Vol. 5 No. 1, Spring 1998
A publication of the FacioScapuloHumeral Society
Provided by the FSH Society, Inc.
Inside ...
As a response to the testimony of the FSH Society and resultant Congressional report language, the National Institutes of Health are issuing a program announcement for Facioscapulo- humeral Disease (FSHD) titled Pathogenesis and Therapy of the Muscular Dystrophies.
NIH has responded to Congress as follows:
"The NIAMS and the National Institute of Neurological Disorders and Stroke (NINDS) support research on the many forms of muscular dystrophy including facioscapulohumeral disease (FSHD). In 1990, scientists discovered the general location of the defective gene for FSHD on chromosome 4. However, much remains to be learned about the functional changes that accompany the disease and treatments. In April, 1997, the NIAMS, NINDS and the NIH Office of Rare Diseases, along with the Facioscapulohumeral Society, held a FSHD conference designed to identify medical problems associated with the disease and to help focus research efforts by identifying new research opportunities. As the next step in an effort to increase research interest on FSHD, NIAMS and NINDS are developing a program announcement to follow up on recommendations from the April meeting. NIAMS, NINDS and the NIH Office of Rare Diseases will continue to work closely on encouraging FSHD research and to share relevant scientific advances."
The FSH Society wishes to thank the following people for meeting with Daniel Perez, President, FSH Society, and for their continued interest: Drs. Richard Lymn (NIAMS), Floyd Brinley (NINDS), Paul Nichols (ORD), Stephen Groft (ORD), Audrey Penn (NINDS), Stephen Katz (NIAMS) and Harold Varmus (NIH).
The FSH Society hopes that the members of both the national and the international research community will avail themselves of this opportunity to contact NIH with ideas and proposals for research on FSHD.
The FSH Society has given testimony again this year to further funding for FSHD research.
Questions and Answers about DNA testing for Facioscapulohumeral Dystrophy (FSHD)
—Marsha Speevak, Ph.D.
Recently, scientists have discovered new information about the molecular basis of FSHD. This information has led to the development of a new DNA diagnostic test that allows the specific diagnosis of FSHD in the majority of cases.
What causes FSHD?
The cause of FSHD is not yet precisely known. Scientists do have some pieces of the puzzle and more knowledge is being gained each year. The most important discovery to date is that FSHD is usually associated with a small DNA deletion on chromosome 4. This deletion can be detected using a DNA test.
How is the FSHD DNA test performed?
DNA is analyzed using a method called Southern blotting. DNA, which is a very long molecule, is cut into small, measurable fragments. The size of the DNA fragments in the region of chromosome 4 that is important for the diagnosis of FSHD is measured. Individuals who have FSHD almost always have a DNA fragment that is unusually small, due to the deletion on chromosome 4.
Is there an association between the size of the deletion on chromosome 4 and the severity of FSHD in an individual?
There does appear to be a relationship between the size of the deletion and the severity and age of onset of FSHD. Large deletions (resulting in very small fragments) appear to be associated with earlier onset and more severe symptoms. Also, large deletions are more likely to be sporadic rather than inherited. Small deletions tend to be associated with later onset, and milder symptoms.
Is FSHD always associated with a deletion on chromosome 4?
No. In about 5% of individuals who have symptoms of FSHD, no deletion is detected on chromosome 4. It is probable that these individuals have a different, unknown gene mutation on another chromosome, which results in similar symptoms.
How accurate is DNA testing for FSHD?
About 90% of individuals with FSHD can be accurately diagnosed by the DNA test due to the detection of a deletion. In comparison, healthy individuals in the general population are extremely unlikely to show a deletion in the same region of chromosome 4. However, within some FSHD families, some individuals may be found who appear to have a deletion, but do not show obvious symptoms of FSHD. This situation is more likely to occur when the deletion is small.
How is DNA obtained from an individual who has FSHD?
DNA is isolated from white blood cells. A single tube of blood (about a tablespoon) provides enough DNA to perform the test.
I have symptoms of FSHD. How can I arrange for a DNA test to confirm FSHD?
You can ask your doctor to refer you to your local genetics clinic. There, a detailed family history will be taken. The geneticist will be able to identify those individuals in your family who could most benefit from DNA testing. The geneticist will also be able to arrange for the blood sampling and shipment of the blood to a testing center.
If I have the test, when should I expect a result?
DNA tests often take 8 weeks or more before a result is ready. The DNA test results are reported to the referring physician (usually a geneticist). Since DNA test results can be difficult to interpret and understand, it is essential to have a skilled professional, such as a geneticist, explain the results of DNA testing.
What is meant by sporadic FSHD and inherited FSHD?
Sporadic FSHD means a single individual in a family has FSHD, but no one else in the family has symptoms. It also means that the FSHD deletion was identified in the affected individual but not in his/her parents. Once someone is diagnosed with sporadic FSHD, the risk of transmitting FSHD is the same as in the inherited form of FSHD. Inherited FSHD means that the disorder is present in multiple members of the family, over two or more generations.
We have been told that our child has sporadic FSHD. Is there any risk FSHD could occur in our next child?
Up to 20% of apparently sporadic cases of FSHD arise due to mosaicism for the FSHD deletion in one parent. This means that one parent has a mixture of cells; some with the deletion and some without the deletion. This mixture of cells may or may not be detectable by the DNA test, depending upon the extent of mosaicism in the individual. Therefore, there is a risk of having another child with FSHD, even if there is no detectable deletion in either parent.
I have FSHD. What is the risk that I could have a child with FSHD?
Individuals with FSHD have a 50% chance of having a child with FSHD in each pregnancy.
Is there a prenatal test for FSHD?
Prenatal testing for FSHD is possible. In prenatal diagnosis, fetal cells are obtained primarily by one of two procedures. The earliest procedure is called chorionic villus sampling (CVS). This procedure is performed at about the 10th to 12th week of the pregnancy. The alternative procedure is called amniocentesis. This procedure is performed at about the 15th to 16th week of the pregnancy. Individuals at risk to have a child with FSHD should see a geneticist for counseling as early as possible in the pregnancy, or even before becoming pregnant since it is necessary for their DNA to be tested in order to obtain accurate results. Prenatal diagnosis must be arranged many weeks in advance, through a genetics clinic. Prenatal tests have risks associated with them, and therefore it is important to obtain genetic counseling, and consider all the information about prenatal testing carefully before deciding to proceed. In general, molecular diagnostic laboratories make a special effort to process prenatal DNA samples as rapidly as possible. Prenatal DNA test results are therefore usually available between 3–4 weeks (CVS) or 4–6 weeks (amniocentesis).
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Marsha Speevak, PhD, Molecular Diagnostic Laboratory, Genetics Department, Children’s Hospital of Eastern Ontario, Canada. For information on DNA testing for FSHD at Children’s Hospital of Eastern Ontario, Canada, contact Brenda Levesque, Coordinator, at 613/738 3230.
Program Announcement for Facioscapulohumeral Disease (FSHD)
The FSH Society wishes to inform you that on March 20, 1998, the NIH issued PA Number: PA-98-044, titled: Pathogenesis and Therapy of the Muscular Dystrophies. This is a direct result of efforts to inform NIH of the critical needs in FSHD research and testimonies given before Congress year after year.
Sponsored jointly by NINDS and NIAMS, applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators.
The support mechanisms for grants in this area will be the investigator-initiated research project grant (R01) and the program project grant (P01) and may include studies in appropriate animal models or preclinical or clinical studies in patients with facioscapulohumeral dystrophy (FSH).
Some possible areas of research that are specific to one form of muscular dystrophy include: facioscapulohumeral muscular dystrophy, and continue the sequencing of the entire 4q35 region; and to investigate the position effect hypothesis and its basis in chromatin structure.
The FSH Society encourages you to apply for these grants.
$300,000 Grant Established for Fellowships in Molecular Genetics of FSHD
The FSH Society proudly announces the establishment of the Marjorie Bronfman Grant for postdoctoral research fellowships in molecular genetics of Facioscapulohumeral Muscular Dystrophy (FSHD). The generosity and commitment of Mrs. Marjorie Bronfman to FSHD research permits the FSH Society, starting in 1998, to award four or more two-year research fellowships (US $30,000/year) for research projects that show extraordinary promise to find the cause of FSHD. This foresighted contribution to FSHD research propels the International FSHD research community and the FSH Society into the forefront of scientific endeavor for those living with FSHD. The FSH Society is deeply indebted to Mrs. Bronfman for this significant opportunity to advance research activity.
In September, 1997, Daniel Perez, President of the FSH Society and David Housman, Ph.D., Chairman of the Scientific Advisory Board of the FSH Society, met with Mrs. Bronfman to establish the terms of the grant. These terms were unanimously approved at the December, 1997, meeting of the FSH Society’s Board of Directors.
The FSH Society looks forward to a productive collaboration with Mrs. Marjorie Bronfman to advance FSHD research. Research projects will be selected by the Scientific Advisory Board of the FSH Society in accordance with the procedures described on page 17 of this newsletter. These fellowships are available to researchers worldwide.
Dear Fellow Member,
As we head into the first half of 1998, we can see that the FSH Society is most definitely having an impact.
1997 was a year in which the FSH Society was increasingly successful in raising awareness for FSHD and in making change happen for people involved with FSHD. Our Society is unparalleled by any organization in the world in the area of accumulating and disseminating information on FSHD research and FSHD patient issues and in the area of raising visibility for FSHD. This is due largely to the many extraordinarily talented and dedicated members who agree with our principle and vision. In addition, the Board of Directors and the Scientific Advisory Board of the FSH Society has performed consistently by demonstrating excellent judgement, solid guidance and clear direction on the issues at hand.
Our 1998 goals are to continue milestones already met and go the distance by increasing our membership, providing much needed infrastructure and full time salaried personnel for the Society, providing more research fellowships and more research equipment, assuring DNA testing and information on genetic testing for FSHD in the United States (this may well be achieved if all goes well in the next few weeks) and advocating for FSHD research in all forums around the world and in the United States. We are pleased with the NIH Program Announcement 98-044 (March 20, 1998) which covers FSHD research and will be working to expand on gains made in this area by looking for larger and more specific programs targeting FSHD research. We will be asking the United Sates Congress to earmark 2 to 4 million dollars for FSHD research. We have asked you to contact your Senators and Representatives. You have done so, and the work is paying off. We have given eight congressional testimonies and will return as many times as it takes and as many as they will allow. We will also voice the need for research on FSHD anywhere and anyplace we can.
The FSH Society has given and will continue to give a clear message that research must happen on FSHD.
Extraordinary progress has been made in FSHD research in the past ten years after a century of neglect. The FSH Society is working hard with the Congress of the United States, the National Institutes of Health (NIH), the Institute of Medicine (IOM) and the Muscular Dystrophy Association (MDA) in the United States, the Association Francaise contre les Myopathies (AFM) in France, the Vereniging Spierziekten Nederland (VSN) in the Netherlands, other foreign agencies and private foundations in helping to understand the necessity to increase and accelerate research on FSHD. We are creating a place for FSHD researchers to come together around the world. As you can see, our research grants have gone to exciting research projects outside of the United States as well as within. Additionally, many multinational collaborations have formed since the April 1997 Symposium (FSH Society/NIH/MDA) on FSHD in Boston and the October 1997 Workshop (FSHD) in Baltimore.
We are extremely fortunate to have people such as Mrs. Marjorie Bronfman and Larry and Ida Laurello who understand the Society’s capacity to create research opportunities for FSHD and who have trust in our ability to create research opportunities for FSHD. Mirroring that, we are extremely fortunate to have a Scientific Advisory Board (SAB) unsurpassed by any in the world in evaluating FSHD research issues. Under the chairmanship of David Housman Ph.D. of M.I.T., the SAB understands our commitment to FSHD research and the necessity to select first rate research projects for funding and for providing scientific and clinical direction on FSHD.
We are also extremely fortunate to have researchers as dedicated and talented as Stephane Plaisance Ph.D., Sara Winokur Ph.D., Rossella Tupler M.D. Ph.D. and Silvere van der Maarel Ph.D. who wish to pursue research in FSHD. Drs. Tupler and Plaisance are the first recipients of the Delta Railroad Construction fellowship and Drs. van der Maarel and Winokur are the first recipients of the Marjorie Bronfman fellowship for FSHD research. We should also find solace and comfort in the fact that, without question, the top minds and the leading scientists are currently working on FSHD. It appears that at this moment the research must move laterally rather than straight ahead due to difficulties with this type of research. However, the lateral directions are proving to be quite innovative and fruitful. Researchers are trying many novel approaches to the problem in addition to the standard reverse genetics. International communication between researchers on FSHD is at an unprecedented all time high. Please see the minutes of the October 1997 workshop for details.
This has been a year in which we have worked closely with Ohio State University and the University of Rochester in their study of FSHD and drug trials. Thanks to our work members have responded to their request to join the study and continue to show interest in furthering the research.
Most notable are the increased awareness and education of the Internet bulletin board system (BBS) and chat room consumers due to the efforts of many under the strong and persistent leadership of Cindy Gilman and Paul Closson. Many kudos to the FSHD Support Group leaders and members who continue to make valuable contributions to the Society and provide resources for us when we call on them. It is heartwarming and reassuring to know that we are a part of a larger group worldwide who are deeply committed to help one another and to solve FSHD.
It is my hope that in my letter to you in the year 2000, I will be discussing how quickly we are curing this disorder with known treatments.
The challenge is still before us. We must push on and continue our journey. Please help us achieve our fundraising goal for 1998. Join, get others to join, help us, and please support the Society in any way you can.
As always, I hope you find the information in this newsletter as valuable as I do.
—Sincerely, Daniel Paul Perez, President, FSH Society
Tissue Donated for Facioscapulohumeral Muscular Dystrophy Research
On Thanksgiving Day, 1997, Dr. Stephen J. Jacobsen, Vice President, FSH Society, received a call from the family of Steven Chestnut with the news of his unexpected death. Glen and Donna Chestnut, Steven’s parents, knowing Dr. Jacobsen’s efforts and the efforts of the FSH Society, expressed the wish to donate tissue for FSHD research. Dr. Jacobsen put the family in contact with Sally Wisniewski of the Maryland Brain and Tissue Bank to facilitate the donation of much needed tissue.
This decision by the Chestnut family in their time of sorrow represents a major contribution to the FSHD research efforts. For the first time, tissue from an individual with FSHD is now available to researchers. The FSH Society expresses its deepest sympathy and the gratitude of the FSHD community to Steven’s parents, his sister Rita, brother Robert and niece Deirdre for their thoughtful decision.
Many thanks go to Dr. Michael Altherr who recommended (several years ago) that the FSH Society could help the research efforts by facilitating tissue donation. The FSH Society has been running an article in the FSH Watch (see page 18 - letter from Wisniewski) and has built relationships with Sally Wisniewski and Dr. Ronald Zielke of the Brain and Tissue Bank to support this endeavor. Also, many thanks to Dr. Barbara Weiffenbach and Dr. Rabi Tawil for compiling a list of tissues thought to be of value to the research.
—Richard A. Lefebvre, Chairman, Fundraising Committee
The FSH Society has achieved remarkable progress to date because of the hard work, persistence and determination of just a few people under the direction of Daniel Perez, President, FSH Society, and the contributions of our fellow members and grassroots supporters, and some very generous donations. Despite our lack of full time personnel, the FSH Society was able to raise some $330,000 for FSHD research fellowships during 1997 with an all volunteer staff, while the NIH and MDA provided roughly the same amount each towards FSHD research. Although the FSH Society has negotiated overhead from the foundation grants, every effort will be made to achieve 100% granting of monies donated for FSHD research fellowships. That’s right — one hundred percent.
The FSH Society has proven to be effective. We are now at the point where our efforts are limited by the volunteer resources available to us. In addition to enhancing FSHD research, we need to enhance our infrastructure. We have several individuals who would love to work on the FSH Society on a full time basis. We need your help immediately at this point in raising money to allow us to salary individuals to continue our work.
Because of the growth in the activities of the FSH Society, we now need Dan Perez to work full time on a paid basis to run this organization and to be available to do the myriad of things that are necessary to be done. You may not be aware that Dan works full time to support himself and works full time on the Society, as well, without pay. Having donated ten years of hard work at no cost to the Society, Dan has let the board know that he wants to work on the Society full time on a paid basis. I personally will be the first to say that he most deserves the opportunity to pursue his vision fully backed by those of us who ultimately benefit from the work. Without individuals such as Dan working with the utmost intensity in matters regarding FSHD, we are going to lose ground to other people’s agendas. Without our support, Dan is not going to be able to continue with the same effectiveness and intensity. I am sure that, given a short interval of one or two years backed by membership and the Board of Directors, he will be able to build the financial resources to take us to the next level to enable us to achieve our mission. We will be able to achieve much more if we have a person developing external and internal resources who is able to focus on research funding on a full time basis. We are very close to the achieving this critical next step.
In the summer issue of the FSH Watch, I discussed the challenges we face organizationally as well as the need to raise significant amounts of money to promote and expedite research for FSHD. The research money is out there and the organizations that have the internal resources have a real opportunity before them. Therefore, our first goal is to raise enough money internally to build an organizational structure that will enable us to effectively compete for those funds. This is our first hurdle and we are making progress. From 1996 to 1997, we doubled our contributions, membership, and network total. Good job!
The internal funding needed to achieve this first step is approximately $180,000 annually to cover the costs of operating the Society and all the necessary programs separate from the research dollars and grants. This can be achieved only if we double our contributing membership and donor base as we have done in past years. As of February, 1998, our network total suggests that we have the potential to reach our goals.
Now it’s time again for ALL of us to step up to the plate again and put our money where our chat is. Each of us must increase our personal giving goal and new member recruitment goal for this year. If we need to raise $180,000 internally, and we currently are achieving $88,000, we can achieve this if we ALL remain aggressive and make it a priority in our daily lives. Our future is in our own hands. Believe me, we can do this, but we need your help because no one else can do this for us.
FSH Testimony to Congress February 5, 1998
Mr. Chairman, it is a great pleasure to submit this testimony to you today.
My name is Karen Johnsen, of Bowie, Maryland and I am testifying as a member of the Board of Directors of the Facioscapulohumeral Society and Mid-Atlantic FSHD Support Group and as an individual who has this rare disorder.
The Clinical Picture of FSH Muscular Dystrophy.
The FSH Disorder, otherwise known as Facioscapulohumeral Muscular Dystrophy or FSHD, is an inherited neuromuscular disorder affecting one in twenty thousand people. FSHD causes a progressive and severe loss of skeletal muscle with initial weakness of facial, scapular and arm muscles and subsequent loss of other skeletal muscles.
Living with FSHD.
As an American with FSHD and generations of my family afflicted with facioscapulohumeral dystrophy, I will tell Congress just how hard it is for a typical family to deal with this disease.
Both my brothers have FSHD. I have watched them endure it for a lifetime.
FSHD has physically diminished me. There is no cure. There is no treatment. I live with physical and emotional pain and the frustration of losing independence daily.
My only son has FSHD. I wish that he not see his mother progressively weaken knowing that he is watching what is certain to be his fate. Surely, he knows, at his age, that without a cure, he too will progressively weaken and be burdened with a diseased body.
It is physically impossible for me to put my arms around my son to hug him. I can not look him in the eyes anymore and tell him, "It will be all right." I worry about the day he brings home his forever love with the fear that she will not be strong enough in seeing what will become of my son. I worry for the happiness and future of my grandchildren because FSHD is inherited. I watch helplessly as my son’s young carefree personality changes into that of a young man depressed and burdened with the realization and shock that he has inherited his disease from me.
My husband will soon be my care-giver for I can not walk. I can not roll over or get out of bed. I can not close my eyes to sleep and feeding myself is getting more and more difficult. I need assistance with bathing, toileting and dressing.
And all the while, my son sees my pain, my anguish and my increasing disability. And I see his fear. How can a mother reassure her child if she too is unsure?
This is the reality for families living with FSHD who are your neighbors, your colleagues and your friends! We want more of life. I want more for my child! Please help us get the ammunition to fight Facioscapulohumeral dystrophy!
The Need For NIH Funding For FSHD.
Largely, thanks to your efforts, Mr. Porter, National Institutes of Health research funding continues to grow.
We have met at NIH about the current crisis in FSHD research. We all realize the continuing need to attract, retain and maintain talented researchers and programs solely focused on FSHD.
In the past year, there has been an unprecedented level of communication between the research community, the FSH Society, NIH and Congress. We are indebted to the members of this subcommittee and to your colleague, Representative Edward J. Markey from Massachusetts, for his support, for the report language submitted to you last year co-signed by Representatives Barney Frank, John McHugh, Martin Meehan, Charles Schumer and Robert Wexler. While we wait for a formal response to last year’s report language from Congress to the Director of NIH, we need Congress to help NIH with resources to act now on FSHD research. The FSHD community understands that the process takes time and we are positive that we will see major and bold initiatives in this area.
Today, I am asking Congress to communicate to the Public Health Service and National Institutes of Health the need for a CORE center and the need for intramural and extramural research on the FSHD disorder.
Current Funding Sources For FSHD Research
Mr. Chairman, there presently is very little funding of FSHD from NIH—perhaps two hundred thousand dollars. This is clearly insufficient given the recent advances and significant progress now possible.
FSHD Research Needs.
The FSHD community appeals to the Congress of the United States of America to take action on the one item that this community can not do for itself—fund research on FSHD. We ask today for a contract with people living with FSHD committing funds to FSHD research in the areas that the international community of scientists working on FSHD have proposed.
Conclusion.
The men, women and children who live with the daily consequences of this devastating disease are your friends, neighbors, fellow taxpayers and contributors to the American way of life. With an historical 88% employment rate and an average educational achievement level of 14 years, we personally bear our burden of the health care costs and training expenses to prepare for and maintain financial and personal independence.
We appeal to you today to take our hard earned tax dollars commensurate with our numbers and valuable contributions to American Society. We urge the United Sates government to allocate a proportion of our tax burden towards research on FSHD. The current amount per person per year living with FSHD is unacceptable.
We ask the subcommittee to assign a dollar amount to FSHD research. We request that an amount of not less than two (2) million and not more than four (4) million dollars be earmarked for FSHD research.
Time is of the essence here. Lives are in the balance and the race against this disease is ongoing. The FSHD community demands persistent and innovative research programs now and the willingness to take risks in previously uncharted territory. We, who are losing physical strength daily, are gaining rapidly in collective numbers. We who are least able to do the simplest physical tasks daily, have undertaken the most complex task of FSHD. We, who have the most severe limitations imposed on us, have mobilized. We have moved to action and are prepared to act cooperatively with the NIH and with Congress.
I have brought a longer statement from the FSH Society to be included in the record with comprehensive details on current FSHD research needs.
Mr. Chairman, again, thank you for providing this opportunity to testify before your subcommittee.
1998 FSH Society Contact Day Denver, Colorado
An FSH Society meeting is tentatively scheduled
for the weekend of October 31–November 1
to coincide with the American Society of Human
Genetics conference to be held in Denver, Colorado, from October 27–31, 1998.
More details to come.
Report: FSHD Workshop at the American Society of Human Genetics Conference
The Facioscapulohumeral (FSH) Society sponsored a workshop at the 47th annual meeting of the American Society of Human Genetics in Baltimore, MD, on October 30, 1997. Researchers and clinicians from North America, Europe, Japan and South Africa met to discuss issues related to FSHD. This was the first such workshop sponsored by the FSH Society and all in attendance were grateful for their support and extensive efforts to organize this meeting.
Daniel Perez, President of the FSH Society, welcomed the participants and conveyed several important opening remarks. Mr. Perez reviewed the recent initiatives to increase federal funding in support of FSHD research. He recently testified, on April 23, 1997, before a House of Representatives Committee regarding appropriations for research on FSHD. He asked the attendees at the workshop to compose a list of ten priority areas of research/clinical focus so that he could present them at a follow-up meeting with NIH the following day. Morgan Downey, the legal counsel based in Washington, D.C., who has been instrumental in approaching Congress for such funds, was introduced. Daniel Perez also informed the workshop members that funding has been made available by the Delta Railroad Construction Company for one Young Investigator Research Award, and that others may be available shortly. An announcement was also made that a large North American foundation is committed to significant financial support of FSHD research.
The FSHD workshop was chaired by Michael Altherr of Los Alamos National Laboratory. He proposed an agenda which consisted of recent genetic findings, examination of animal models, genotype/phenotype correlations, description of unlinked families or cases in which no short fragments have been identified, an update on therapeutic trials, and a discussion of future strategies, collaborations and meetings. Sara Winokur, a postgraduate researcher who has previously worked with Dr. Altherr on the molecular genetics of FSHD, took the minutes of the workshop.
Alexandra Belayew (University of Leuven, Belgium) presented some interesting data regarding a known transcription factor, HLTF, and its DNA target sequence, Heft1, which is 87% identical to a portion of the D4Z4 repeat. Heft1 was shown to have promoter activity when used in a luciferase reporter system. A portion of Heft1 was used to isolate a novel cDNA, Dux1, which contains a double homeodomain, and its corresponding 20 kD protein. Dux1 is also a DNA binding protein. This cDNA does not arise from the 3.3 kb D4Z4 repeat, but the similarities between the HLTF target sequence and the overall structure (double homeodomain) of the gene is striking and warrants further investigation.
Rossella Tupler (Institute of Cellular Biology, Rome), who is currently on a two year sabbatical at the University of Massachusetts, presented her results from mRNA differential display experiments using deltoid muscle from FSHD and control individuals. She found that 1 of 20 differentially expressed genes mapped to 4q35. This gene was ANT1, which was found to be upregulated in FSHD individuals. George Padberg (Nijmegen, The Netherlands) mentioned that he had also seen increased ANT1 levels, even in light of a general decrease of mitochondrial components.
Discussions of animal models revolved around three species: the puffer fish Fugu rubipes, the myd mouse, and some initial studies in the fruit fly Drosophila melanogaster. Pam Grewal, in Jane Hewitt’s laboratory at the University of Manchester, presented her results on comparative mapping of the FRG1 syntenic region in human, mouse and Fugu. The FRG1 gene is highly conserved in Fugu and the region does not contain the repetitive sequences and pseudogenes present in the human FSHD region. However, the syntenic region to mouse chromosome 8 (containing the FRG1 gene) is inverted in Fugu, so that this organism is not ideally suited to identifying candidate genes for FSHD in the immediate vicinity of FRG1.
Kathy Mathews (University of Iowa) reviewed some data suggesting that the sarcolemnal membrane may be disrupted in FSHD. Evans blue is a dye that is taken up by cells with a loss of integrity of the cellular membrane. This dye is taken up by skeletal muscle in the Myd mouse just as it is in the Mdx mouse, leading to the conclusion that, at least in Myd affected muscle, the membrane is disrupted. This is consistent with the elevations of creatinine kinase (CK) seen in both Myd and FSHD.
Dr. Mathews also presented some very intriguing data regarding initial position effect variegation studies she has done in Drosophila in conjunction with Pam Geyer at the University of Iowa. Preliminary studies have indicated that the D4Z4 repeat, when transfected in trans with a white minigene reporter leads to repression of the white gene and the phenotypic variegated expression of yellow to red eyes. These results suggest that D4Z4 may indeed be heterochromatic and that proteins that bind to the repeat when transfected into Drosophila may spread to adjacent genomic regions, and suppress the expression of nearby genes.
Jane Hewitt suggested that members of the FSH group attend her talk entitled "Inter- and intra-chromosomal duplications of distal chromosome 4q35; and example of telomere plasticity" the following day. She has sequenced the telomeric region of 4q and identified a long-range polymorphism at the 4q telomere (4qA and B). The distal 25 kb of the 4qA allele is homologous to 4p, 10q and 22q. The sequence of 4qB is 99% identical to 4p, suggesting that this allele arose through a more recent intrachromosomal exchange.
Michel van Geel presented a poster at ASHG entitled "Sequence annotation of the FSHD1 region on chromosome 4q35 covering 160 kb proximal of the tandem repeat locus (D4Z4)." Except for the repeat regions and the FRG1 and TUB4q gene-related sequences, no significant sequence homology to known genes were identified upon EST and protein database searching. He has identified additional PAC clones with which to extend the FSHD region sequence further proximally.
The discussion then moved into the clinical realm, with Marsha Speevak describing the function of her diagnostic laboratory at Children’s Hospital of Eastern Ontario, Canada. DNA diagnostic testing for FSHD is publicly supported for residents of Ontario, with charges incurred for out-of-province individuals. The focus of her lab has been to develop testing for diseases that require unusual (i.e. non-PCR or Southern-based) types of DNA analysis. She was therefore interested in receiving input from members of the FSHD workshop on the complexities of diagnostic testing for FSHD. The challenges in identifying the FSHD-associated chromosome 4 allele were discussed by several individuals, including Silvere van der Maarel, Egbert Bakker, Rune Frants (Leiden University), Peter Lunt (Bristol) and George Padberg (Nijmegen), who have been instrumental in developing DNA diagnostics for FSHD. The need to develop techniques to sort out translocated 4/10 chromosomes by PCR, PFG or FISH probes was also reiterated.
The question of where clinicians and researchers in North America could refer individuals with FSHD for testing was brought up. Meena Upadhyaya (University of Wales, Cardiff) offered to do the testing in Cardiff if appropriate counseling were given by geneticists in North America prior to consent for testing. The diagnostic lab in Ontario, Canada, is also currently providing diagnostic testing for FSHD.
Marcy Speer (Duke University) discussed the issue of heterogeneity in FSHD. She has excluded much of the genome as harboring another FSHD locus. However, one large family with findings consistent with FSHD has been evaluated at Duke which shows no linkage to 4q35 markers and has no EcoR1 short fragment associated with the disease.
Ongoing clinical trials of potential therapeutic agents for FSHD were discussed by Rabi Tawil (University of Rochester) and George Padberg (Nijmengen). A pilot trial of albuterol conducted by Rabi Tawil and by Jerry Mendell (Ohio State University) demonstrated an increase in lean body mass after three months of treatment. This is in contrast to the clinical trial of prednisone, which yielded an increase in total body mass, most of which was due to fat increase, with an actual decrease in lean body mass. They are conducting a large ongoing double blind study in which individuals with FSHD are given varying (0, 16 and 32 mg) amounts of albuterol.
George Padberg (Nijmengen) is conducting a similar trial of albuterol in The Netherlands, in which he is training one arm and not the other. He is following 60 patients for one year and will collaborate with Marc Jeanpierre (Hospital Cochin-Maternites) in France, who is also following a large group of individuals affected with FSHD.
Discussion of a future meeting followed, with all in agreement to meet next year at the ASHG meeting in Denver, CO. Clinical will try to convene at an upcoming meeting in France. The EMC will fund European attendees for a FSHD international consortium workshop in Europe. Daniel Perez remarked that a large North American foundation with an interest in FSHD will consider a proposal to fund future FSHD workshops as well. The minutes from the ENMC FSHD workshop on July 19–21, 1996, in Naarden, The Netherlands, was distributed by Peter Lunt (Bristol Children’s Hospital). An announcement for a Facioscapulohumeral Muscular Dystrophy satellite meeting (to the August, ‘98, Neuromuscular Diseases Conference in Adelaide) in Sydney, Australia, was circulated.
At the conclusion of the workshop, the attendees composed the focus list that Daniel Perez had requested in his opening remarks. The areas of focus are 1) to continue to search for candidate genes through such approaches as differential display and genomic scanning, 2) to investigate experimentally the position effect hypothesis and its basis in chromatin structure, 3) to further pursue animal models such as the mouse and drosophila, 4) to examine genetic heterogeneity, 5) to examine phenotype/genotype correlations regarding intra/interfamilial variation and nonmendelian inheritance, 6) clinical trials, 7) continued sequencing of the FSHD region, 8) examining the structure/function relationship of the D4Z4 repeat, 9) diagnostic improvements, 10) examining the role of non-muscular sensory systems, 11) creating a bank of important reagents and resources and 12) developing cell-based assays for gene expression.
Management of Cardiac Complications in Neuromuscular Disease
William R. Lewis, M.D., Assistant Professor, Division of Cardiovascular Medicine, University of California, Davis, Board of Directors, Facioscapulohumeral Society
The presence of cardiac abnormalities in facioscapulohumeral muscular dystrophy (FSHMD) is debated. While most authors have noted the presence of diverse electrocardiographic abnormalities, some have found no abnormalities on electrocardiography, chest radiography, Holter monitoring, or echocardiography. Nuclear scanning with thallium-201 has demonstrated diffuse defects consistent with diffuse fibrosis. 168 abnormalities in systolic time intervals on echocardiography 90 and elevations in atrial natriuretic peptide are consistent with subclinical cardiomyopathy.
Atrial paralysis, an unusual condition in which the atrium is devoid of electrical or mechanical activity, has been reported by several investigators. An in-depth investigation of cases of atrial paralysis found that 33% of all cases were associated with Emery-Dreifuss muscular dystrophy (EDMD). These authors feel that the finding of atrial paralysis distinguishes EDMD from other similar dystrophies, such as FSHMD. The association of atrial paralysis with FSHMD or EDMD will remain clinically uncertain until the advent of genetic testing that can reliably distinguish between these similar forms of muscular dystrophy.
Cardiac complications in FSHMD are rare, and patients in general have normal longevity. This predisposes them to the usual age-related cardiac complications, and management of these problems are the same as in non-dystrophic patients.
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Pull out the envelope inserted into the middle of this newsletter, fill it out and send it in today!
David Housman Elected to the Institute of Medicine
David Housman, Ph.D., professor of biology, Center for Cancer Research, Massachusetts Institute of Technology, and Chairman of the Scientific Advisory Board of the FSH Society, was elected to the Institute of Medicine (IOM), raising the total active membership to 558. Current active members elect new members based on major contributions to health and medicine or related fields.
Members make a commitment to devote a significant amount of volunteer time on committees that study a broad range of health policy issues. Current projects include a series of reports on dietary requirements and studies on community-based drug treatment, control of cardiovascular diseases in developing countries, and the medical use of marijuana.
Questions you may have for your genetic specialist
Note: This article is reprinted to help individuals with FSHD as they prepare to visit a geneticist or genetic counselor. These questions may help you with gathering information about a condition that may seem overwhelming. It is difficult for most of us to take in all the information in one visit. Some people have found that tape recording their conversations was beneficial. Time may not permit you to have all your questions answered in one visit. We hope this will help you identify the issues that are important to you.
Checklist of key questions:
· What is the diagnosis and what does it mean?
· How accurate is the diagnosis?
· How does an individual get this condition?
· What tests are available to see if a person has or carries this condition?
· What diagnostic procedures are recommended and what are their risks?
· Where can I obtain a second opinion?
· What are the characteristics of this condition?
· Is there a cure for this condition?
· What is the life expectancy of someone with this condition?
· What is the treatment and follow-up for this condition?
· When might it be appropriate to see you again?
· What specialists will I need to see?
· How do you care for a person with this condition?
· How is this condition passed from one generation to the next?
· What should I consider before having more children?
· Is there a prenatal test for this condition and are there any special pregnancy precautions?
· Can a person have this condition and still pass it on to his or her children?
· Will my other children/siblings be affected?
· Where can I get additional information about this condition?
· How will this diagnosis affect my health insurance?
· What are the medical costs likely to be?
· Is there any financial assistance for those who have this condition?
· Which organizations or support groups might be helpful?
Printed with the permission of the Pacific Southwest Regional Genetics Network (PSRGN). For further information contact: Pam Cohen, Regional Coordinator, Regional Coordinator, 2151 Berkeley Way, Annex 4, Berkeley, CA 94704-1101
Announcing a New FSH Watch Feature!
The FSH Watch welcomes your questions about DNA testing for FSHD. Evelyn Gage, Ph.D., will answer your questions about FSHD testing and inheritance in the next edition of the Watch. Please send or E-mail your questions to the FSH Society, 3 Westwood Rd., Lexington, MA, 02420. E-mail: carol.perez@fshsociety.org.
Mission Statement of the Facioscapulohumeral Society, Inc.
The specific objectives and purposes of the Corporation shall be:
1. To create a clearinghouse for information on the Facioscapulohumeral disorder (FSHD) and drugs and devices for the treatment of same, and to foster communication among individuals, families, caregivers, charitable organizations, government agencies, industry, scientific researchers, academic institutions, and interested individuals;
2. To accumulate and disseminate information about FSHD;
3. To encourage and promote increased scientific and clinical research and development on the causes, alleviation of suffering and the cure of FSHD, including with that limitation, the promotion of research and development for which funding may not otherwise be generally available;
4. To solicit grants and contributions from private foundations, the pharmaceutical industry and others to support such research and development;
5. To make grants and awards to qualified applicants so that such applicants may accomplish such research and development;
6. To act as a liaison among consumers and government and industry concerning research and development with respect to drugs and devices for FSHD.
7. To represent individuals and families with FSHD not otherwise represented by effective organizations and to work cooperatively and collegially with related organizations including, but not limited to, the Muscular Dystrophy Association and the National Organization of Rare Disorders;
8. To educate the general public, relevant government bodies, and the medical profession about the existence, diagnosis, and treatment of the FSHD disorder for which funding for research and development concerning diagnosis and treatment may not be generally available.
—Dr. Halsall and Professor Ellis, Academic Unit of Anesthesia,
St. James University Hospital, Leeds, The United Kingdom
Who should read this?
· Everyone who has a neuromuscular disorder, even if their symptoms are very mild.
· Everyone who has, or had, a relative with a neuromuscular disorder
· Professionals involved with the care of people with NMD around operations or treatment under local anesthetics.
Anesthetics
People with neuromuscular disorders must take great care if they are to have a local or general anesthetics. Even someone with very mild, or non-existent symptoms, or someone who has a family history of a disorder, needs to let the anesthetist know well in advance so that tests can be carried out and proper care after the operation can be arranged.
Many people are afraid of having an anesthetics, mainly through ignorance, but when we look at the rate of complications and even deaths arising from anesthesia we see that it is, in fact, very safe. This safety is the result of a thorough understanding of the patient’s medical condition with a careful assessment before the operation, marked technical improvements in monitoring facilities during the operation, and the provision of good recovery facilities such as High Dependency Units (HDU) and Intensive Care Units (ICU).
Patients with neuromuscular disorders (NMDs) deserve special attention when it comes to anesthesia because many of the agents used (gases and chemicals) have effects on both muscle and nervous tissue. The main areas of concern are how the anesthetics agents will affect the muscle and nervous tissue including the heart, which is, itself, a muscle. A skeletal deformity such as scoliosis, or curvature of the spine, can also affect the way the patient responds to anesthesia so it is important to consider that, too.
Anesthetics and the heart
An article printed in the Winter, 1995, No. 20 edition of The Search, showed how people with NMDs could sometimes have associated heart disease. This can occur as a cardiomyopathy, when the heart muscle doesn’t work effectively, or as a defect in the way the electrical activity of the heart is transmitted, a conduction defect. The anesthetics vapors—the smelly agents such as ether and halothane that are inhaled—can reduce the effectiveness of the heart’s muscle contractions and also aggravate any conduction defect. The vapors are all slightly different from each other, some having more effect on the heart than others. So it is important that the anesthetist makes a good assessment of the heart’s condition before the operation which would include the level of physical activity that the patient can manage, and an ECG. Occasionally a more extensive assessment is needed.
Anesthetics and breathing
Doctors need to measure how weak the patient’s muscles are, usually by assessing the amount of physical activity that the patient can perform, and by taking a blood test to measure levels of a muscle enzyme, creatine kinase (CK). Any anesthetics agent that affects the muscles will also affect the muscle we use to breathe. Strong analgesic or sedative agents will affect these muscles indirectly, and muscle relaxants will have a direct effect on them. As breathing (or respiration) may already be difficult for patients with NMDs, these drugs should be used cautiously, and monitoring of breathing after the operation is absolutely essential. As a result, the patient is usually best cared for in a High Dependency Unit or Intensive Care Unit immediately after the operation. The muscles used for swallowing can also be affected which is another reason why good post-operative care is important.
Muscle relaxants
Muscle relaxant drugs should only be used if essential because they tend to have a more profound and prolonged effect in NMD patients compared to other patients. One type of muscle relaxant, called suxamethonium, should usually be avoided. It causes the release of potassium ions (K+) from the muscle tissue into the blood. In normal patients this is usually of little practical significance. In patients with NMD the muscle may normally leak K+ so that a further increase in the levels of K+ in the blood may cause abnormal heart rhythms. A pre-operative blood test to check K+ levels is therefore important.
Local anesthetics
A local anesthetic works by preventing the normal electrical activity in the nerve around which the anesthetics agents are placed. For minor procedures, such as stitches for cuts, they are probably the first choice for patients with NMD because they have few, if any, side effects. However for major local anesthetics techniques, e.g. spinal or epidural, careful assessment of the patient is needed and the type of NMD considered well before the operation.
Changes in body temperature
and pre-operative ‘starvation’
Patients with NMD do not tolerate changes in body temperature or the starvation often associated with anesthesia or surgery as well as normal patients, so steps need to be taken to minimize these problems by keeping the patient warm and well hydrated using drips.
Malignant hyperthermia (MH)
and Central Core disease
Malignant hyperthermia (MH) is an inherited disorder, which causes an unexpected, sometimes fatal, reaction in the patient to certain anesthetic drugs. Because some patients with NMD have sometimes experienced similar problems during anesthesia, there have been claims that patients with NMD may also have MH. However, it is generally accepted that the only neuromuscular condition truly related to MH is Central Core Disease (CCD), although this is not always the case. Patients with CCD should be considered potentially susceptible to MH unless proved otherwise by a special type of muscle biopsy, which screens for MH.
To sum up . . .
· Clearly anesthesia for patients with a NMD is not to be undertaken lightly. Such patients should expect the anesthetist to make a careful and thorough assessment of their particular condition and their current state of health.
· They are not suitable to be treated as ‘Day Cases’ because doctors should carry out pre-operative investigations, and enough time and recovery facilities should be available after the operation.
· It is absolutely essential that the person affected by a NMD should inform the anesthetist even if there are only minor symptoms or no symptoms at all. Occasionally a neuromuscular disorder in a person who had no symptoms has come to light only because of an unexpected problem with anesthesia, particularly in young children. The anesthetist should also be warned if there is an inherited NMD in the family.
· If possible, ask for the anesthetist to be forewarned before admission to hospital and consider wearing a Medic Alert bracelet or similar informational device in case of accidents.
· It is always a good idea to make sure hospital staff have copies of "Fact Sheets" about your condition. If you are going to have an anesthetics, you might want to show your anesthetist this article.
1996
Bakker E Van der Weilen MJR Voorhoeve E Ippel PF Padberg GW Frants RR Wijmenga C Diagnostic, predictive and prenatal testing for facioscapulohumeral muscular dystrophy: diagnostic approach for sporadic and familial cases. J Med Genet 33:29-35 (1996)
Clark LN Koehler U Ward DC Wienberg J Hewitt JE Analysis of the organisation and localisation of the FSHD-associated tandem array in primates: implications for the origin and evolution of the 3.3 kb repeat family. Chromosoma 105(3):180-9 (Sep 1996)
Coelho PC Morgado F Reis P de Queiroz MV Facioscapulohumeral dystrophy with myositis associated with rheumatoid arthritis. Clin Rheumatol 15(2):185-8 (Mar 1996)
Connolly AM, Pestronk A, Planer GJ, Yue J, Mehta S, Choksi R Congenital muscular dystrophy syndromes distinguished by alkaline and acid phosphatase, merosin, and dystrophin staining. Neurology 46 (3): 810-814 (Mar 1996)
Deidda G Cacurri S Piazzo N Felicetti L Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD). J Med Genet 33(5):361-5 (May 1996)
Faustmann PM, Farahati J, Rupilius B, Dux R, Koch MC, Reiners C Cardiac involvement in facio-scapulo humeral muscular dystrophy: a family study using Thallium-201 single-photon-emission-computed tomography. J J Neurol Sci 144 (1-2): 59-63 (Dec 1996)
Grewal PK, Van Deutekom JC, Frants RR, Hewitt JE A search for genes in the facioscapulohumeral muscular dystrophy region. Biochem Soc Trans 24 (2): 282S (May 1996)
Ichikawa Y Yamada H Motoyoshi Y Shimizu T Kawai M [Abnormal head drooping in facioscapulohumeral muscular dystrophy] Rinsho Shinkeigaku 36(3):503-6 (Mar 1996)
Isozumi K, DeLong R, Kaplan J, Deng HX, Iqbal Z, Hung WY, Wilhelmsen KC, Hentati A, Pericak-Vance MA, Siddique T Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31. Hum Mol Genet 5 (9): 1377-1382 (Sep 1996)
Kaneko K Ohnishi Y Atsumi T Hozumi I Miyatake T On the heterogeneity of neurogenic facioscapulohumeral muscular atrophy [letter; comment] Muscle Nerve 19(4):533-5 (Apr 1996)
Kohler J Rupilius B Otto M Bathke K Koch MC Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occurring predominantly in oogenesis. Hum Genet 98(4):485-90 (Oct 1996)
Mathews KD, Mills KA The molecular genetics of human facioscapulohumeral muscular dystrophy and the myodystrophy mouse model. Curr Opin Neurol 9 (5): 394-399 (Oct 1996)
Nakagawa M Higuchi I Yoshidome H Isashiki Y Ohkubo R Kaseda S Iwaki H Fukunaga H Osame M Familial facioscapulohumeral muscular dystrophy: phenotypic diversity and genetic abnormality. Acta Neurol Scand 93(2-3):189-92 (Feb-Mar 1996)
Reimers CD, Schlotter B, Eicke BM, Witt TN Calf enlargement in neuromuscular diseases: a quantitative ultrasound study in 350 patients and review of the literature. J Neurol Sci 143(1-2):46-56 (Nov 1996)
Song MD Arahata K [Gene hunting of facioscapulohumeral muscular dystrophy] No To Shinkei 48(4):307-13 (Apr 1996)
Tawil R Forrester J Griggs RC Mendell J Kissel J McDermott M King W Weiffenbach B Figlewicz D FSH- DY Group. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. Ann Neurol 39(6):744-48 (1996)
Tupler R Berardinelli A Barbierato L Frants R Hewitt JE Lanzi G Maraschio P Tiepolo L Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy. J Med Genet 33(5):366-70 (May 1996)
Twyman RS Harper GD Edgar MA Thoracoscapular fusion in facioscapulohumeral dystrophy: clinical review of a new surgical method. J Shoulder Elbow Surg 5(3):201-5 (May-Jun 1996)
Ueyama H Kumamoto T Mita S Kimura E Nakagawa M Uchino M Ando M Facioscapulohumeral muscular dystrophy with chromosome 9p deletion Neurology 46(2):566-9 (Feb 1996)
van der Kooi AJ, Barth PG, Busch HF, de Haan R, Ginjaar HB, van Essen AJ, van Hooff LJ, Howeler CJ, Jennekens FG, Jongen P, Oosterhuis HJ, Padberg GW, Spaans F, Wintzen AR, Wokke JH, Bakker E, van Ommen GJ, Bolhuis PA, de Visser M The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands Brain 119 ( Pt 5): 1471-1480 (Oct 1996)
van Deutekom J C T Lemmers R J L F Grewal P K van Geel M Romberg S Dauwerse H G Wright T J Padberg G W Hofker M H Hewitt J E Frants R R. Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35. Hum Mol Genet 5(5):581-591 (May 1996)
van Deutekom JC Bakker E Lemmers RJ van der Wielen MJ Bik E Hofker MH Padberg GW Frants RR Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1 Hum Mol Genet 5(12):1997-2003 (Dec 1996)
Winokur ST Bengtsson U Vargas JC Wasmuth JJ Altherr MR The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region. Hum Mol Genet 5(10):1567-75 (Oct 1996)
1997
A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. The FSH-DY Group. Neurology (1997 Jan) 48(1):38-46
Fisher J Upadhyaya M Molecular genetics of facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 7(1):55-62 (Jan 1997)
Fowler WM Jr, Abresch RT, Koch TR, Brewer ML, Bowden RK, Wanlass RL Employment profiles in neuromuscular diseases. Am J Phys Med Rehabil 76(1):26-37 (Jan 1997)
Grewal PK, van Deutekom JC, Mills KA, Lemmers RJ, Mathews KD, Frants RR, Hewitt JE The mouse homolog of FRG1, a candidate gene for FSHD, maps proximal to the myodystrophy mutation on chromosome 8. Mamm Genome 8(6):394-398 (Jun 1997)
Hsu YD, Kao MC, Shyu WC, Lin JC, Huang NE, Sun HF, Yang KD, Tsao WL Application of chromosome 4q35-qter marker (pFR-1) for DNA rearrangement of facioscapulohumeral muscular dystrophy patients in Taiwan J Neurol Sci 149 (1): 73-79 (Jul 1997)
Milanov I, Ishpekova B Differential diagnosis of scapuloperoneal syndrome. Electromyogr Clin Neurophysiol 37(2):73-78 (Mar 1997)
Nakagawa M, Matsuzaki T, Higuchi I, Fukunaga H, Inui T, Nagamitsu S, Yamada H, Arimura K, Osame M Facioscapulohumeral muscular dystrophy: clinical diversity and genetic abnormalities in Japanese patients. Intern Med 36(5):333-339 (May 1997)
Ohya K Tachi N Kozuka N Kon S Kikuchi K Chiba S Detection of the mutation in facio-scapulohumeral muscular dystrophy patients. Acta Paediatr Jpn 39(1):92-6 (Feb 1997)
Tawil R McDermott MP Pandya S King W Kissel J Mendell JR Griggs RC A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology 48(1):46-9 (Jan 1997)
Upadhyaya M, Maynard J, Rogers MT, Lunt PW, Jardine P, Ravine D, Harper PS Improved molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD): validation of the differential double digestion for FSHD. J Med Genet 34(6):476-479 (Jun 1997)
Winokur ST Bengtsson U Vargas JC Wasmuth JJ Altherr MR The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region. Hum Mol Genet 6(3):502 (Mar 1997)
1998
Spuler S Engel AG Unexpected sarcolemmal complement membrane attack complex deposits on nonnecrotic muscle fibers in muscular dystrophies. Neurology (Jan 1998) 50(1):41-6
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Brain and Tissue Banks for Developmental Disorders
The Brain and Tissue Banks for Developmental Disorders at the University of Maryland in Baltimore and the University of Miami are tissue resources established to further research aimed at improved understanding, care and treatment of developmental disorders. The Brain and Tissue Banks were funded by the National Institute of Child Health and Human Development to serve as intermediaries between people who wish to have tissue donated for research upon the time of their death and the researchers who need this tissue for their vital work. If you are interested in becoming a registered donor, or if you have any questions or concerns regarding the donation process, please contact Sally Wisniewski, Project Coordinator, at 1-800-847-1539. Thank you for taking the time to consider the possibilities offered to humanity through the great gift of tissue donation. Internet site: gopher://gopher.btbank.ab.umd.edu:1070
Leuven, Belgium
Researcher(s): Alexandra Belayew
Address: Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000-Leuven, Belgium
Interest(s): Molecular genetics
Update: We have recently cloned by serendipity a new member of the 3.3-kb dispersed repeat family, and identified in this element a promoter and an open reading frame, features that were never shown for any 3.3-kb repeat. We have submitted for publication a manuscript presenting the cloning and characterization of this 3.3–kb repeat (genomic and cDNDA’s), study of its promoter and of the encoded protein which is a new transcription factor with a double homeodomain (DUX1) expressed mostly in heart and skeletal muscle. Although the repeat we isolated does not map to 4q35 and is thus not linked to FSHD, sequence alignment with known repeats from the FSHD locus indicates that some of them have a homologous promoter and open reading frame, suggesting that a DUX1-related protein might be expressed from the FSHD locus.
Sao Paulo, Brazil
Researcher(s): M. Rita Passos-Bueno, Mayana Zatz
Address: Depart. de Biologia, Instituto de Biosciencias, Universidade de Sao Paulo, Rua de Matao 227, 05508-900, Sao Paulo, SP, Brazil
Interest(s): Clinical and occupational
Bristol, England
Researcher(s): Peter Lunt, Philip Jardine
Address: Bristol Royal Hospital for Sick Children, Clinical Genetics Service, St. Michael’s Hill, Bristol BS2 8BJ, England
Interest(s): Molecular genetics and clinical
Update: Dr. Lunt is revising the 21 Question leaflet UK FSH MD group.
Cardiff, England
Researchers: Peter Harper, Meena Upadhyaya
Address: Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, England
Interest(s): Molecular genetics
Abstract: Improved molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD): validation of the differential double digestion for FSHD. M. Upadhyaya, J. Maynard, M.T. Rogers, P.W. Lunt, P. Jardine, D. Ravine, P.S. Harper. A major advance in the molecular diagnosis of facioscapulohumeral muscular dystrophy is the recently reported elimination of confounding DNA fragments arising from homologous sequences located at 10q26. In order to evaluate the specificity and sensitivity of this important diagnostic test, we have compared a group of 130 patients fulfilling the diagnostic criteria for FSHD with 200 control subjects not known to have an increased risk of having an FSHD mutation. Among the FSHD cases the smallest BinI/EcoRI fragment sizes ranged from 10 to >48 kb with 94.6% (95% CI 89.2-97.8%) of cases having fragment sizes of 34 kb or less. Among the 400 chromosomes from controls the smallest BinI/EcoRI fragment observed with the EcoRI/BinI double restriction enzyme digest was 38 kb + 2 kb, suggesting a test specificity at a fragment size <34 kb of or very near to 100% (lower 95% CI 98.2%). Test sensitivity at <34 kb is estimated at 94.6% (95) CI 89.2-97.8%), all outliers having fragments >38 kb. The Southern blot analysis with DNA probe p13E-11 has created a valuable molecular diagnostic test for FSHD. J Medical Genetics 1997; 34:476-479)
Manchester, England
Researcher(s): Jane Hewitt, Robert Lyle, Lorraine Clark, Elizabeth M. Valleley, Pam Grewal
Address: Department of Cell and Structural Biology, Stopford Building, University of Manchester Medical School, Oxford Road, Manchester M13, United Kingdom
Interest(s): Molecular genetics
Paris, France
Researcher(s): Jon Andoni Urtizberea
Address: The Institut de Myologie, Batiment Babinski, Hopital Salpetriere, 75651 Paris, Cedrix 13, France
Interest: Clinical and molecular genetics
Researcher(s): Michael Fardeau
Address: Institut National de La Sante et, de le Recherche Medicale,
17 Rue du Fer-a-Moulin, 75005 Paris, France
Interest(s): Clinical
Researcher(s): Marc Jeanpierre, Jean-Claude Kaplan
Address: Hospital Cochin-Maternites, Sericede Biochemie Genetique 123,
Boulevard de Port-Royal, 75014, Paris, France
Interest(s): Molecular genetics
Poitiers, France
Researcher(s): Yves Rideau
Address: Unite Duchenne de Boulogne, Centre Hospitalier Universitaire, BP 577, 86021, Poitiers Cedex, France
Interest(s): Orthopedic Surgery (Scapula Fixation), Corrective Procedures for FSHD.
Pavia, Italy
Researcher(s): Rossella Tupler*
Address: Universita di Pavia, Biologia Generale e Genetica Medica, via Forlanini 14, 27100 Pavia, Italy
Interest(s): Molecular Genetics, Clinical
Note: *Rossella Tupler is currently working on FSHD research at the Howard Hughes Medical Institute, Worcester, MA, USA
Update: Our group at the University of Pavia is devoted to studying the molecular aspects of Facioscaphumeral Muscular Dystrophy (FSHD) since 1993. We have set up the molecular analysis of FSHD patients, both sporadic and familial, and their families, provide genetic counselling established a close collaboration with neurologists belonging to University clinics or Neurologic Divisions of Northern Italy. We have collected 38 FSHD families and 20 sporadic cases.
In 1993 and 1995, to study FSHD, we were awarded two grants from Telethon, an Italian association supporting research projects on genetic diseases. Furthermore, we collaborate with a research group at the Institute of Human Physiology, University of Pavia, that is performing a physiological analysis of isolated skeletal muscle fibres of FSHD patients.
It has to be noted that FSHD, along with the Duchenne and Becker forms, is one of the three major muscular dystrophies, with an incidence of 1 in 20,000. Attempts to devise effective therapeutic tools for FSHD has been hampered by an incomplete knowledge of its etiology and biochemical pathogenesis. As a result, no effective therapy currently exists. The fact that FSHD is inherited in an autosomal dominant fashion and the observation that the disease has an almost complete penetrance suggested that molecular genetics techniques might be applied to isolate and characterise the genetic defect causing the disease. The international effort to identify the FSHD gene(s) led to map the FSHD locus in the chromosome 4q35 region and to isolate a DNA probe (pl3E-l 1, D4F104S1 locus) that revealed chromosomal rearrangements in familial and "de novo" FSHD cases. Those rearrangements correspond to deletions of repeated DNA sequence units of 3.3 kb occurring in the subtelomeric heterochromatin of the chromosome 4 long arm (D4Z4). Heterochromatin is the most condensed form of chromatin and is related to low transcription activity.
Therefore, it has been postulated that the deletions detected by p13E-11 might cause rearrangements in the chromatin organisation and thus interfere in the gene expression. Based on the hypothesis that FSHD might not be caused by a gene mutation but might be related to the chromatin condensation of a specific chromosomal region altering the expression of genes located in the vicinity, we have undertaken an experimental approach alternative to those applied till now. Our experiments have been carried on in the laboratory directed by Professor Michael R. Green, HHMI, University of Massachusetts.
Our major goal was the isolation of genes whose activity is altered in the dystrophic muscle and among the differentially expressed genes, those that are critical for the FSHD pathogenesis. To achieve this target, we have compared the mRNAs extracted from muscle biopsies of a normal individual and a FSHD patient. By this experiment, we have been able to isolate several mRNAs representing genes that are differentially expressed in the FSHD affected muscle.
We have constructed two subtractive libraries that should represent either genes that are overexpressed or underexpressed in the FSHD affected muscle. Further analysis of those genes may provide new hints about what occurs inside the defective muscle cell in terms of gene expression and shed a new light on the pathogenic mechanism of FSHD. The genes that we have isolated should fall into several categories: a) genes that are mutated or influenced by the structural modification of the chromatin containing D4Z4; b) genes that are affected by the primary genetic defect; c) genes that are involved in the dystrophic process and could be related to a non specific sufferance of the diseased muscle.
The genes whose altered expression is specific for FSHD may be studied through different approaches: a) they may be used as biological markers for monitoring the progression of the disease by analyzing either the expression of specific mRNAs by in situ hybridization or the presence of specific proteins by immunohistochemistry on muscle histological section; b) we may isolate their homologues in other species and set up in vitro or in vitro studies to study their function or the effect of their deregulation; c) their function and their interaction with other genes may be also tested on cultured myoblasts.
A better knowledge of the molecular machinery that is deregulated in the FSHD muscle cell should establish the basis for future therapeutic approaches. We believe that our findings represent a starting point for the delineation of the biochemical basis of the disease and lay the basis for the identification of genes which are directly affected by the genetic defect responsible for FSHD. —Rossella Tupler, M.D., Ph.D., Assistant Professor of Medical Genetics
Rome, Italy
Researcher(s): Giancarlo Deidda, Luciano Felicetti
Address: Department of Molecular Biology, Istituto di Biologia Cellulare, 43 viale Marx, 00137, Roma, Italy
Interest(s): Molecular genetics
Tokyo, Japan
Researcher(s): Kiichi Arahata, J.H. Lee, Chirhiro Akazawa, Masanori Funakoshi
Address: Division of Neuromuscular Research, National Institute of Neuroscience, NCP, 4-1-1 Ogawahigashi, Kodiara, Tokyo, 187, Japan
Interest(s): Molecular genetics and clinical
Leiden, Netherlands
Researcher(s): Oebo F. Brouwer
Address: Department of Neurology, University Hospital Leiden, P.O. Box 9600, 2300 RC Leiden, The Netherlands
Interest(s): Molecular genetics
Researcher(s): Rune Frants, Marten Hofker, Egbert Bakker, Silvere van der Maarel
Address: Institute for Anthropogenetica, MGC-Department of Human Genetics, Leiden University, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands
Interest(s): Molecular genetics
Nijmegen, Netherlands
Researcher(s): George W.A.M. Padberg, Oscar Vogels
Address: Institute for Neurology, University Hospital Nijmegen, Department of Neurology, Reinier Postlaan 4, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
Interest(s): Molecular genetics and clinical
St. Petersburg, Russia
Researcher(s): Valery M. Kazakov, Dimitry Rudenko
Address: Department of Neurology, Pavlov's Medical Institute, L. Tolstoy Str. 6/8, 197089 St., Petersburg, Russia
Interest(s): Clinical
Update: The collaboration between Pavlov’s Medical University (Valery Kazakov) and the National Institute of Neuroscience (Kiichi Arahata), Tokyo, Japan has been extended to the year 2000 for a clinical and molecular genetics study of FSHD using clinical data as well as DNA samples from Russia to establish the correlation between phenotype and genotype in FSHD families.
Dr. Kazakov with Professor Yves Rudeau of Poitiers, France published an article in the Journal of Readaptation Medicale, Volume 16, Nov., 1996, page 182 -190 on Recherche en paternite de la myopathie facio-scapulo-humerale: II-Donnees historiques (1re partie) and in Volume 17, Mar., 1997, 5-11, Recherche en paternite de la myopathie facio-scapulo-humerale: II-Donnees historiques (2e partie).
Research Study: MR Image of lower limbs muscle in autosomal dominant FSHD patients. D. Rudenko, V. Kazakov, Department of Neurology, I.P. Pavlov State Medical University, St. Petersburg, Russia. 34 patients from 12 families and 10 normal control were studied. MRI of 20 muscles bilaterally in each patient was performed to estimate the peculiarities of pathological changes and sequency of muscle involvement. Axial 10 mm thick sections of midthigh and midlower leg muscles and T1 and T2 weighted image of 0.04T were created with visual and quantitative evaluation. More frequently in the symptomatic patients (SP) were found the next MRI patterns: heterogeneity with focal increase of fat within muscles ("moth-eaten") and two varieties of homogeneity density with high signal intensity one of which corresponded to clinical muscle weakness (all muscle replaced by fat) and another one did not correspond to clinical muscle weakness. In presymptomatic patients (56%) one could usually notice a homogeneity hyperdensity only in soleus (S) and gastrocnemius (G) muscles without their weakness. In these patients the "moth-eaten" pattern was never found. In all SP muscle the density changes appeared earlier than the decrease of muscle volume. When process extended to the lower limbs, the anterior compartment of lower legs was involved at an earlier stage, although the changes of density of S and G without their weakness were evident as well. MRI affection of posterior group of the thigh muscles appeared later, but quadriceps, gracilis and sartorius muscles were well spared. The asymmetry of muscle affections was established without predominant affection of the sides.
Pretoria, South Africa
Researcher(s): Antonel Olckers
Address: University of Pretoria, Dept Human Genetics and Developmental Biology, PO Box 2034, Pretoria, South Africa 0001
Interest(s): Molecular genetics
Marburg, West Germany
Researcher(s): Manuela Koch
Address: Med. Zentrum fur Humangenetik, Abtlg 1, der Philipps Universitat Marburg, Bahnhofstrasse 7, 35037 Marburg Germany
Interest(s): Molecular genetics
United States of America
Davis, CA
Researcher(s): K. Devereaux; D.D. Kilmer; R.T. Abresch; S.G. Aitkens;
G.T. Carter; W.M. Fowler; E.R. Johnson; G.T. Carter; J. Wright
Address: Research and Training Center on Neuromuscular Disease, Department of Physical Medicine and Rehabilitation, University of California, Davis, TB 191. Davis, CA 95616-8665; and National Institute on Disability & Rehabilitation Research (NIDRR)
Interest(s): Rehabilitation, Occupational and Clinical
Update: NIDRR has proposed research priorities that include such topics as 1) interventions that maintain functional capacity, 2) evaluating techniques for enhancing community integration (home, workplace, school, recreation), and 3) examining the risks and benefits of genetic testing. These broad areas include more specific issues such as maintaining muscle strength, minimizing fatigue, ensuring adequate nutrition, and minimizing problems related to breathing. Comments are welcome. Kathryn Devereaux, Ph.D. Director, Information Dissemination RRTC in Neuromuscular Diseases.
Current Research Articles:
Abresch, R.T., Seyden, N.K., Wineinger, M.A. Quality of life issues in neuromuscular diseases. Physical Medicine & Rehabilitation Clinics of North America, (G.T. Carter, editor). W.B. Saunders: Philadelphia. February, 1998. Summary: The goal of rehabilitation is to help people with disabilities live productive and satisfying lives, yet few studies have systematically examined what determines the quality of life of an individual with a neuromuscular disease . . . compares the historic patient-doctor relationship from earlier in this century with the current medical model of involving patients in important medical decisions and concludes that the current model is not effectively applied to persons with neuromuscular diseases . . . the affected individual’s assessment of his or her own life situation is incorporated into the analysis and serves to mediate the value of objective measures such as ability to work or to breathe without assistive technology. In addition to influencing health care policy, this study may also serve as an inspiration to affected individuals who assume that quality of life will be diminished when assistive technologies are needed.
Abresch, R.T., Walsh, S.A., Wineinger, M.A. Animal models of neuromuscular diseases: Pathophysiology and implications for rehabilitation. Physical Medicine & Rehabilitation Clinics of North America (G.T. Carter, editor) W.B. Saunders: Philadelphia. February, 1998. Summary: How animal models can be utilized to develop rehabilitation strategies to help treat the pathophysiology of neuromuscular diseases and illustrates how these models can be used to test the effects of therapeutic physical interventions (exercise, stretching, immobilization, etc.).
Hart, D., McDonald, C.M. Spinal deformity in neuromuscular disease: Role of bracing and surgery. Physical Medicine & Rehabilitation Clinics of NorthAmerica (G.T. Carter, editor). W.B. Saunders: Philadelphia. February, 1998.
Kilmer, D. Role of exercise in neuromuscular disease. Physical Medicine & Rehabilitation Clinics of North America (G.T. Carter, editor). W.B. Saunders: Philadelphia. February, 1998.
Kilmer, D. Case studies in neuromuscular disease exercise prescription. In:Physical Medicine and Rehabilitation, State of the Art Reviews (K. Shankar,editor). W.B. Saunders: Philadelphia. February, 1998.
Kilmer, D. Aitkens, S., McCrory, M. Nutrition in neuromuscular disease. Physical Medicine & Rehabilitation Clinics of North America (G.T. Carter, editor). W.B. Saunders: Philadelphia. February, 1998.
McCrory, M., Kim, H., Wright, N., Lovelady, C., Aitkens, S., Kilmer, D. Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. American Journal of Clinical Nutrition.
McDonald, C.M., Im, D. Limb contractures and the role of stretching, orthotics, and surgery in neuromuscular disease. Physical Medicine & Rehabilitation Clinics of North America (G.T. Carter, editor). W.B. Saunders: Philadelphia. February, 1998.
—Reprinted with permission from the UC Davis Rehabilitation Research and Training Center in Neuromuscular Diseases January 1998 newsletter.
Irvine, CA
Researcher(s): Sara T. Winokur; Ulla Bengtsson; Michael Altherr*
Address: University of California, Irvine, School of Medicine, Department of Biological Chemistry, D240 Medical Science Institute, Irvine CA 92717
Interest(s): Molecular genetics
Notes: *Michael Altherr is currently with the Genomics and Structural Biology Group, LANL, Los Alamos, NM
San Francisco, CA
Researcher(s): David S. Bredt
Address: Department of Physiology, University of California, San Francisco, Box 0444 Room S-859, San Francisco, CA 94143-0444
Interest(s): Molecular Genetics; Actinin-associated LIM protein and facioscapulohumeral (FSH) muscular dystrophy
Iowa City, IA
Researcher(s): Kathrine Mathews, Kate Mills, Jennifer Tresnak
Address: Department of Pediatrics, 216 MRC, University of Iowa Hospitals and Clinics, Iowa City, IA 52242
Interest(s): Molecular genetics, clinical and mouse model
Chicago, IL
Researcher(s): Anthony A. Romeo, Irwin Siegel
Address: Rush Arthritis and Orthopedics Institute, 1725 West Harrison Avenue, Chicago, IL 60612
Interest(s): Orthopedic Surgery, Scapulothoracic fusion
Update: I have been working with Irwin Siegel, one of the pioneers in the orthopedic treatment of the impairments related to FSHD. We are in the early phases of organizing a clinical follow-up study on the patients who have undergone a scapulothoracic fusion. Over the last three years this has been performed in approximately 15 patients with good or excellent results in all of them. Fortunately, none of them have had a major complication, and all have fused on the first attempt. Patients have been universally pleased with the function of their first fusion, and have requested the second fusion be performed within six months of their initial surgery. This procedure is highly effective in stabilizing the scapula and providing patients with good deltoid and biceps muscle strength, the opportunity to use their arms with a higher level of function, not only for activities of daily living, but also for recreational activities.
—Anthony A. Romeo, M.D.
Worcester, MA
Researcher(s): Jeanne B. Lawrence
Address: University of Massachusetts Medical Center, Department of Cell Biology, 55 Lake Avenue North, Worcester, MA 01655
Interest(s): Molecular genetics: Organization and expression of muscle genes,
transgenes and facioscapulohumeral muscular dystrophy locus
Researcher(s): Rossella Tupler*
Address: Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachussetts, 373 Plantation St., #309, Worcester, MA 01606
Interest(s): Molecular genetics
*Note: Dr. Tupler’s update is under Pavia, Italy, in this newsletter. The research in Worcester is under the direction of Professor Michael R. Green, Howard Hughes Medical Institute.
Los Alamos, NM
Researcher(s): Michael R. Altherr
Address: Life Sciences Division, Los Alamos National Laboratory, Group LS 2, Mail Stop M880, Los Alamos, New Mexico 87545
Interest(s): Molecular genetics
Buffalo, NY
Researcher(s): Pieter de Jong, Michel van Geel
Address: Roswell Park Cancer Institute, Department of Human Genetics, Elm & Carlton Streets, Buffalo, NY14263
Interest(s): Molecular genetics
Rochester, NY
Researcher(s): Robert Griggs; Rabi Tawil; Denise Figlewicz; Lynn Cos; James Forrester; Michael McDermott
Address: University of Rochester School of Medicine, Department of Neurology, 601 Elmwood Avenue, P.O. Box 673, Rochester, New York 14642
Interest(s): Molecular genetics and clinical
Update: Request for participants for albuterol study and muscle biopsy
Albuterol Study Update: Both Ohio State and the University of Rochester have each entered approximately 20 patients. The first patients entered are coming in for their one-year study completion visits. Both Ohio State University and the University of Rochester are recruiting participants with FSHD. The success of this study depends on being able to recruit enough individuals affected with FSHD. The medication Salbutamol, which is being studied in the Netherlands, is the same drug as albuterol. Salbutamol is the name used in Europe.
Human Study Update: Occupations of FSHD participants in the Rochester study include business management, housekeeping, retail, homemaker, truck driver, accountant, environmental engineer, forest researcher, computer programmer, child care, teacher, medical student, medical office assistant, retired, drug counselor, and student. Current laboratory studies are focused on two areas of research: 1) Two approaches are being taken to isolate and characterize candidate genes from chromosome 4q35. 2). We are characterizing FSHD deletions in familial and sporadic patients. The data obtained from this study will provide important clues about the molecular mechanisms underlying FSHD. In addition, we are continuing to define the relationship between molecular findings and clinical phenotype. —Lynn Cos, R.N.
Abstract: A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. R. Tawil, M.D., M.P. McDermott, PhD; S. Pandya, MS, PT: W. King, PT; J. Kissel, MD: J. R. Mendell MD; R.C. Griggs, MD; and FSH-DY Group Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant, 4q35-linked, slowly progressive muscular dystrophy with no known effective treatment. Since prednisone improves strength in Duchenne dystrophy, we performed a pilot, open-label trial of prednisone in eight subjects fulfilling strict diagnostic criteria for FSHD. Prednisone (1.5 mg/kg/day; maximum 80 mg/day) was administered for 12 weeks. Manual muscle testing, maximum voluntary isometric contraction testing, and muscle mass estimates by dual energy x-ray absorptiometry and urinary creatinine excretion were performed at baseline and at 12 weeks. There were no significant changes in strength of muscle mass. We conclude that prednisone given for 12 weeks does not produce major improvement in strength or increase muscle mass in FSHD. The study did not have sufficient power or length of follow-up to address the possibility that prednisone might arrest or slow disease progression. Neurology 1997; 48:46-49
Abstract: Use of gold weights to correct lagophthalmos in neuromuscular disease. Valeria Sansone, MD; James Boynton, MD; and Cynthia Palenski, MSNP. Upper eyelid gold-weight implants are widely used in the correction of lagophthalmos in many neuromuscular conditions, most commonly facial palsy. The paralytic lagophthalmos that occurs in facioscapulohumeral muscular dysptrophy (FSH) is common and can cause severe ocular complications. It is not usually considered for surgical correction. Upper lid loading with 24K gold implants and reconstructive lower lid surgery in a 64-year-old woman with FSHD corrected eyelid deformity and exposure keratitis. Surgical treatment also markedly improved facial appearance. This treatment may merit wider use in FSHD.
Neurology 1997:48:1500-1503
Durham, NC
Researcher(s): Margaret Pericak-Vance, John R. Gilbert, Marcy Speer
Address: Duke University Medical Center, CARL Building, Room 026, P.O. Box 3445, Durham, North Carolina 27710
Interest(s): Molecular genetics
Update: Request for participants forgenetic study of FSHD
Columbus, OH
Researcher(s): Jerry Mendell, John T. Kissel
Address: Department of Neurology, Ohio State University Hospitals, Room 463-Means Hall, 1654 Upham Drive, Columbus, Ohio 43210
Interest(s): Clinical
Update: Request for participants for albuterol study
Current information for researchers
The following is provided to assist FSHD researchers to keep abreast of current grants, workshops/conferences,
and medical information. We hope this information is helpful to each of the dedicated researchers committed to FSHD research.
Tissue is now available at the Brain & Tissue Bank
Facioscapulohumeral (FSH) Society, Inc. Research Grant and Fellowship Applications Process
The Facioscapulohumeral (FSH) Society offers basic research grants and fellowships to support research relevant to understanding the molecular genetics and cause of Facioscapulohumeral Muscular Dystrophy (FSHD).
To obtain an application, please submit a letter of intent. The letter of intent should contain a single page introductory cover letter plus a one or two page descriptive summary of the proposed research—enough for a decision from the Scientific Advisory Board. A well thought out and tight rationale for a research project can easily lend itself to one page. The letter of intent may be submitted at any time to the FSH Society, attention: Dr. David Housman, Scientific Advisory Board Chairman.
Support will be for research projects that will contribute to identifying and understanding the basic defect in FSHD. The maximum award for the regular research grant is $30,000.00. Grants are usually for one year, with the possibility of renewal for up to three years.
In addition to its regular grants, the Society offers a special Delta Railroad Construction Grant for innovative proposals accelerating the discovery of a treatment and cure for Facioscapulohumeral Muscular Dystrophy (FSHD). A Delta Award can be funded for one year for up to $30,000.00 per year. Areas of interest include tissue, cell and molecular biology studies of FSHD and the development of animal models for FSHD. Proposals are sought for research that involves isolation and characterization of the causative gene(s) and understanding of the genetic, neuromuscular and developmental mechanisms of the disease. Further, there is interest in the development of gene therapy, and other therapeutic programs that may arise from that understanding.
As the Society has limited funds, grants that are funded are considered "seed money." If the project shows promise, it is hoped that other institutions will fund it thereafter. Generally the Society does not include salaries of the principal investigator. Indirect costs are not allowed, but fringe benefits are considered part of the personnel costs and are acceptable.
Recipients of the Delta Railroad Construction Fellowships
Researcher: Stephane Plaisance, Ph.D.
Institution: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Project Title: Characterization of a protein expressed from a 3.3 kb element not linked to FSHD
Dr. Plaisance works under Dr. Belayew in Leuven. They have begun research on FSHD and have been in collaboration with FSHD researchers in France and the Netherlands. This is a new start for FSHD research in Belgium in a very promising area.
Researcher: Rossella Tupler, M.D., Ph.D.
Institution: Howard Hughes Medical Institute, University of Massachusetts Medical Center, Worcester, Massachusetts, U.S.A.
Project Title: Characterization of differentially expressed genes in facioscapulohumeral muscular dystrophy affected muscles.
Dr. Tupler M.D., Ph.D., has been involved in FSHD as both researcher and clinician in Italy. She has come to work with Dr. Michael Green in the leading laboratory for transcription research in the United States. Her studies will be carried out under the auspices of Dr. Green in the United States.
Recipients of the Marjorie Bronfman Fellowships
Researcher: Silvere M. van der Maarel, Ph.D.
Institution: Department of Human Genetics, Sylvius Laboratory, Leiden University, Leiden, the Netherlands
Project Title: Generation of Transgenic Mouse Models for FSHD.
Dr. van der Maarel works under Dr. Rune Frants in Leiden on FSHD research and co-authored research papers on FSHD. The Leiden laboratory is the leading research center for FSHD studies and has generated many breakthroughs in the FSHD genetic studies.
Researcher: Sara T. Winokur, Ph.D.
Institution: Department of Biological Chemistry, University of California, Irvine, Irvine, California, U.S.A.
Project Title: Analysis of Chromatin Structure and Skeletal Muscle-Specific Gene Expression in Facioscapulohumeral Muscular Dystrophy.
Dr. Winokur has worked on FSHD research projects in the past and co-authored many research papers on FSHD. The Laboratory in Irvine, under Drs. Moyzis and Hamkalo, is considered the leading institute for this area of study and is a continuation of FSHD research begun under Dr. Wasmuth with Dr. Altherr.
Satellite Meeting on FSHD in Sydney, Australia
A full-day professional satellite meeting on facioscapulohumeral dystrophy will be held at the historic Intercontinental Hotel, Sydney, Australia, on Saturday, August 29th, prior to International Congress on Neuromuscular Disorders in Adelaide, Australia (from August 30th).
FSHD Subjects: genetic counseling and diagnosis, orthopedic management, finding treatment, unusual clinical presentations, ocular and hearing associations, significance of inflammation, scientific progress. Speakers will include Drs. K. Arahata, P. Lunt, G. Padberg, R. Tawil, and many others. Meeting organizer: Dr. Robin Fitzsimons.
Sydney is a natural gateway to Australia for travelers from the US. The meeting will be followed by a harbourside dinner or Opera House visit. For further details and registration ($A220.00), please contact G. Weaver, SAPMEA Conference Organizers, Fax: 61 8 8239 1566; E-mail: gweaver@sapmea.asn.au. Abstracts welcome.
The following information is provided as a convenient pull out page. Included is information about current research involving patients, and the researcher’s requests for patient participation. We hope this pull out makes it easier for our readers to respond to these requests.
Muscle Biopsies · Rochester, NY
We would like to recruit ten adults affected with FSHD to obtain muscle samples. In most individuals this can be done using a needle muscle biopsy procedure done under local anesthesia. In some individuals, an open biopsy may be necessary. The biopsies will be done at the Clinical Research Center at Strong Memorial Hospital, and the whole visit will take less than six hours. There is no upper age limit for this study, but there is a lower age limit of 18. Individuals who have had muscle biopsies in the past can volunteer for the present study. In order to find the gene, it is critical at this point to study the DNA and protein components of muscle from individuals with FSHD. If you are interested in volunteering, please call Lynn Cos, R.N. at 716/275-7680 for more information.
Albuterol Study · Rochester, NY & Columbus, OH
We are seeking participants for a clinical trial of a medicine called Proventil® for facioscapulohumeral muscular dystrophy. Proventil (drug name, albuterol) is an epinephrine-like drug usually used for asthma and other lung diseases, which in preliminary studies increased muscle mass in patients with FSHD. The study is being done at Ohio State University Hospitals in Columbus, OH, and the University of Rochester in Rochester, NY. The plan is to study 100 patients who will be randomized into 1 or 3 groups, namely low-dose Proventil, high-dose Proventil, and placebo.
None of the investigators involved in the study will know which group you are assigned to until the whole study is completed. Because of the nature of the study, we are restricting it to patients between the ages of 18 and 60 who are able to walk at least 30 feet. The study involves three hospital stays of three days each in the Clinical Research Center at the beginning of the study and after 6 and 12 months. Two additional out-patient visits one month and three months after the start of the study will also be required.
Although Proventil is a safe drug, it does have side effects which are outlined in the consent form (and will be discussed with you in detail before you agree to participate). Since the medication does have effects on the heart, we are obtaining screening electrocardiograms on all patients before they participate. In addition, we are asking any patients who are considering being in the study who have had any type of chest pain, rapid heart beats, shortness of breath, previous abnormal EKGs, a prominent family history of heart disease or other symptoms which have caused them concern to please consult their family doctor before being evaluated for participation. People with known prior heart disease, including prior heart attacks or rhythm disturbances, will unfortunately have to be excluded from the study. If there are any questions concerning the status of your heart, we can have you evaluated by one of our Ohio State University cardiologists, but this must be covered by your own private insurance and will not be paid for as part of the study.
Please call Cheryl Kacvinsky or Karen Downing, our study coordinators, at 614/292-1234 if you are interested in participating in the Ohio study, and Lynn Cos, R.N. at 716/275-7680 if you are interested in the New York study.
Linkage Study · Durham, NC
We continue to enlist the assistance of families with FSHD, and if you would like to participate in our linkage studies, please feel free to contact Jeff Stajich at 800/283-4316 or via email at stajich@morgan.mc.duke.edu
Many of us battle throughout our lives with various inherited or spontaneous neurological disorders or other physical disabilities. Many of these disorders, including Facioscapulohumeral muscular dystrophy (FSHD), are still a mystery to the medical community. The Brain and Tissue Bank at the University of Maryland exists to further medical research by enabling researchers to study a most precious resource: human tissue obtained from donors of all ages, both with disorders and without.
By examining human tissue, comparing the unaffected with the affected, or comparing different age groups, sexes, etc., a host of endless questions may be answered offering hope to the future lives of all afflicted individuals and their families.
Until now, no tissue was available for research of relatively rare disorders such as FSHD. The University of Maryland Brain and Tissue Bank is reaching out to individuals with FSHD in the United States and to the FSH Society to establish a national registry of donors. Through the registry, the Bank gathers and stores vital information about donors, which is needed in case of a sudden death. Sometimes seemingly simple information such as the name, address and phone number of the donor’s physician can save precious hours. Working on a national basis, the Maryland Brain and Tissue Bank depends on pathologists in other hospitals for tissue recovery. In some areas, a pathologist can work with the BTB only if the patient has been treated by a physician associated with his or her particular hospital. This information may sometimes only be available from the physician himself to avoid having to find another pathologist.
It is important to note that tissue recovery needs to take place as rapidly as possible after death. Although in most cases tissue is still useful even after a delay of 24 hours, most researchers ask for a delay of eight to twelve hours. This means the Brain and Tissue Bank must move rapidly and each added phone call or change of plans makes a major difference.
For some individuals, advance registration may be difficult to consider in light of the emotional stress that they are already suffering or, as in the case of FSHD, they are not comfortable making plans for events that may not occur for years. Others may find that making a commitment to donate offers a sense of purpose. It may offer comfort in knowing that the search for knowledge and medical understanding will carry on.
The Brain and Tissue Bank for Developmental Disorders urges donors to register in advance. Because the decision is such a deep one, the time of death may be too stressful a time to manage the details of tissue donation. We also encourage donors to discuss their decision with family members, close friends, and their family physician. At the time of death, one or all of these individuals will need to be involved with the Brain and Tissue Bank to assure a successful donation. Advance registration also assures researchers that support groups are interested in and support their ongoing research. When donors register, researchers know that future work will become a realization. It is sometimes possible for researchers to obtain funding for preliminary work when large numbers of individuals with a specific disorder have registered to become donors.
For all of these reasons, we urge those who are interested in becoming tissue donors, or would like more information about the Bank, to call 1-800-847-1539 or write to The Brain and Tissue Bank, Pediatric Research, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201. All inquires will be most welcome and addressed with immediate and sensitive attention. It is important to know that although we do place emphasis on advance registration, donors do not have to be registered in advance to donate at the time of death. Our "800" number is answered on a 24-hour basis for emergencies.
—Dr. Ronald Zielke and Sally Wisniewski
Second FSH Society Delta Railroad Construction Research Grant Established
The Delta Railroad Construction Company of Ashtabula, Ohio, has contributed a second FSH Society Young Investigator Fellowship Grant for research on Facioscapulohumeral Muscular Dystrophy (FSHD). The FSH Society is indebted to the Delta Railroad Construction Company and their family for this ground-breaking effort on behalf of the FSHD community.
An Open Letter to the FSHD Community Regarding the Albuterol Study
The FSH-DY Study Group held a meeting in Rochester, New York on 3/6/98 to discuss the ongoing albuterol (Proventil) study in FSH. The study is going extremely well. Recruitment is right on schedule and we hope to enroll our final patient towards the latter part of this year. One issue that was discussed at length is a recent tendency for many patients to get albuterol from their own neurologists or family physicians and taking the drug outside of the research study. While this is certainly convenient for patients, since they do not have to return for as many follow-up visits and do not have to travel to one of the study sites (Columbus or Rochester), there are many problems with this approach, both for the individual and for the FSH population patients in general.
The first obvious problem with this approach is that the only unequivocal way to determine whether albuterol is effective or not is to do a randomized, double-blind, placebo-controlled trial. The history of therapy for muscular dystrophy is full of treatments that were initially thought to be beneficial only to be later shown in randomized, controlled trials to be ineffective. Unless patients are willing to participate in such a study, the final answer about whether a drug is effective or not will never be determined.
Secondly, the problem is that the appropriate dosage of drug cannot be determined if patients take the drug on their own. The FSH-DY group is already planning a follow-up study to check several different doses of albuterol if the current study shows that albuterol is effective. Patients taking the drug on their own will have no way of determining what the optimum dose should be. Similarly, the optimum duration of therapy also needs to be determined through controlled trials. Patients taking albuterol outside of the study setting are going to be faced with a decision about whether they want to stay on albuterol (or any other agent) for the rest of their lives! Only carefully designed trials will determine the long term effects of albuterol, and whether there are any deleterious effects to coming off of the drug.
Another practical issue concerns FDA approval for albuterol. Unless FSH patients participate in randomized controlled trials, the data necessary to achieve FDA approval and widespread acceptance for drugs will never be generated. It is only by getting FDA approval for drugs that a treatment becomes "accepted" in the general medical community. This has a ‘trickle down effect" in that non-neurologist practitioners (internal medicine specialists, family practitioners, pediatricians, etc.) will only learn about and embrace a treatment if it achieves FDA approval and general acceptance in the medical community. Medical students are usually not instructed in non-approved therapy, so this has implications even at the level of basic medical education.
Fourth, and most importantly for the individual patient, participation in a study is the only way patients will know how a particular drug affects them. Patients in randomized controlled trials are followed very closely for the positive effects of the drug (on strength and muscle mass in the albuterol study, for example) and side effects. At the end of the albuterol study, the participating patients are going to receive their individual data on how their strength measured with a computerized system and muscle mass changed in the course of the study. This will help them make future decisions about staying on albuterol or possibly even participating in another trial. A patient who is taking albuterol outside the randomized controlled trial will never know in such detail the effects of that drug, and will therefore have difficult decisions to make concerning their long-term care. This issue is particularly important for a disease like FSH dystrophy where progression may be extremely slow and it might be very difficult to determine whether a drug like albuterol is slowing (or stopping) progression.
There is one final point that we would like to mention. Randomized controlled trials, particularly if effective, always generate interest and "raise the profile" of a given disease drawing the attention of funding agencies, lay donors, political figures, and basic and clinical research scientists. As a result of the albuterol trial in this country for example, a similar trial is being organized in Europe, and several other studies are "on the board." This kind of interest and enthusiasm cannot help but accelerate the process by which effective treatments for FSH dystrophy are discovered.
Thank you very much for your time and attention to this matter.
Sincerely, John Klssel, MD, The Ohio State University, Columbus, OH; Rabi Tawil, M.D, University of Rochester, Rochester, NY
(Seeking a diagnosis half way around the world)
After two very long years searching for a diagnosis for my progressive muscle loss, the news that I had FSHD was almost a welcomed relief. Slowly, after reading as much information as I could find on this disease, the real impact of having FSHD became alarmingly clear not only to myself but also to my family.
I was born 53 years ago in England. At birth, my left foot was noticeably turned inward. No treatment was advised. The foot slowly straightened out though there was always some weakness, and through childhood, I would stand with the foot bent sideways. I just thought I was different and I never brought it to anyone’s attention.
In 1972, after traveling and working in the West Indies, I came to Santa Barbara, California and met and married Jerry. Living in such a wonderful climate, I began to play tennis, swim and got very involved in jogging. My foot always flopped sideways, but I found I could jog quite well and enjoyed this for many years. I was working at this time and very much desired to start a family. After many tests and treatments, we realized that I could never conceive and took our first tentative steps towards adopting a baby. We were thrilled and delighted when our adopted daughter, Jennifer Rose, was born in September, 1985. She has been a constant joy to us.
My foot had slowly weakened and I tried to compensate by lifting my hip to walk, but I soon had to admit that I had a very significant foot drop. In October, 1995, the muscles in my left upper arm deteriorated. It seemed quite sudden, though I suspect now it was a gradual process. Two months later the same muscle wasting appeared in the right upper arm. At this point, I was having difficulty with normal household chores and I became very concerned.
The doctor thought I had a serious condition that was destroying healthy nerves at random. He suggested an intensive course of Prednisone. I was extremely opposed to taking this drug, knowing the side effects, but my resolve was weakening. Then I received a very costly intensive course of gamma globulin. Still, this produced no improvement.
Jerry mentioned my awkward scapular formation and inability to raise my arms to every doctor at every visit. During all these tests and procedures, Jerry was with me and, sometimes, our daughter, Jennifer, then 10 years old. I was beginning now to lose hope and was despondent at the prospect of more tests. I tried to remain positive and cheerful as I realized Jennifer was becoming increasingly fearful about my prognosis.
I asked my sister to arrange an appointment for me to coincide with my visit with my family in England. She made an appointment with Dr. John Morgan-Hughes at the National Hospital in London, England. He gave me a thorough neurological exam and, as always, Jerry pointed out my strange scapular formation. Within half an hour he diagnosed Facioscapulohumeral Muscular Dystrophy. We were astounded though none of us had ever heard of this disease with its strange sounding name.
We realized my mother also had FSHD. I knew it was not going to be easy to tell her about this hereditary disease. My mother would not completely accept the diagnosis of a serious hereditary disease in our family. However, my parents did see a Medical Genetics consultant in Cambridge, England. They both had an examination and a DNA blood test.
The English consultant requested that I have the same test done. We were in Santa Barbara and my doctor could not find a laboratory in the United States to do the same DNA study. My blood sample was sent to England to the same laboratory as my parent’s. I went to England when the result was available. The Genetic Consultant confirmed that my mother and I had FSHD. The news was extremely distressing to my mother who blamed herself for passing it on to me. She has always been very concerned about my progressive weakness and continues to be so while still not accepting her own diagnosis.
The journey to find the diagnosis of FSHD was long and tedious but n