M S U D Newsletter Volume 16 #2

M S U D Newsletter

Articles selected from Vol. 16 No.2, Fall/Winter 1998-99

GENE REPAIR THERAPY FOR MSUD

R. Michael Blaese, M.D.,

Chief, Clinical Gene Therapy Branch, National Human Genome Research Institute,

National Institutes of Health

What is it, and when might it become available?

We have all heard about the possibility that gene therapy could be developed to treat MSUD and other serious diseases that are caused by a defective or misspelled gene.Ê So far that possibility has seemed to be just out of reach.Ê Traditional methods of gene therapy try to take a ãnormal copyä of the gene that is causing the disease, and deliver it to the cells in the patientâs body that are crippled by the defect with the hope that this new ãnormalä gene will reverse the disease.Ê This treatment has worked in some very special cases where the diseased cells from a patient can be removed from the body and the corrective gene inserted while the diseased cells are growing in a test tube.

Unfortunately, for MSUD and the majority of other serious genetic diseases, the ãdiseased cellsä cannot be removed for treatment in a test tube, and therefore the corrective gene needs to be delivered to the cells where they ordinarily live inside the body÷for example, the liver or brain.Ê Most of the traditional ideas for gene therapy have run into this ãdeliveryä brick wall and their development has been stopped at this stage.

Many genetic defects can be thought of as a ãtypoä that causes the code contained in the gene to be misspelled.Ê Such typos in the spelling of the gene, called mutations, can occur while a gene is being duplicated during cell division or as a result of external factors such as radiation exposure, etc.Ê Since genes are inherited, once a misspelled gene develops for any reason, it has the potential to be transmitted from generation to generation, just as the normally spelled genes are passed on.Ê For many genetic diseases, a misspelling involving only a single letter in a gene that is made up of thousands of letters (or bases) can cause disease.Ê As an ãideal treatment,ä physicians would like to have tools to correct the typo in the spelling of the gene in those cells in the body where that genetic defect is causing a problem.

Recent research at Kimeragen, a biotechnology company, has led to the discovery of a way to correct, or mutate, the spelling of a gene directly in the cells of the body.Ê Now, rather than needing to replace an entire gene that does not work, because just one letter out of the thousands in the gene is misspelled, it will be possible to treat genetic disorders with a much simpler idea÷gene repair.Ê This new gene repair technology is very different from the usual pharmaceutical product, because it uses a small molecule that is custom designed and produced for each individual or family in order to correct the unique gene defect that is found in that family. The molecule, called a chimeraplast, is a combination of both DNA and RNA sequences that direct the bodyâs own molecular tools used to repair genes in order to change the defective gene sequence to a normal sequence.Ê To test the feasibility of this idea, rats with inherited genetic defects affecting the liver have been treated using a simple intravenous infusion of a chimeraplast which was specifically designed to correct their mutations.Ê Because early results in two different genetic disorders in rats have shown such promising results, active plans are now underway to begin treating an inherited human disease of the liver, called Crigler‑Najjar syndrome, beginning next summer.

Is this a treatment that could be used in MSUD, and when might it be available?Ê Theoretically, many (but probably not all) of the mutations leading to MSUD should be correctable using this new technology, but no work has been done yet to actually test mutations from different MSUD families.

Kimeragen plans to develop this new treatment for patients with many kinds of genetic defects involving the liver including MSUD, PKU, OTC deficiency, hypercholesterolemia, hemophilia, etc., etc.Ê When treatment will become available for each of these diseases will depend on the success of early human clinical trials in Crigler‑Najjar patients, as well as cooperation from the FDA in helping move this treatment from the experimental trials to general availability.Ê Also, Kimeragen is a small company with limited resources.Ê We are working to establish partnerships with larger pharmaceutical companies in order to fund more rapid development of this treatment for a broader range of diseases.Ê If the early clinical trials show promise, clinical trials testing this treatment in MSUD could begin sometime in 2000 or 2001.

Dr. Blaese was the last speaker at Symposium â98.Ê He explained a very technical subject in a simple way we could all understand.Ê However, we wondered if we really were understanding?Ê One mother said she looked around the room and saw many of us sitting with our mouths hanging open.Ê Just the idea that there is hope for a cure in the not so distant future was hard to fathom.Ê Previously, cures were only dim hopes÷always many years away.Ê Dr. Blaese sounded so certain of this technology.

Dr. Blaese submitted this article on Nov. 19 and plans to keep us updated on developments.Ê We need to keep our hopes from soaring too high just yet.Ê Funding is the major delay in getting testing started.Ê FDA approval is still pending.Ê So parents PRAY; pray for the success of this company and gene repair.

SYMPOSIUM â98 REVIEW

A strong, united effort by the families of children with MSUD in Pennsylvania, along with the support and involvement of the Clinic for Special Children, paid off in a highly commended symposium.Ê Over eighty families from across the United States and six other countries gathered at the Willow Valley Conference Center, south of Lancaster in the middle of June.Ê Many parents brought their families for a great vacation in the heart of Pennsylvania Dutch Country.Ê One hundred children and adults with MSUD, along with their siblings, a number of grandparents, other family members, and many professionals, brought the total to 480 at lunch on Friday, the day with the highest attendance.

Following are two reports on the Symposium reprinted from the Clinic for Special Children Newsletter (Spring 1998 issue).Ê The Clinic chooses to call MSUD Maple Syrup Disease (MSD), but we have changed the name in the following articles to MSUD for clarity.Ê Following these reports on the medical meeting held on Wednesday, June 17 and the Symposium (on 18 and 19), is a report of responses from persons who attended the Symposium and kindly filled out the questionnaires.Ê I hope those who could not attend will gain a little information and an idea of the importance of these meetings to many of the families.

MSUD Scientific Meeting

The National Biennial Symposium for Maple Syrup Disease was held in June in Lancaster County with an overwhelming turnout of families and professionals from this country and overseas.Ê Lectures and discussions followed the theme of ãProgress, Problems, and Promises.äÊ Prior to the two day symposium for parents, the Clinic sponsored a day long scientific meeting to examine neurological effects of MSUD and to provide an overview of the clinicâs approach to management of MSUD as presented in a first draft of a Manual for Care.Ê Dr. Morton and Dr. Kevin Strauss, Resident in Pediatrics at Boston Childrenâs Hospital who spent four months of his senior year of Harvard Medical School in study at the Clinic, discussed a ãnewä disease model for MSUD which recognizes the greater role of leucine as a modulator of amino acid transport into the brain and out of the cells.Ê Much of the information presented at the Scientific Meeting was based upon work by Dr. Halvor Christensen who attended the meeting.Ê Dr. Christensen remarked that some of his most important observations about how leucine influences the transport of other amino acids were made at Boston Childrenâs Hospital in 1949.Ê His early experiments led to the discovery of the transport system that regulates entry of the neutral amino acids into the brain and provided the first observations that increased concentrations of leucine and phenylalanine cause intracellular entrapment of selective amino acids.ÊÊ Dr. Christensenâs discoveries are key to clearer understanding of how high serum leucine causes a complex neurologic syndrome that includes sudden changes in level of consciousness and coordination, brain edema, as well as chronic malnutrition of the developing nervous system.Ê After Dr. Christensenâs remarks, Dr. Morton and Dr. Strauss presented their studies of the neurological signs and MRI findings of acute leucine intoxication, described management protocols that allow recovery from cerebral edema, usually irreversible and fatal, and presented MRI findings of patients after prolonged imbalances in serum amino acids caused arrests of brain growth and development.

Douglas Wilmore, MD, Professor of Surgery, Harvard Medical School and Brigham & Womenâs Hospital in Boston discussed biochemical, endocrinologic, and inflammatory variables that must be controlled to prevent endogenous protein catabolism and sustain protein synthesis in ill or injured patients.Ê His studies and recommendations of the use of glutamine in nutritional management were important contributions to the meeting.

Quentin R. Smith, PhD, Chairman, Department of Pharmacology, Texas Tech University, presented data about neutral amino acid transport across the blood brain barrier and what that suggests about acute neurological dysfunction and chronic amino acid deficiencies in the central nervous system of patients with MSUD.

Attended by approximately 35 physicians and researchers (including Dr. Hugo Moser of Kennedy Krieger Institute and an early supporter of the Clinicâs work), the scientific session concluded with discussion of new strategies to prevent illness and injury in patients with MSUD.Ê The current strategy, based on the central idea of simply lowering leucine to control MSUD, does not necessarily promote optimal growth and development.Ê Children survive but are often compromised with some degree of malnutrition, poor brain growth, and mild to severe physical impairment.Ê The new strategy developed by Dr. Morton and used by the Clinic seeks to balance the ratios of the amino acids leucine, isoleucine and valine by modifications in formulas and uses glutamine and alanine to help promote protein synthesis and catabolism in muscle and liver.Ê This strategy has enabled many of the younger MSUD children in care by the Clinic to achieve and maintain normal growth and development.

Following the day long meeting, we enjoyed a Lancaster County supper graciously hosted by friends and neighbors, Marilyn Lewis and Marian Ware.Ê We thank them for such a lovely evening to conclude our meeting.

The MSUD â98 Symposium

Parents of children with MSUD from this region of Pennsylvania dedicated much time and energy as hosts of the two day meeting held at the Willow Valley Resort, located a short distance from the Clinic.Ê The Symposium provided opportunity for parents and physicians to present and discuss the latest in research and treatment protocols, for teenagers to discuss their issues together and for younger children to simply have fun.

Dr. Holmes Mortonâs lecture to open the meeting entitled ãProgress, Problems, and Promisesä gave an overview of the evolution of treatment of MSUD for Mennonite families in Lancaster County.Ê He introduced the first draft of a Manual for Care for MSUD based on the Clinicâs ten year experience and approach of diagnosis and care of 30 neonates and 60 patients who range in age from a few months to 33 years.Ê The manual is intended for use by physicians and parents and will be revised for a more complete version during the coming year.

Other speakers included Dr. Harvey Levy, Harvard Medical School and Boston Childrenâs Hospital, who presented an update on newborn screening for MSUD in the U.S.; Dr. Vivian Shih, Harvard Medical School and Massachusetts General Hospital, discussed how neonates and children with MSUD are managed in centers in other regions of the U.S. as well as other countries; Dr. Phyllis Acosta, Director of Metabolic Diseases for Ross Products Division discussed formulas and special foods necessary to children and MSUD and Dr. Neil Buist, Professor of Pediatrics at Oregon Health Sciences University in Portland, assessed nutritional problems associated with MSUDâs very restrictive diet and how certain problems can be prevented.Ê In a second lecture Dr. Morton analyzed effects of MSUD on the brain such as cerebral edema, muscle weakness, appetite and sleep patterns, and the development of myelin.Ê Contrasting MRI images with clinical observations he gave all of us a greater understanding of the complex involvement of the brain in this disorder and provided parents, children and practitioners a frame of reference for their daily observations.Ê In other presentations, the liver transplant and progress of a 7 yr. old MSUD patient with liver failure due to vitamin A toxicity was described by Dr. Morton and by Dr. Paige Kaplan, metabolic specialist of Childrenâs Hospital of Philadelphia where the transplant was preformed.Ê This experience demonstrated there are possibilities of ãcuringä MSUD with correction through the liver.Ê Dr. George Mazariegos of the Thomas Starzl Transplant Institute in Pittsburgh described all that is involved with liver transplant.Ê Transplant bears high risks and requires lifelong medication to prevent rejection.

Dr. Richard Kelley, Kennedy Krieger Institute & Johns Hopkins and the Clinic, discussed the nature of metabolic diseases in light of recent developments in the field of gene therapy.Ê Dr. Rody Cox, Dean and Professor of Internal Medicine at the University of Texas, Dallas, outlinedÊ progress of gene repair by viral vectors and insertion of new genes.Ê The final presentation of the symposium revealed the promise of a new approach to gene therapy called chimeraplasty, presented by Dr. Michael Blaese, Chief, Clinical Gene Therapy Branch of NIH.Ê In chimeratherapy, gene correction is achieved through infusion by IV of a chimera gene which corrects the abnormal gene sequence in the liver of MSUD patients (also potentially in Crigler-Najjar patients).Ê With low risk to the patient, this therapy has the potential to be effective for infants as well as older children.Ê Dr. Blaese, the Kimeragen Company, and the Clinic hope to begin trials within a year

÷Reprinted from the Clinic for Special Children Newsletter (Spring 1998)

Symposium Î98 Greatly Appreciated

At the Symposium, I asked the audience to write down what they liked about Symposium â98, and to share what they learned while attending the Symposium.Ê Each family and professional received a questionnaire to complete.Ê I said I would use this information in a review in the fall/winter issue of the Newsletter.Ê I received responses from 30 family members and five professionals.Ê Following is a summary of these responses.

ãDid you enjoy the Symposium?äÊ Yes, yes, yes!Ê No one marked ãnoä in answer to this question.Ê Some even emphasized their ãyes.äÊ They would all consider attending another one.Ê Motel accommodations were rated excellent on 11 questionnaires; other ratings included: very good, superb, very nice, and good.Ê The comments on accommodations included some advice:

J Excellent facility although a smaller facility makes it easier to interact with each other.

J Excellent, gets better with every Symposium.

J They were very nice, though the lecture room was often cold.

J Very well organized.

J It was wonderful, but as Ivan said during the Symposium, ãIâd attend in a tent to be with these families and hear the latest.ä

J Very nice, but a little over-priced.

J Fine; there was plenty of room, and I didnât get lost going from place to place.

J Very nice÷I think you should only offer the discount toÊ parents who need it, and allow parents who can pay the full fare to do so.Ê It is too much money to raise, and many families could have paid the extra two hundred or so dollars.Ê (The fund-raising by Pennsylvania families provided enough money to pay a percentage of the hotel bill for each of the attending MSUD-affected families.)

This is how families answered the question: What did you like best about the Symposium â98 experience?

¯ Sharing with parents our experiences and learning from doctors and also parents.

¯ Substance-there was a lot of medical information.

¯ That I didnât have to do any work this time.Ê I liked all the speakers. (from ReneŽ Eck who helped with Symposium â96)

¯ As always, the interaction with the families canât be beat.

¯ Everything nice and complete.Ê Day was not long enough to get all topics in.

¯ It was great to hear from many different ãexpertsä who work with people who have MSUD.Ê The idea of parents and professionals sharing information is helpful.Ê I enjoyed seeing the children with MSUD and how well many are doing.Ê Also keeping up with families that have moved away and talking with professionals.

¯ Accommodations, good food, good organization, and amount of information given.

¯ I liked renewing old friendships, learning more dietary necessities÷comparisons of leucine, isoleucine and valine quantities.

¯ Learning from Dr. Holmes Morton.

¯ Doctors and professionalsâ views and discussions.

¯ Talking, sharing with other parents and just being here and part of the big family.

¯ Everything was special!Ê I liked having activities for children while we were in the conference room.

¯ The sense of a big family and the children all eating the same; comparing notes with other parents and seeing the kids growing up. Everything was great.Ê I hope two years from today it goes just as well.

¯ Meeting new families!Ê New information.

¯ Gene therapy update; leucine and isoleucine relationship and supplements; visiting with old friends and meeting new families.

¯ The discussion in the evening with the parents.Ê Also Dr. Mortonâs speeches.

¯ It is always a highlight seeing and visiting with other MSUD families.Ê Just the gathering is a blessing.

¯ Information!Ê Networking; sharing experiences; catching up with families and seeing growth and development among the MSUD kids; socialization for Elan with other MSUD teens.

¯ Information; hearing accomplishments of research; meeting with other families.

¯ 1) The kindness and respect (love) that was prevalent.Ê 2) The bringing together of, and the opportunity to befriend, people from all different cultures.

¯ That the information Iâm taking back may improve my daughterâs health.

¯ The baby sitters were wonderful!!Ê I didnât need to worry.

¯ Canât say which÷it was just GREAT!

What the professionals liked best:

¯ Just being with the families, learning their experiences and seeing the progress of their children.

¯ The genetic and medical information was extremely well presented, informative and timely.Ê I enjoyed the biochemistry explanations.

¯ 1) The health care providers sessions, especially Wednesday at the Clinic.Ê 2)Meeting new patients/families.

¯ Dr. Mortonâs talk on how MSUD affects the brain; seeing adults and children with MSUD.Ê The meeting was well run and organized.Ê I learned quite a bit.

¯ Sharing experiences with families.Ê Very well paced.Ê Excellent job of keeping people on schedule.

When asked if there was something they did not like about the Symposium, most answered no, or nothing, and some leftÊ a blank space.Ê There were a few comments and suggestions:

L Everything was interesting; I think that the genetic research and gene therapy was a little confusing.

L We would have liked more small groups of parents with children of same age.Ê We found the doctors meeting the most valuable.

L Some talks were more technical than they needed to be.

L Not enough time to talk in groups about common MSUD problems.

L We did not have enough time to get into small groups for discussion.Ê More Dr. Buist÷heâs very entertaining!

L Too many scheduled meetings and speakers; too short a lunch break.

L Not enough time for all the questions, but could easily understand with all the people attending.

L Never seems to be enough time to cover all questions.

L Not all the questions on the index cards were answered.

L Excellent speakers, but some needed to put lectures on level we parents could understand.

L Gene therapy talk was over my head; itâs so exciting and I wanted to better grasp it.

Professionalsâ suggestions:

L It is hard to sit all day and into the evening.Ê I would recommend 1¸ hours be scheduled into the program for exercise.

L It was difficult to keep comfortable, warm temperatures.

The parts of the program families enjoyed most and the reasons they were special:

In answer to these two questions, the three most frequently mentioned parts of the program were the three that most directly involved the families: the Coping Workshops, the Personal Perspective Panel, and the Question and Answer Panels.

Coping Workshops: Families could choose to attend a workshop for parents of teens, one for parents of children between the ages of 6 to 12 years, or one for parents of newborns to 6 years old.Ê These sessions proved to be very emotional and extremely interesting and helpful to the parents.Ê Here are some comments on the Coping Workshops:

¯ I enjoyed everything, but I found very stimulating the Coping Workshops÷seeing all that parents are going thru and understanding what you are going thru.Ê You can really realize that you are not alone and your feelings are normal.

¯ Sharing personal thoughts and ideas about MSUD.

¯ The families discussing their personal experience with their child or children was interesting.

¯ I liked the splitting of the big group, for a part of an afternoon, into several smaller groups.Ê People are more apt to share their experiences when the group isnât so large.

Question/Answer Panels:Ê Twice during the program, a panel of doctors fielded questions from the audience.Ê The questions were written on 3x5 cards and handed to the moderators who recorded them on large flip sheets.Ê Each flip of the paper revealed another question.Ê This kept the answering very orderly.Ê Following are comments:

¯ Learned day-to-day coping skills.

¯ The parents got a chance to ask questions; we need the professionals.

¯ Real concerns were answered by many different people to get more than one view.

¯ Good communication between parents and doctors.

¯ Everyone had a chance to ask just about anything.

¯ We picked up some useful information to take home with us on daily management.

Personal Perspective Panel: On this panel were adults with MSUD who gave their views on questions asked by moderator Bobbi Wanta, and also answered questions from the audience.Ê Many persons mentioned this as being particularly interesting.Ê But the only specific comments were: that it was very interesting as far as coping with diet and peer pressure; and that it was very encouraging.

Dr. Mortonâs speeches:Ê Dr. Morton made sense when he explained the many aspects of MSUD that tend to puzzle parents.Ê His knowledge of MSUD and personal interest in each child were evident and appreciated.

¯ Dr. Mortonâs explanations:Ê It is encouraging to know that he is trying to comprehend the complexity of this disease, so that all of our children can benefit.

¯ Dr. Mortonâs presentations:Ê His responses to questions were in laymanâs terms; very knowledgeable about MSUD.Ê Also appreciate his research findings.

¯ Iâve been wanting to meet/hear him speak about MSUD since I had my daughter (3 yrs.).

¯ The amount of knowledge that Dr. Morton has and passed on to us parents.Ê Especially the MSUD effects on the brain.

¯ I am really glad Dr. Morton wrote all his information down, so maybe our doctors will get a better idea on how to treat the children they see with MSUD.

¯ He was so easy to understand and everything made so much sense.Ê Gave me some direction to consider to improve the treatment of my son.

Liver Transplant: Families found the information presented on the topic of Kathryn Burkholderâs liver transplant of great interest; most stating that it was interesting and educational.

Genetic Research: The possibility of gene therapy aroused a great deal of hope and fascinating interest.Ê Some specific comments were:

¯ I enjoyed learning about genes.

¯ That MSUD may have a cure soon÷I felt like it would not happen in my childâs life time.

¯ Dr. Blaeseâs genetic discussion: itâs hard to beat the kind of hope heâs given that some day, in the not too distant future, we may have a cure for MSUD (or MSUD).

¯ Explanation of liver transplant and gene therapy gave us hope for the future

¯ Obviously the highlight and surprise was the announcement of a possible cure.Ê Dr. Blaese probably never should have gone so far out on a limb, but now, I hope you can follow up and keep us informed.

¯ The session on gene therapy was very difficult to understand, but feel that the research being done is very hopeful for the future.

Comments from professionals about the parts of the program they enjoyed and why they found them interesting:

¯ The professionalsâ day at the Clinic on Wednesday was a unique experience.

¯ I only attended Friday but enjoyed the entire day.Ê The speakers were interesting and interested in the MSUD young people themselves.

¯ 1) I enjoyed the health professionals session at the Clinic most.Ê I enjoyed hearing about Dr. Mortonâs unique experience.Ê He has what many of us dream of, the ability to get ãSTATä labs and MRIâs÷which leads to insights and documentation of objective and quantitative changes needed to improve our understanding and ability to treat.Ê 2) Also enjoyed visiting and ãinterpretingä for our patients and families.Ê Our patients are always special.

¯ Arguments for better treatment.

How could the Symposium be improved?

Two persons felt the Symposium couldnât be improved.Ê Others had some comments, ideas and suggestions:

¯ You all did a great job and the children enjoyed their workshops, which is important, too.

¯ Considering how many issues there were, I donât think it could have been much better.

¯ I wish it was closer.Ê But then all the great people who made it possible probably would be too far away to attend!Ê And it wouldnât even come close to this yearâs symposium.Ê Iâve never met so many nice people in one place.Ê How can we be kept up-to-date on the research?

¯ We need organized activities in the evenings so that families can interact.

¯ It would be good for parents to introduce themselves and give the name of their child when they speak from the audience.Ê It would help to get to know the different families better.Ê Possibly have introduction of families during a separate session÷maybe the first night, so families can learn to know each other sooner.

¯ I think it would be good to allow parents with children similar in age to talk together for 2 to 3 hours.Ê I think every group would then benefit from a ãround tableä discussion with parents from the next age group older to theirs.Ê For example, parents with new babies might enjoy talking to parents of children 6 to 8.Ê And parents of pre-teens would enjoy talking to parents with teens.Ê What about more business time÷not to talk about finances or anything else like that, but maybe things we feel the general support group should vote on.Ê Or do we just leave all decisions to the board?Ê (For example, name change from MSUD to MSUD)?

¯ One doctor was talking in terms I could not understand, and took it for granted that we all understood him.Ê He was very hard to follow.

¯ I would be very interested in having the children with MSUD in a panel to express their feelings about their disease, like the young adults with MSUD did.Ê Have them divided into different ages, so the parents can have a better idea of what to do better, or what to expect from the children as they grow.

¯ It would be helpful if the doctors could present their information in a more simplified form for ease of understanding by families who donât have a medical background.Ê Some speakers did a better job with this, such as Dr. Buist, Dr. Kaplan, Dr. Mazariegos, and Dr. Blaese.Ê Iâd like to hear more about the day-to-day management of MSUD, such as how families do the diet, count milligrams of leucine, or count grams of protein?Ê Do they keep daily diet records?Ê Are low protein foods used?Ê What is frequency of blood tests?Ê Is urine testing routinely done and how often?

¯ Allocate more time for parent-to-parent interaction.

¯ It would be great if we could add a day and spend more time in smaller groups discussing our personal questions and problems.Ê It would be great to have a list of all the people/places who are in attendance.Ê This way we could seek friends and make new acquaintances of those in our areas.Ê Unless you have met them before, or are introduced, you may not get a chance to meet.

¯ Need more than one hour for the break-out groups.Ê Also, a medical professional could be added to each group.

¯ Group time for workshops increased to 1¸ or 2 hours; have a 3-day symposium vs. a 2-day symposium.

¯ Emphasis on managing day-to-day problems

¯ More professional interaction with patients and educate in the newer aspects of treatment and theory.

Suggestions for improvement from physicians and dietitians:

¯ More ãdoctorsâ panelsä to answer patient questions from the audience÷it is helpful for patients to have their doctor up there with other doctors treating the disorder and get everyoneâs opinion on issues.

¯ More recipe sharing÷maybe a cooking class for parents and teens with advice on how to improve your own cooking.

¯ Sessions combining patients, their parents and professionals all together.Ê When I am in professional and adult meetings, I feel that I am missing what the kids or their parents are saying.

¯ A workshop/talk on diet to see if we all manage it the same, or what other methods are used.Ê A cooking class for parents to exchange ideas/tips/recipes and to help new parents overcome the fear of working with the low protein products.

Persons were encouraged to write more about what they learned from the speakers and in what way the Symposium helped them and their families:

We attended the MSUD Symposium in Lancaster and want to extend our heartfelt thanks to all of those involved in the planning and implementation of the meeting.Ê In addition to the meeting itself, the level of support from the community was also impressive.Ê Unfortunately, we were only able to attend on Friday, and as we were traveling with our 3 toddlers, did not have much opportunity for conversation with other families.Ê Hopefully we will be able to remedy this at the next Symposium, which we will look forward to.

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ

÷Karen & Jerry Dolins

Obviously, we feel this way because Nikolai was on the panel, but it was touching to hear from the adult MSUD for the sake of the younger ones.Ê It probably helped the parents.Ê Iâm sorry not more younger children attended.

I think the location was the key to having so many attend.Ê If Boston is chosen next time, there may be interest in new speakers÷only if Dr. Shih takes an active role.Ê But it will be much more expensive.Ê Nevertheless, no future symposium can be planned now without specific attention given to the progress of the cure.Ê It may be necessary to direct the location around that company.

I think all parents should take a moment to consider how difficult it is to have 400 people, with kids who have special needs, come to talk, eat, sleep, play, and learn.Ê We are so busy, even this evaluation is late.Ê Our hats are off to the organizers!Ê Barbara and I think they did a fabulous job, down to the details of having gifts in each room!

The only other issue which may be raised is the silent one of how the doctors disagree with one another.Ê It can be difficult for parents to be convinced of one approach in a lecture, recommend it to their doctor, only to be told that it is a wrong, or at least not necessarily the best, approach.Ê That is the conflict of getting parents involved, but as you know, it is needed.

Nikolaiâs comments: He liked it. The only negative: kids didnât have much time to get to know each other again, because they kept being separated.Ê Everything else is positive.

Ê ÷Eric & Barbara Rudd

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ~\~\~

The information I have learned at the Symposium will be brought back to my sonâs metabolic physician to update her on new findings and research.

÷Jody Carrington

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ~\~\~

I always enjoy attending the Symposium even if I donât leave with more information.Ê Just the discussions with other MSUD parents makes it worth attending.Ê My problems donât seem so bad after I talk with other parents.Ê It is nice to just visit with everyone.Ê It also gives my MSUD child an opportunity to be around other MSUD children, and she doesnât feel like she is the only one with the disease.

÷Mary Ann Peters

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ~\~\~

I have been reading and re-reading the manual that we received at the Symposium.Ê There is a wealth of information that can benefit all of our MSUD children.Ê At the Symposium, I learned a great deal from Dr. Morton including the relationships between leucine, isoleucine, and valine and other amino acids.Ê Also, the effect on the brain and development of MSUD children when these amino acids are not balanced correctly.Ê It was encouraging to learn that Dr. Morton has gained an understanding of cerebral edema in MSUD children.

Dr. Naylor from PA spoke about the benefits of mass tandem spectrometry for newborn screening.Ê Wouldnât it be wonderful in the future if all newborns could be screened so quickly for so many rare diseases?Ê Dr. Michael Blaise from the NIH explained about chimeroplasty.Ê It seems to be the most promising gene therapy for our kids.Ê It is encouraging to know that someone is working to improve our childrenâs future and that the liver will likely be the targeted organ

.ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ

÷Sandy Bulcher

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ~\~\~

Maybe we donât need another MSUD Symposium in two years if these children can all be healed!JÊ We appreciate the good clinic and care we get in this area after hearing of the care some others are getting.Ê Really appreciated that Neil Buist could be here and sure enjoyed his talk.Ê We need more people like him.Ê Very thankful for what Dr. Blaese is doing and sure hope it will work out.

÷A parent

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ~\~\~

I had a great time and my son too.Ê Even with the long drive ahead, I would do it every year.Ê I can see there is a lot of hard work and time put into it.Ê God bless everyone who did this Symposium.Ê We really enjoyed this time we had together.Ê See you in two years in the year 2,000.

This one child threw us into a frightening world.Ê But now it is a big part of our life, and we love it.Ê We are happy to be a part of this family.Ê Life would seem so empty without it.Ê We made more friends through this one child than through all our others combined.Ê This includes not just the families, but the professionals as well.Ê Our love to all.

After her liver transplant, Kathryn Burkholder asked her mother why she was never 6 or 7 years old.Ê ãI was 4 and 5, then 8 and 9, but I wasnât 6 or 7.äÊ (The years she was very sick.)Ê ãOther children are 6 and 7 years old but I wasnât.ä

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ÷Kathrynâs grandmother, Mrs. Isaac (Rachel) Newswanger

My nephew (who has MSUD) enjoyed the socializing.Ê For me (great aunt, aunt, grandmother, and mother), it was wonderful talking to parents of children the same age as my great nephew, finding similarities of problems, hearing other doctors, of course, especially Dr. Morton.Ê All were wonderful.Ê Dr. Blaese (God willing the cure) and Dr. Kelly and Dr. Cox so brilliantly explaining the chain reaction of trouble cells.Ê Thank you.

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ~\~\~

I feel grateful for Dr. Mortonâs help for our problems over the years, and for the doctors that traveled from Philadelphia, Pittsburgh and many other states to help with the ãforward movementä of new information to help or cure MSUD patients.Ê Thanks so much to all who made the Symposium possible.

ÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊÊ ÷Norman & Mabel Burkholder

We learned that we have much to be thankful for to have Dr. Morton as our doctor.Ê Talking with some other parents you find out some doctors are still doctoring the way they did 15 to 20 years ago.Ê We also found it very interesting to see all the adult MSUD doing so well.

I have benefitted greatly from this Symposium and will now take back ideas on how to better care for my daughter, Samantha.Ê Her life will be better because of this.

Thank you for making it so well organized.Ê Every minute was utilized to the fullest to bring us the most information possible in two days.Ê Thank you for the nice gift basket.Ê It was a nice touch to the end of a hectic, long journey.

I admire and appreciate the strength and comradery of this community and wish I lived closer.Ê We are looking forward to the next Symposium.Ê A million thanks.

Comments from the professionals: