talk with you about the results of genetic testing. Being evaluated by and working with physicians, nurses and genetic counselors that have experience with the Fabry disease provides access to up to date medical information and management strategies as well as a sense of comfort because there is some experience with the disease.
For additional information about testing related to Fabry disease
Lysosomal Disease Center
University of Pittsburgh
1-800-334-7980
erin.orourke@mail.hgen.pitt.edu
GeneTests
www.genetests.org
Enzyme News
Since our last newsletter a number of press releases relative to Fabry patients have been issued by Genzyme Corporation, Transkaryotic Therapies, Inc and Oxford GlycoSciences Plc. Since we do not have enough room to present all of them in their entirety I have pulled excerpts of the most relative information for the purposes of this article.
Genzyme General Reports 2001 Earnings At High End of Guidance
SOURCE: www.genzyme.com/corp/media/GENL%20PR-041702.asp, Genzyme Corporation, Company Press Release, April 17, 2002.
…
Fabrazyme(tm) (agalsidase beta) sales were $2.3 million in the fourth quarter and $5.8 million for the year. The product has been approved for sale in the 15 European Union countries, as well as Iceland, Norway, the Czech Republic, and New Zealand. Reimbursement approval has been obtained in most of these countries. In Europe, more than 180 Fabry patients are on therapy with Fabrazyme, and more than 300 patients worldwide are receiving the product. Sales of Fabrazyme in Europe and other markets outside the United States are expected to generate $25-$40 million in 2002. Genzyme remains confident that it will receive marketing authorization for Fabrazyme in the United States this year.
Genzyme has implemented an extensive program to educate physicians about Fabrazyme and Fabry disease. Earlier this week, it sponsored a symposium at the Society for Inherited Metabolic Diseases (SIMD) meeting that included a presentation by renowned nephrologist Barry M. Brenner, M.D., of Brigham and Women's Hospital on GL-3 clearance and stabilization of renal function in Fabry patients. The symposium also featured the presentation of laboratory data comparing the biochemical properties of Fabrazyme and Replagal(tm) (agalsidase alfa) showing that the products are structurally similar and functionally equivalent in vitro.
At the American College of Medical Genetics (ACMG) annual meeting next week in New Orleans, the biochemical comparison of Fabrazyme and Replagal will be presented to a broader audience. In addition, a new study of the prevalence of Fabry disease among hemodialysis patients that Genzyme conducted in collaboration with Gambro Healthcare Inc will also be presented. Genzyme will also host its third European roundtable on Fabry disease April 5 in Copenhagen.
...
OGS receives Complete Response Letter from the FDA on Vevesca (OGT 918) SOURCE: Oxford GlycoSciences Plc Press Release, June 24, 2002.
Oxford, UK, 24 June 2002 — Oxford GlycoSciences Plc (LSE: OGS, Nasdaq: OGSI) today announced that it has received a complete response letter from the U.S. Food an Drug Administration (FDA) on its new drug application (NDA) for Vevesca (OGT 918). In the letter, the FDA stated that, in its opinion, the product is not approvable, as OGS has not provided sufficient support for the safety an efficacy of Vevesca (OGT 918). Therefore, the FDA has stated that the application may only be approved if a number of issues are addressed and further clinical studies are conducted.
In addition, the letter stated that with in 10 days from its receipt, OGS must either amend its application, notify the FDA of its intent to file an amendment, withdraw the application or request an opportunity for an informal meeting on whether there are grounds for denying approval of the application. OGS will formally request a meeting with FDA representatives as soon as possible to review this letter and to find the best way forward. Following this meeting, OGS will then notify the FDA which alternative it will pursue.
OGS has also filed a Marketing Approval Application for Vevesca (OGT 918) with the European regulatory authority, the EMEA. This process is at an advanced stage and a decision form the EMEA is anticipated during the third quarter 2002.
Genzyme Announces FDA Panel Will Review Fabrazyme BLA SOURCE: www.genzyme.com/corp/media/GENL%20PR-070802.asp, Genzyme Corporation, Company Press Release, July 8, 2002.
Genzyme General (Nasdaq: GENZ), a division of Genzyme Corp., on July 8 announced that its biologics license application for FabrazymeŽ (agalsidase beta) will be reviewed by the U.S. Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee on September 26.
Fabrazyme is an investigational enzyme replacement therapy intended for the treatment of Fabry disease, a rare and potentially fatal genetic disorder. Genzyme looks forward to the opportunity to present its application to the advisory committee and is confident in a positive outcome. Fabrazyme has been approved for use in the 15 member states of the European Union and in several other countries.
...
TKT Announces Meeting of FDA Advisory Committee to Review Replagal(TM) BLA for Fabry Disease SOURCE: www.tktx.com/newsbureau/press.htm, Transkaryotic Therapies, Inc., Company Press Release, July 8, 2002
CAMBRIDGE, Mass., Jul 8, 2002 /PRNewswire-FirstCall via COMTEX/ --
- Endocrinologic and Metabolic Drugs Advisory Review Scheduled for September 27, 2002 -
Transkaryotic Therapies, Inc. (Nasdaq: TKTX) today announced that the Company's Biologics License Application (BLA) for Replagal(TM) (agalsidase alfa), an enzyme replacement therapy for the long-term treatment of Fabry disease, will be considered before the U.S. Food and Drug Administration's (FDA) Endocrinologic and Metabolic Drugs Advisory Committee. The advisory panel will meet to discuss Replagal on September 27, 2002.
"We are pleased that the FDA is taking this next, important step in the review of our BLA," said Richard F Selden, M.D., Ph.D., President and Chief Executive Officer of TKT. "We look forward to the opportunity to make Replagal available to patients in the United States."
Advisory committees provide the FDA with independent advice on marketing applications. The FDA generally follows the recommendations of its advisory committees, but is not bound to do so.
Since August 2001, Replagal has been approved for commercial use in over 20 countries, including the European Union, the Czech Republic, Iceland, Israel, New Zealand, Norway, and Switzerland.
...
OGS Announces Positive CPMP Opinion for Zavesca™* for Type 1 Gaucher Disease in European Union SOURCE: Oxford GlycoSciences, July 29, 2002.
...
I am pleased to announce the European Union Committee for Proprietary Medical Products (CPMP) has issued a positive opinion recommending that Zavesca (OGT 918) be granted a marking authorization for oral treatment of adult patients with mild and moderate type 1 Gaucher disease and for whom existing therapy is unsuitable. Final approval for the European Commission is expected within 90 days. Once approved by the Commission, OGS would obtain a license to market Zevesca throughout the European Union.
This is great news for OGS and clearly demonstrates that our commitment has proved beneficial, and represents a significant step towards bringing this important new therapy to patients who are suffering from the debilitating effects of Gaucher disease.
It also goes a long way to ease the disappointment of the FDA’s decision that stated that the application to market Zavesca in the US may only be approved if a number of issues are addressed and further clinical studies are conducted. Based on this news it is with regret that we have decided to close our offices in Bridgewater, New Jersey...
Additional Thoughts
These press releases from Genzyme, Oxford GlycoSciences (OGS) and Transkaryotic Therapies (TKT) have been presented to keep you informed. These press releases speak of increased activity and availability of treatment in the European Union as well as other countries. They inform us of activities to educate the medical community about recent developments in enzyme replacement therapy. Such meetings and symposiums have been conducted by all three drug companies in various sites around the world. Although the competition between Genzyme and TKT is not as evident in this series of press releases it is still very much alive. Much has been made lately of the differences or lack there of between the two companies products as well as the potential safety concerns. Opinions on these points vary and I’m sure will for some time yet.
OGS has worked to develop a different approach to treat Fabry and related lysosomal diseases. We see that they are having success with Gaucher Type 1 disease outside the U.S. It was thought this approach could be beneficial to Fabry patients and someday may prove to be. I’m not certain what successes or failures may have resulted from clinical trials in this area since I am not aware of any resulting publications. They have not been able to satisfy the Food and Drug Administration (FDA) and as a result their activities in the U.S. will have to wait for further developments.
What is very exciting to the Fabry community is the upcoming Advisory Committee meeting between the FDA, Genzyme and TKT. These meetings finally provide an opportunity for us Fabry sufferers to let our voices be heard directly by the FDA. Not as statistics and data endpoints but as the ones who really have it all on the line. This is more fully addressed elsewhere in this newsletter. In previous issues of this segment I have expressed frustration in not being able to have a direct impact where the FDA was concerned. This has been due to legal restrictions on the FDA. I have stated that we must be patient and wait. Well now it would seem things have changed. Patience is still required but we will not have to continue waiting in silence.
Jack Johnson
Second International Symposium
The Second International Symposium on Lysosomal Storage Diseases, Fabry disease: clinical Heterogeneity and management challenges was held April 26-27 in Cannes, France. Dr. Rolf Gunnarsson on behalf of TKT Europe - 5S welcomed approximately 400 physicians, researchers, nurses and patient representatives from 35 countries.
Information was presented by participants from around the world, much of which resulted from past and ongoing study efforts. The challenges of providing care for the management of Fabry disease was just one of the important topics discussed.
Meetings such as this are crucial to providing the latest data and creating an environment where clinicians can benefit from information exchange. As attention is drawn to developments in Fabry and other Lysosomal Storage Diseases we all will benefit.
Of interest were presentations on Enzyme Replacement Therapy (ERT) and clinical benefit resulting from this form of treatment. All indications in this area are very encouraging which bodes well for the future of Fabry patients. Due to marketing approval in the European Union and elsewhere the number of patients receiving treatment is continually growing.
Increased research is leading to greater understanding of Fabry disease and long held views are being seen in a new light. One of these is the X-linked role Fabry plays in female patients that explains the great variation in their symptoms. This new examination of X-linked traits could completely change the perception of how Fabry disease affects females.
These developments are very encouraging. As knowledge is gained and awareness spreads, increased diagnosis and patient care will provide benefits for affected patients throughout the world.
FSIG Looking For A Few Good Helpers
As we at FSIG strive to meet the increasing demands of our growing organization we are finding that additional help is necessary. Areas where we could use some assistance include this newsletter, accounting for nonprofits and fundraising. We are also interested in any talents you feel may be of benefit to FSIG and our mission to help those affected by Fabry disease.
We are open to hearing your ideas and are constantly striving to create a better organization for all concerned. It is as a team we can reach our goals and it is with your help we will obtain our full potential. Please consider this important issue and let us know your thoughts or desires to take part in this effort.
FSIG Thanks
FSIG would like to thank the many physicians, health care professionals,
researchers, scientists and industry working on our behalf. Their efforts are often not seen but make such a difference.
Contributions in Memory of… Ray Beiberby Paul & Kay Beiber William Wayne Butler by William Doeppe Richard & Karyl Myrick Clint Desonia by Bruce Desonia Jack Hellandby Daniel Tweeton Roy B. Jarrettby Johnette Jarrett Chaz Leibowitzby Marc & Ellen Horowitz Doug Lodenby B&B Industries, Inc. Beverly & Jeffrey DeSilets Susan Kious Bruce Malangaby Gary Malanga Warren ‘Nick’ Nichols by Rose Mary Dickerson Scott Johnson Evelyn Krockenberger Lynda Leibowitz Gary & Teresa Magill Carol & Doug Myers Robert A. Myers Edith Nichols Wayne Nichols Mildred Poleski Martha J. Porter Juanita Pugh Tom & Rose Reese families Frances Sharpe Mary Slinkard Ruth Wiggins Geraldine Wiram Michalena Saletnikby Helen Bernadis Ms. Dale Berthiaume Edwin & Ann Bishop Julie Bodoh Lynn Boudreau Vincent Gallo Denise & Stephen Gross Lillian Kessler Sophie & John Killips Mary Larese Doreen & Melvin Lipman Richard & Ruth McGuire Jane & Jack Zaraya Johnnie Smithby Judy Smith George Whitenackby Preston & Eleanor Haney Suzanne & Dave Geissler
Additional Donations… Paul & Kay Beiber Lewis Betts Charles & Claudia Branham Children in the Sunday School Classes at the Congregational Church of Northridge Herman & Lillian Director Foundation Brian Freer Dom Greico Hefland & Deponte Tom Jackson Kathy Johnson Jay Johnson Anne Norsworthy Christine & Peter Radasch Steve & Jan Schrader James & Kelly Sheffield Linda Todsen Joe Wessel Maureen Wrobleski
FSIG would like to thank Genzyme Corporation, Transkaryotic Therapies, Inc. and TKT Europe - 5S AB for their continued support of our efforts.
Also we would like to acknowledge BioMarin Pharmaceutical, Genzyme Corporation, Novazyme Corporation, Oxford GlycoSciences, Plc., Transkaryotic Therapies, Inc. and TKT Europe - 5S for their support of the GOLD collaborative.
Genetic Disease Foundation Fundraiser
On Wednesday June 5th the Genetic Disease Foundation held its 2002 Gala Benefit Dinner. Stanely B. Michelman, Chairman, kicked off the evenings’ events. The Gala was hosted by Judd Hirsch of Taxi fame who added his own unique flair. Various presentations were made and awards were presented. Dinner was followed by a live auction and dance.
This was the second time my wife Debra and I have had the pleasure of attending this event. In 2000 Jon Secada provided entertainment and support. Other notable names from past events include Rosie O’Donnell and Roberta Flack among
others.
The efforts of the Genetic Disease Foundation are important for many reasons. Their work benefits those suffering from a number of genetic diseases including Fabry, Gaucher, Niemann-Pick, Sickle Cell disease, Tay-Sachs and more.
Through efforts such as this millions of dollars have been raised over the years. FSIG would like to thank all the dedicated and caring individuals, physicians, researchers and celebrities for contributing their time and expertise. We of course can not forget the many supporters that make it all worthwhile through their generous contributions, they are the ones who really make events like this such a success.
Jack Johnson with Dr. Robert J. Desnick, one of the evenings speakers and Doctor’s Committee Chair.
Help Educate About Fabry Disease
Interested in being in a web site about Fabry? Dr. Matthew Taylor and genetic counselor Jennie Feiger at the University of Colorado Health Sciences Center are creating an educational web site about Fabry Disease. The web site is for both doctors and lay people. The goal is to teach people about the signs and symptoms of Fabry. Their hope is that Fabry can be diagnosed more quickly and treated properly. They want to put interviews of people describing their experiences with Fabry on their web site. They are looking for men and women to be interviewed for 15-30 minutes. Depending on your location, it will be either videotaped or audio-taped. If audiotaped, you would also be asked to provide some photos.
If you are interested, contact Jennie Feiger by phone, e-mail or letter.