FSH Watch

Vol. 6 No. 1, Fall 1999
A publication of the FacioScapuloHumeral Society
Provided by the FSH Society, Inc.

Inside ...

• NIAMS requests input from the FSH Society on long-range planning issues in the area of muscle biology and muscle disease
• Molecular genetics advances research
• You will receive that, and more than you have asked for as well
• Advances in FSHD clinical research sheds light
• FSH Society Statement
• Dr. Louis Kunkel receives Dana Award
• FSH Society presents 1999 FY2000 testimony before Congressional Committees
• PA-98-044: A program announcement for Facioscapulohumeral Disease (FSHD)
• Bibliography
• Researchers
• The Association Française contre les Myopathies (AFM) makes direct appeal for researchers to submit proposals on FSHD
• FSH Society issues grants
• International Network and Contact Progam, Denver, October 31, 1998
• Denver, CO October 31, 1998 Network Conference report
• Perez welcomes participants to the 1998 Network Conference
• FSH Society President Perez addresses International Workgroup
• NIH/NINDS requests researchers to submit grants on FSHD
• Then and now: FSH Society addresses the Institute of Medicine (IOM)
• NIH "Panel On Scientific Boundaries For Review" Releases Draft Report
• Brain and Tissue banks for developmental disorders available to researchers
• NIAMS and NINDS offer career development research award programs
• NIH/NIAMS requests researchers to submit grants on FSHD
• FSH Society research grant & fellowship applications process
• More resources soon available for FSHD researchers at the Coriell Cell Repository
• What’s new @ www.fshsociety.org
• Ms. Wheelchair Maryland, Inc. donates $5000 for research to the FSH Society
• Marjorie Bronfman Grant for Molecular Genetics Research on FSHD continues through 2001
• Third Delta Railroad FSH Society Research Grant Established
• Pen pals wanted
• Winning the race -- Luigi Giuliani, Italian Race Car Driver with FSHD
• In her own words: Betsy Conron successfully juggles life and FSHD
• I have muscular dystrophy, but I’m lucky
• Acknowledgements

On July 20, 1999, the FSH Society participated in the Muscle Biology and Muscle Disease long-range research panel at the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) in Bethesda, Maryland. At the invitation of Stephen I. Katz, M.D., Ph.D., Director of the NIAMS, Daniel P. Perez, President of the FSH Society, served on this panel and was the only Volunteer Health Organization presenting input on the panel. The NIAMS brought together a small and diverse group representing different interests within muscle disease and muscle biology to help determine long term (two to four years) research opportunities. Dr. Stephen I. Katz, Richard Lymn, Ph.D., Director, Muscle Biology Branch and Extramural Program Officer, Kuan Wang, Ph.D., Chief, Laboratory of Physical Biology and Intramural Program officer, Helen Simon, Chief of the Office of Program Planning and Janet Austin, Director, Office of Communications and Public Liaison (OCPL) were present. The NIAMS indicated that some of the needs presented by the panel may be addressed in a shorter time frame if resources are available.

Both the FSH Society, and the director and staff of the NIAMS agreed that the panel yielded insight and progress in understanding issues from varied perspectives. Lastly, the discussion led to excellent progress regarding research opportunities and needs for NIAMS in the area of Muscle Biology and Muscle Disease, including facioscapulohumeral muscular dystrophy.

The NIAMS is requesting input into this plan from the public and the NIH Advisory Council on its Internet Web site to develop the final presentation to Dr. Harold Varmus, Director of the National Institutes of Health (NIH) later this year.

The following recommendations from over 35 members of the scientific community working on FSHD, the FSH Society’s Scientific Advisory Board, Board of Directors, members and General Counsel were presented:

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of inherited muscle disease following Duchenne and myotonic dystrophy. The incidence of FSHD is conservatively estimated at 1 in 20,000 (or as many as 15,000 cases in North America). The estimated incidence of 1/20,000 may be low and there may be three times as many cases due to the number of sub-clinical and undiagnosed cases. In spite of the great successes in positional cloning in the past decade, the gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has not been identified. The genetic defect associated with FSHD was mapped to the terminus of the long arm of chromosome 4 nearly ten years ago (in 1990) and the identification of a genetic rearrangement, deletion of 3.3 kb repeats, followed quickly in 1993. Since then, progress on FSHD has been painfully slow.

It has been demonstrated that the 3.3 kb repeat is immediately adjacent to the telomere of human chromosome 4q, that it has significant sequence similarity to known classes of constitutive heterochromatin, and that related loci exist throughout the human genome, predominantly in regions known to be heterochromatic. Furthermore, evolutionary studies of the repeat demonstrate the dispersion of the repeat was a relatively recent event in primate evolution. The immediate proximity of the 3.3 kb tandem repeat to the telomere and the sequence similarity to constitutive heterochromatin suggest that this repeat, deleted in FSHD, lies in telomeric heterochromatin. This conclusion is further supported by the fact that, despite intense efforts over the past seven years, there have been no protein coding transcripts identified from this repeat sequence. In addition, inter-chromosomal translocations suggest that the gene responsible for FSHD lies proximal to, and not within, the repeat itself. Integral deletions of the heterochromatic D4Z4 repeat appear to disrupt the normal expression of these genes, a phenomenon akin to position effect variegation in Drosophila and telomere silencing in yeast. Attempts to identify the gene(s) involved in FSHD have been thwarted by its unusual molecular genetic mechanism and the repetitive nature of the genomic region. It appears that we are dealing with a novel disease mechanism with respect to FSHD that once understood will yield tremendous scientific opportunities in many other areas.

What then are the most significant long range research opportunities and issues for the NIH in the area of Facioscapulohumeral Disease (FSHD) research over the next two to four years (FY 2001-2003)?

The first area of opportunities/issues for FSHD Research at the NIH commits to funding FSHD research in the following areas:

The second area of opportunities/issues for FSHD Research at the NIH are extramural contact programs or intramural programs for FSHD whose areas of focus are:

The third area of opportunities/issues for FSHD Research at the NIH are the following five (5) "Out-of-the-box (OOTB)" strategies and projects requested as necessary areas for funding by the FSH Society Scientific Advisory Board (SAB) to accelerate information and progress on Facioscapulohumeral Disease (FSHD) research.

Project 1. The complete sequencing of chromosomal band 4q35 is ongoing, should continue and should not be distracted by "genome politics." Given the repetitive complexity of the region, sequence-based gene identification may be the only way to identify all of the potential coding segments. In fact, it is not clear that we have in hand the informatics tools necessary to identify genes based solely on sequence but we will not want to wait for the sequence if such tools become available. Furthermore, a variety of efforts utilized clone-based gene finding methodologies (like exon amplification and direct selection). Unfortunately, many of the subsequent products also turned out to be mildly repetitive. Together co-linear genomic sequence and these apparently "transcriptionally" competent sequences may be used to identify protein encoding genetic elements.

Project 2. Cloning syntenic loci from non-human primates. The demonstration that the amplification and dispersion of the D4Z4 repeats is a relatively recent event in primate evolution, and is an important finding. Much of chromosome structure and gene organization is conserved in primates. The further one descends down the primate tree, the fewer the number of copies of D4Z4 repeats. So that, in the rhesus monkey, perhaps only two repeat segments exist. It may be that protein encoding genes that were obscured by the amplification and dispersion of repeats during primate evolution could be isolated by a focused effort in rhesus using the D4Z4 syntenic sites as a nucleation point. Cloning these segments and subsequently employing clone-based and sequence-based gene finding methods could identify the rhesus homologs of genes important to the pathophysiology of FSHD. The human homologs of these genes could then be identified and the biochemical and physiological properties of the genes assessed.

Project 3. There exists in mice a genetic defect with a dystrophic phenotype that maps in a region syntenic with several loci from 4q35. The D4Z4 locus is not found in mice. Therefore, the mechanism of dystrophy may be quite different. However, the finding of a gene linked to 4q35 loci that contributes to a dystrophic phenotype in the mouse is significant and should be vigorously pursued. The gene should be cloned and human homologs sought. Mechanistically, the role of D4Z4 repeats in chromatin-mediated gene expression is being studied in Drosophila. If successful, this approach could be employed in reconstitution experiments to identify components of the process.

Project 4. The ability to track the expression of complete cellular populations of genes in response to specific stimuli is one of the most exciting recent developments in cell biology. A variety of methods have evolved for this purpose, including: differential display, a PCR-based method that identifies differences in mRNAs present in two cell populations; array based hybridization, in which specific nucleic acids are immobilized on a solid support and interrogated by probes derived from specific cell types and imaged digitally; and SAGE, the serial analysis of gene expression, in which the frequency of a specific sequence signatures can be measured.

The use of two-dimensional microarrays is particularly infatuating. Not only because it represents a rapid and quantitative approach for the study of genetic regulatory networks, but also because microarray proponents exalt that the entire coding component of the human genome could be interrogated in a single experiment occupying the space of a postage stamp. Unfortunately, the current costs of manufactured arrays and devices for reading them have limited their widespread availability and use. However, it is likely that these technologies will emerge as important contributors to our understanding of cellular differentiation at the molecular level, whether these differences are cell type (i.e. skin vs. neuron) or cell state (FSHD affected vs. non-affected).

When hybridized with labeled probes synthesized from total cellular mRNA, the microarray provides a snapshot image of the expression level of all the genes represented by the arrayed cDNAs. Using double labeling techniques, microarrays allow the simultaneous comparison of gene expression generated from two different cellular states providing a powerful means for elucidating the cellular biochemistry of disease in its entirety. The expression of tens of thousands of genes can be simultaneously monitored, so that the basic pathophysiologic process reveals itself through identification of the protein pathways and complexes involved. FSHD is particularly amenable to this approach, as current data implicates a global deregulation of genes effected by deletions of regulatory chromatin in this disease. Microarray analysis is also a potent means of discriminating between the primary cause and secondary effects of muscular dystrophy as well as the evaluation of therapeutic approaches to FSHD.

Project 5. The D4Z4 repeat is likely involved in the regulation of genes in the FSHD region. Heterochromatin is known to regulate gene expression in many other species. Although the DNA components of this heterochromatic complex in FSHD are now well defined, virtually nothing is known about the proteins that are involved in this regulatory complex. Indeed, little is known in general about the mechanism by which higher order chromatin structure regulates gene expression in the human.

Identification of these protein components is critical to our understanding of FSHD and may provide a means in the future to therapeutically approach the aberrant regulation of genes in this disorder. Recent developments employing mass spectrometry (MS) for the analysis of multi molecular complexes provides an approach to the identification of small quantities of proteins isolated from biological systems. As little as one to two ng of protein isolated from a silver-stained 2-D electrophoretic gel can be accurately identified by this approach. It may be possible to isolate FSHD-associated heterochromatic complexes and analyze these by MS.

The NIH needs to re-evaluate and re-assess the research granting process at the NIH for FSHD and the mechanisms in place for facilitating and enhancing research progress on FSHD. The NIH needs to evaluate the process of requesting applications on FSHD, evaluating grants on FSHD and coordinating intramural and extramural efforts on FSHD. The current process is not adequately designed for new, novel, untried and untested research ideas that require "Out-of-the-box" (OOTB) thinking and experimental strategies. The broad-based study sections are not structured to recognize the major difficulties and nuances of the FSHD problem. To re-iterate, we are dealing with a novel disease mechanism with respect to FSHD and FSHD research is an extraordinarily interesting, challenging and difficult scientific problem with tremendous application to other areas of research.

At present, the NIH conventional funding and broad-based study section evaluation strategy does not readily lend itself to the needed focus on FSHD. The research community needs a clear call for research and a clear assurance that the time consuming and labor intensive effort of writing NIH grants will be met with responsible calls for research through contract, RFA, RFP mechanisms, or any other mechanism that indicates to the research community that there are monies set aside and associated with the request. We were pleased with Program Announcement PA-98-044 titled "Pathogenesis and Therapy of the Muscular Dystrophies" but had concerns regarding the routing for grants and evaluation of grants and monies available for applications.

The FSH Society suggests that the NIH, with NIAMS leadership, establish a National Task Force on Muscle Biology Research Organization to consider the following questions:

and,

Since the conventional broad-based study section is inadequately designed for evaluating grants on FSHD or unaware of the complexities of FSHD, a new "special" study section must be created to evaluate research grants on FSHD. A broad-based study section evaluates 80 to 90 grants. We would not request that a new broad-based study section be enacted for FSHD, but would suggest that a new broad-based study section should be created for Muscle Biology and Muscle Diseases. NIH should enact a newly created "special" study section for FSHD that must be comprised of bright, creative, focused and OOTB thinkers capable of evaluating FSHD research. Researchers capable of evaluating FSHD grants in this manner might be Michael Altherr, Ph.D. (Los Alamos), David Housman, Ph.D. (MIT), Robert Griggs, M.D. (University of Rochester), Doug Marcheuk, Ph.D. (Duke), Rita Shiang, Ph.D. (Virginia Medical College) and Jeff Murray, Ph.D. (University of Iowa).

What is the rationale for the creation of a special study section for FSHD? FSHD presents challenges and issues that are unique in the field of genomics and will yield scientific opportunities in many other areas. FSHD needs a set aside with a special call for research in the areas determined valuable by advisory panels in the form of an RFA. An RFA is needed given the difficulty of the FSHD problem and the need for a concerted and focused effort in this area. The subsequent proposals should then be evaluated by a "special" study section capable of peer reviewing and providing evaluation on the unique and complex aspects of research on FSHD.

Furthermore, NIH should consider the creation of an Office for Muscle Biology and Muscle Disease Research (OMBMD) or an Office for Muscular Dystrophy Research to coordinate inter-institute initiatives. The Office for Muscle Biology and Muscle Disease Research (OMBMD) should be at the Director’s level in Building 1 and, following that, should be located at the institute level (NINDS, NIAMS). FSHD research has been significantly impaired by inter-institute competition for jurisdiction over the area and has created the situation of allowing FSHD to "fall through the cracks." Lastly, the NIH needs to investigate the benefits and gain that would be offered by creating a separate Institute at the NIH for Muscle Biology and Muscle Disease Research (NIMBMD). The muscle biology budget is certainly as large if not larger than current small-sized institutes at the NIH.

The fourth area of opportunities/issues for FSHD Research at the NIH should be:

Many projects to enhance FSHD research at the NIH can be implemented in the immediate future. They include the following fifth area of opportunities/issues for FSHD Research at the NIH:

Lastly, joint projects that would be good for the FSH Society and NIH include the following sixth area of opportunities/issues for FSHD research at the NIH:

Clinical research usually involves high profile diseases with a high enough incidence to attract pharmaceuticals and industry investors. Given the set of diseases in muscle disease and the incidence of muscular dystrophy, it is difficult to conduct clinical trials underwritten by industry and the pharmaceuticals. This is further complicated by the fact that it is more difficult to isolate large single entities of a disease for study as the disease become more characterized. Limb Girdle Muscular Dystrophy (LMGD) now has a dozen different sub-types. Programs to encourage industry and pharmaceutical investment and expansion into FSHD and muscle disease by NIH should be developed. NIH could help with clinical trials in this area.

The genetic information far outstrips the clinical information we have on FSHD and muscle disease. NIH should help to develop programs that help characterize clinical features of FSHD and muscle disease. The genetic information we have needs to better correlate to the phenotype and clinical characteristics of FSHD and muscle disease. We need to know more about these diseases clinically to better understand how to intervene pharmacologically or genetically. NIH needs to establish a patient registry for FSHD and other muscle diseases to assist with this dimension of the problem. Epidemiology studies need to be undertaken now that we have tens of thousands of individuals with FSHD on record.

Muscle biologists and muscle disease experts need to develop surrogate measures and markers to better understand progression and milestones in FSHD and muscle disease. The tools we have now are crude, time consuming and can have difficult chemistry to analyze e.g. using dexascan to calculate lean body mass, urine collection for creatinine. NIH needs to develop technologies and applications to better track muscle disease. Newer technologies such as MRI need to be examined.

NIH can help the clinicians involved with FSHD and muscle disease by forming a multi-centered working group to help strategize and examine problems in muscle disease and to help co-ordinate and initiate new clinical trials, treatments and interventions for FSHD. A muscle study group is needed such as the one for Parkinson’s disorder. FSHD needs the resources and expertise associated with a 20- to 30-center group given the clinical and scientific complexity of the FSHD disorder.

Technology transfer and foreign research investment needs to be evaluated in FSHD. Internationally there are agencies that are interested in gene therapy of muscle disease, myology and vectrology with strong desires to harness American research but need assurance that return on investments will be achieved. FSHD could directly benefit from this investment through the NIH if technology transfer and policies issues are adequate for investors and foreign institutions. •

The genetic mutation that causes FSHD appears to be a very unusual one. In greater than 95% of individuals with FSHD, a deletion in 3.3 kb repeat sequences has occurred in the DNA near the end (telomere) of chromosome 4q. This region of the chromosome contains many repetitive sequences that do not actually encode genes. These repetitive sequences (including the 3.3 kb repeat) are more likely involved in other functions such as chromosome stability and regulation of where (what tissue) and when (during development) genes are expressed. The type of regulation that likely occurs in the FSHD gene region is called a "position effect," meaning that the genes that are close in position to the repeat sequences will be affected by whether or not there is a deletion in the total number of 3.3 kb repeats. The 3.3 kb repeat, when present in more than eight copies or so (corresponding to an EcoR1 fragment of greater than approximately 32 kb) seems to form a specialized structure called "heterochromatin" in which the chromosomal DNA is very tightly condensed. In a position effect, this compact structure inhibits genes in the vicinity from being expressed and therefore the corresponding proteins are not produced.

Therefore, this unusual mechanism has made identification of the FSHD gene a challenge for research. The mutation does not appear to be within the gene itself, but rather in repeat sequences which affect a gene somewhere in that vicinity of the chromosome. Therefore, we must examine any and all genes in the FSHD region as to whether those genes have a different pattern of expression, i.e. whether they are turned "on" in FSHD and "off" in normal muscle, or vice versa.

Many FSHD researchers are now taking the approach of examining gene expression in the FSHD gene region. Drs. Sara Winokur, Denise Figlewicz and Kiichi Arahata are utilizing a very powerful technology called microarray analysis to compare the expression pattern of thousands of human genes in FSHD and normal muscle. Dr. Figlewicz is also utilizing a different approach, competitive RT-PCR, to examine the increase in expression of specific genes in the FSHD region. Dr. Rossella Tupler has used a third approach, differential display, and found that indeed there are skeletal muscle genes that exhibit increased expression in FSHD. Dr. Alexandra Belayew is pursuing the possibility of a gene (Dux) actually being expressed from the 3.3 kb repeat. Drs. Silvere van der Maarel and Rune Frants are examining the expression of FRG2 (FSHD region gene 2) from the normal and deleted chromosomes. They are also constructing a mouse model of the disease to see whether deletion of the 3.3 kb repeats affects gene expression in the mouse.

Another important direction of research over the past year has been the effort to sequence a large region near the telomere of chromosome 4q. This is invaluable, because new genes in the FSHD region are likely to be uncovered by this approach. Michel van Geel and Dr. Pieter de Jong have succeeded in sequencing over 400,000 base pairs of DNA from the FSHD region. This is especially remarkable, as generating sequence is encumbered by the large number of repeats in the FSHD region. Dr. Jane Hewitt has continued with her studies on the evolution of the FSHD gene region which will help to identify those conserved sequences and genes that function in the disease process.

We must keep in mind, however, that although most of the scientific data points to a position effect as causing FSHD, that this remains a hypothesis until proven unequivocally. Therefore, another important direction of research will be to study the biochemical and chromosomal basis of gene regulation and position effect in FSHD. The components of heterochromatin in the FSHD region must be identified as this will yield a greater understanding of the disease mechanism. However, the past few months have been an exciting time in FSHD research as new approaches to identifying and characterizing the gene defect have led to greater insight into the disease mechanism and fostered much interaction between the numerous laboratories working to solve the FSHD "puzzle." The direction of scientific research into FSHD will therefore likely focus on 1) gene expression 2) further sequencing of the FSHD region 3) investigation of heterochromatin and gene regulation and 4) animal models of the disease. The consortium of FSHD researchers will meet at a FSHD workshop in San Francisco on October 19, 1999 to exchange experimental findings and discuss the insight gained over the past year into the FSHD disease process. A detailed summary of the research finding will be published in an upcoming issue of the FSH Watch. •

From the President,

At the request of the Board of Directors of the FSH Society, I accepted the full-time salaried position of President and CEO to bring the Fsh Society to the next stage of organizational development. I am delighted to have the opportunity to facilitate this transition. Dr. Stephen J. Jacobsen has been asked to take the helm of the FSH Society as Chairman of the Board and in May, 1999, we completed the changes.

May, 1999, also was the tenth year anniversary of my first meeting with Dr. Jacobsen at the University of California San Diego in La Jolla. The FSH Society emerged from our meeting then and today we are advancing our cause with the staffing needed to meet the demands of managing FSHD research issues.

This edition of the FSH Watch is dedicated to research and the FSH Society’s efforts to promote FSHD. We continue to create opportunities for solutions for individuals involved with FSHD. We constantly advocate for research and networking, and we push with diligence for progress on FSHD. Our message is clear: research must be done on FSHD anywhere in the world. The FSH Society has done everything possible within the constraint of its current budget to provide the highest quality service, information and efforts for finding a treatment for FSHD. Note that the income of the FSH Society in 1998 (excluding gifts specifically ear-marked for research) was US$87,365.75. Although this money has been carefully monitored and well spent, we need to have staff working full time to become a truly effective organization promoting our cause. We can not do that under our current budget. The Board of Director’s takes its fiduciary responsibilities very seriously and has completed the necessary independent audits and maintained a strong financial position to get to the next stage of organizational development. We still need your concerted help to reach our annual goal of US$400,000 overall with US$160,000 of that needed in unrestricted funds.

There have been exciting developments since our last newsletter. Testimonies were again submitted this year before the U.S. House of Representatives and the U.S. Senate regarding appropriations for research on FSHD. The FSH Society has granted more fellowships to carry out vital research on FSHD. We have had a series of meetings with the Association Française contre les Myopathies (AFM, the French MDA) which resulted in a direct call for research proposals on FSHD. We have increased our communication and education efforts at the National Institutes of Health (NIH). We were asked to help define the two- to five-year long range goals in Muscle Biology and Muscle Disease at the National Institute for Arthritis Musculoskeletal and Skin Diseases (NIAMS/NIH). The FSH Society was the only patient group participating on the muscle planning panel at NIAMS/NIH. Last, we have successfully promoted information on FSHD internationally over the Internet.

The FSH Society fellowship program has been overwhelmingly successful and we are making an appeal to the community involved with FSHD to help double the current number of researchers working on FSHD. The fellowship salaries are typically one or two years at US$30,000 per year. To date, we have funded four (4) two year and three (3) one year fellowships and we continue to have a demand that far outstrips our funding capacity. In this newsletter you will find details of the nature of the projects the Fsh Society has funded and the excellent quality of fellow that we are attracting to carry out such research. We are indebted to Mrs. Marjorie Bronfman, Larry and Ida Laurello and the countless number of members and donors who have made donations to the Research & Education fund to make this program successful to date.

The Scientific Advisory Board (SAB) of the FSH Society is unparalleled in its capacity to evaluate research on FSHD. The SAB has diligently carried out its mission of providing strategy for FSHD research, recruiting and attracting qualified researchers, selecting research proposals, evaluating research proposals, granting fellowships and monitoring ongoing projects. We are thankful for the excellent leadership provided by Dr. David Housman and the expert counsel and advice from the many outstanding members of the SAB.

The stories we hear from people living with FSHD span the entire globe. The Internet has brought our Web site (www.fshsociety.org) and chat room (webboard.novatech.net:7000 #fsh_society) into every corner of the world. We know these people who endeavor and persevere with FSHD through the personal triumphs and contributions they make. The spirit of competition and energy resounds in the pages of the Watch through fundraising efforts involving physical competition (marathons, races) and mental competition (gin rummy contests, read-a-thons, school fairs) and more. We are moved by the indestructible spirit of the race car driver in Italy racing to defeat Muscular Dystrophy, remark at the tireless efforts of promoting disability issues and rights through Miss Wheelchair Maryland and how this benefits those with FSHD, and the unique character of support groups around the country as detailed by a reporter with FSHD. Our annual scientific symposium and network days join researcher and the patient in a dialogue to help in the fight against FSHD.

The FSH Society is a rich resource for patient material and for providing help and contacts for those needing day-to-day support, advice, coping strategies and real world solutions. The hard reality of FSHD imposes a unique set of demands for those living with FSHD. We at the FSH Society are working hard to create the possibilities that will conquer FSHD.

The FSH Watch is a mosaic. Each piece of information gives better definition to the entire picture of FSHD. Combining all will truly tell us the scope, breadth and area that FSHD spans. All aspects of our program are vital to succeeding in conquering FSHD. We hope that this newsletter provides a valuable and optimistic view for those involved with FSHD.

In this newsletter you will see that the complexities and variability of FSHD emerge in every arena. FSHD is an extremely challenging and unique problem. FSHD may be the only human disease currently known to be caused by position effect or by one piece of DNA in the genome affecting other pieces of DNA in the genome. In short, it is possible that FSHD will open up whole new research areas in biology and a new class of disease to study. We are working hard with the research funding agencies worldwide to convey the need for special and focused efforts on this difficult and extremely challenging area of science. Clinically the disease presents an almost endless array of characteristics (phenotype) and strong challenges in correlating, tracking and relating these to the molecular level (genotype).

Some organizations save trees, rivers and the environment. We are working to preserve important human B cell cultures, the source of DNA for FSHD studies, by facilitating the transfer of cell lines to the nationally renowned Coriell Cell Repository. We are working against time to make lives better and to save lives. We are helping researchers get the valuable tissues they need by making known the resources and services available from the Brain and Tissue Banks. We are helping researchers with any request that they may have related to FSHD. We are getting the word out that there is a genetic test for FSHD, helping to make the test available and nearing the completion of a brochure on genetic testing for FSHD.

I recently read "Iron John, A Book About Men," by Robert Bly. In it, he uses the Grimms fairy tale about a genie like wild man named ‘Iron John’ to illustrate a boy’s passage from childhood to manhood and the steps, transitions and fears that accompany it. The tale is a rich metaphor and clearly mirrors the trials and tribulations of those living with and working on FSHD. For so long, FSHD has been journey that few have taken. It is no accident that for almost one hundred years FSHD existed in the center of a forest that sat in deep stillness and solitude that very few researchers and clinicians dared to enter. Then just a decade ago, Dr. Jacobsen and I asked if there was anything that we could do. We have set foot into the forest knowing that we have undertaken a very difficult and risky journey to find clues, search for meaning and to find answers for FSHD. We now know that the FSH Society has made the difference and hope that you will choose to walk with us. As always, we thank you for your steadfast support and hope that you will consider continuing and increasing your financial support. •

Several published studies over the past year address clinical issues in FSHD. Two recent articles examine the issue of genetic testing and confirm the accuracy of the DNA testing procedure as currently performed. They also help define the range of mutation sizes seen in FSHD by screening a large number of families. One of the articles also confirms the previous finding of a strong correlation between the size of the mutation and the severity of muscle weakness.

FSHD is not usually thought of as involving the brain. However, a study from Japan reports a high incidence of mental retardation and seizures in individuals with severe FSHD who have very large DNA deletions on chromosome 4. A single previous report, also from Japan, reported the occurrence of seizures in an individual with FSHD. No such association has been observed in other populations.

The large, controlled trial of albuterol being conducted by the Ohio State University and the University of Rochester is entering its final phase. The target enrollment of 90 individuals with FSHD has been reached and final results from the study are expected in early 2000. Another compound, of potential benefit to individuals with FSHD, has recently received attention in the press. Two small studies which included a variety of neuromuscular conditions, including FSHD, demonstrated improvement in overall strength following short-term supplementation with creatine monohydrate. Creatine is a natural substance found in meat and is the first source of energy used by muscle during vigorous exercise. Creatine supplementation in normal athletes, at best, shows only slight improvement in performance during high-intensity, short-term exercise. These studies, although preliminary, suggest that creatine may have added benefits in muscles affected with a dystrophy. Further, long term studies evaluating the effects of creatine in individual neuromuscular disorders are needed to confirm the long term safety and efficacy of creatine monohydrate. •

Orrell RW, et al.Definitive molecular diagnosis of facioscapulohumeral dystrophy. Neurology. 1999 Jun 10;52(9):1822-6.

Ricci E, et al Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann. Neurol. 1999 Jun;45(6):751-7.

Funakoshi M, et al Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy. Neurology. 1998 Jun; 50(6):1791-4.

Tarnapolsky et al., Creatine Monohydrate Increases Strength in Patients with Neuromuscular Disease. Neurology 1999; 52:854-857.

Walter et al., American Academy of Neurology 51st annual meeting. Toronto, Ontario,Canada. April 17-24, 1999. Abstracts. Neurology 1999 Apr 12;52(6 Suppl):A543.

Facioscapulohumeral Dystrophy (FSHD) is a muscle disease with a frequency in the population of between 4 and 10 per 100,000. The disease is inheritable; the genetic defect or responsible gene(s) is located on chromosome 4 for most individuals with FSHD. For individuals not linked to chromosome 4, the disease locus is still not yet known. The expression of symptoms requires inheritance of the defective gene from only one affected parent. An individual of either sex has a fifty percent chance of inheriting the gene from that affected parent.

The disease pathology includes a progressive loss of skeletal muscle with a usual pattern of initial noticeable weakness of facial, scapular and upper arm muscles and subsequent developing weaknesses of other muscles of the torso and lower limbs. Early facial weaknesses distinguish this disease from other neuromuscular diseases that can be similar in appearance. The age of onset is variable, as is the eventual extent and degree of muscle loss, but noticeable muscle weaknesses are usually present by the age of twenty and are recognizable in all but a small percentage of adults who carry the gene.

The prognosis includes both a loss of muscular strength that limits personal and occupational activities of most FSHD individuals, and a loss of mobility in perhaps twenty percent of the cases. Hearing loss and retinal abnormalities associated with FSHD have been reported, but the frequency of these effects and their relationship, if any, to the causative gene for the muscle defect are uncertain.

The Facioscapulohumeral Society (FSH Society, Inc.) is an independent, non-profit and tax-exempt U.S. corporation organized to address issues and needs specifically and solely related to Facioscapulohumeral Muscular Dystrophy (FSHD). Papers certifying its incorporation, bylaws and tax-exempt status are deposited at the corporation’s east and west coast offices and the office of its General Counsel in Washington, D.C.

The FSH Society was created because of a need for a comprehensive resource for FSHD individuals and families. Several purposes of the organization are:

The Society invites contact from any interested individuals, families, physicians, caregivers, charitable organizations, government agencies, industry, scientific researchers and academic institutions. Any inquiries regarding membership, charitable donations, purposes and goals or other issues pertaining to the Society and FSHD, should be addressed to the east or west coast offices. •

Dr. Louis Kunkel of Harvard Medical School and Children’s Hospital and Dr. James Gusella of Harvard Medical School and Massachusetts General Hospital will share the Dana Award for Pioneering Achievement in Health. Kunkel and Gusella have developed strategies to localize and characterize genes that cause neurological disorders.

Dr. Kunkel is a member of the FSH Society Board and Scientific Advisory Board. •

The FSH Society successfully launched its 1999 (FY2000) Washington agenda with the testimonies of Daniel Paul Perez and Elizabeth "Betsy" Conron on April 23, 1999 before the United States Senate and on April 29, 1999 before the United States House of Representatives. The testimonies were presented to both the U.S Senate and U.S. House Appropriations Committee’s, Subcommittee on Labor, Health and Human Services, Education and Related Agencies which set the funding for the National Institutes of Health (NIH) and for neuromuscular research. The FSH Society has been working intensively with the members of Congress in both the U.S. House of Representatives and U.S. Senate and wishes to expressly thank the following Congressmen for their responsiveness, professionalism and assistance: Rep. John Porter (R-IL), Rep. Sam Farr (D-CA), Rep. Edward J. Markey (D-MA), Rep. Randy "Duke" Cunningham (R-CA), Senator Arlen Specter (R-PA), Senator Edward Kennedy (D-MA), Senator John Kerry (D-MA) and Rep. Steny Hoyer (D-MD).

In an eloquent five minute statement presented on April 29, 1999 before the U.S. House Subcommittee, Ms. Conron described what it is like to live with facioscapulohumeral muscular dystrophy (FSHD). Her testimony included a description of FSHD and what it is like to have the disease. Additionally, the testimony pointed out that although the National Institutes of Health (NIH) budget has grown substantially, FSHD research through the NIH has not benefited even with Congressional report language. She stated that despite all of our work with the NIH and Congress that FSHD funding has gone down stating that our situation worsened in 1997 and 1998 when Congressional directives to the NIH regarding FSHD were ignored or no response was given.

In the past years, the FSH Society has provided Congress with the clinical picture of the disease, what it is like to live with and have the disease, updated the Subcommittee on recent clinical and genetic advances and presented areas of opportunities with detailed explanation of programs to help accelerate FSHD research. This year, the FSH Society has taken a substantially different approach to past year’s testimonies by noting the non- compliance of the NIH with Congressional directives and asking for a five to 10 million dollar earmark for FSHD to move the research ahead at NIH.

Most notable were the time capsule sections of Ms. Conron’s testimony which stated the FSH Society’s track record of going on record by appearing before Congress and other committees and the comparison of what has happened to her personally during the same six year period.

Ms. Conron had the extraordinary honor of being introduced to Chairman Representative John Porter’s (R-IL) Subcommittee by her representative, Representative Sam Farr (D-CA) and special privilege of testifying before Randy "Duke" Cunningham (R-CA) as acting Chair of the Subcommittee. Rep. Cunningham is Dr. Stephen J. Jacobsen’s Representative in San Diego, California. Even more extraordinary was Representative Farr’s introduction of Ms. Conron to the Subcommittee:

Introduction of Elizabeth Conron by Representative Sam Farr:

"Elizabeth Conron is the daughter of a constituent of mine, Dr. William Lewis. Dr. Lewis saved my life after an auto accident 30 years ago.

The following is the transcript of Ms. Conron’s testimony before the U.S. House Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies:

"Mr. Chairman, it is a pleasure to testify today. I am Elizabeth Conron, of Danville, California, a founding member of the FSH Society, who has FSHD.

"Facioscapulohumeral dystrophy or FSHD is an inherited or spontaneous neuromuscular disorder affecting one in twenty thousand people and is the third most prevalent form of muscular dystrophy. FSHD causes progressive and severe loss of skeletal muscle and may be the only dystrophy where the gene has not been identified. FSHD can happen to any of us.

"Diagnosed at Stanford at sixteen, I was physically active until twenty-two. Once an avid snow skier and competitive gymnast, today I walk short distances with assistance.

"FSHD has attacked my major muscle groups. My feet and calf muscles have atrophied so I stand on the outside of my ankles. My hip muscles have weakened so that I no longer rise from a sitting position without assistance. The arch in my back forms the letter "C." I cannot raise my arms above my shoulders. My right hand has weakened and feeding myself is difficult. I now must learn to be left handed. My once big and friendly smile has been replaced with weak and crooked lips. To close my eyes at night, I tape weights to the tops of my eyelids. My joints are swollen and my bones feel as though they rub together.

"Look at me, look at what FSHD has done to me. This is a painful and disabling disease. One by one, we surrender ourselves to wheelchairs. My sister, brother, mother, two aunts and six cousins have FSHD.

"In 1995, I earned a law degree and three American Jurisprudence awards. Writing was so difficult that I had to type my exams and when the elevator broke, classmates carried me up the stairs. This was truly humiliating.

"I have two children – four year old Caroline and two year old William. My husband and I agonized over the decision to have children. They are adorable and I am a good mom. The uncertainty that FSHD brings to the future of entire families is underestimated and can mean the end of a family line.

"FSHD deprives my family of some basic joys. Caroline and William must climb into my lap so that I can hug them. I can not go on a Ferris wheel with my children, supervise them in a swimming pool or walk along a beach with them. Simply combing Caroline’s hair or changing William’s diapers are difficult tasks.

"As soon as I make necessary adaptations, I weaken again. I pray that God will stop my FSHD. I have bruised, cut and torn most of my body from falls. I taught Caroline at age 2-1/2 to dial 911 and say, ‘Mommy fell and won’t wake up.’

"Without a cure for FSHD, I will continue to weaken. Please help me fight this disease now. If you had FSHD, you would fight to defeat it.

"I am a good person. I did not deserve a lifetime of FSHD. I want to walk with dignity, catch William as he comes down a park slide, button Caroline’s dress and hold my husband in my arms. And, I want my smile back.

"Thanks largely to your efforts, Mr. Porter, NIH funding has grown. FSHD research through the NIH has not benefited even with Congressional report language. We have met with the NIH, testified before Congress and FSHD funding has gone down. Our situation worsened in 1997 and ’98 when Congressional directives to the NIH regarding FSHD have been ignored or no response given.

"In 1999, no mention was made of FSHD in the draft of the NINDS’ Neuroscience at the New Millennium. The NINDS has one grant directly titled for FSHD and the NIAMS currently has nothing.

"Mr. Chairman, it is heartbreaking that FSHD, a neurological disease almost exclusively musculoskeletal in effect, can not gain support from the very institutes that have the word ‘neurology’ and ‘musculoskeletal’ in their names.

"We have come before you in 1994, ‘95, ‘97, ‘98 and again this year. In 1994, the NINDS and the NIAMS funded $300-500,000 dollars on FSHD and today are funding less than $250,000.

"I lost my ability to rise from sitting in 1994, to climb stairs in ’95, to drive my car without adaptation in ’96, to walk in ’97 and to get up after falling in ‘98. It is now 1999 and I have to move from the home I love due to lack of progress on FSHD. When will the NIH take responsibility for FSHD research?

"Mr. Chairman, you trusted that the IOM and the NIH would set its priorities correctly. We were forced to give testimony from the back of the room at the IOM because it was not wheelchair accessible. Mr. Chairman, the NIH is not listening to Congress or the scientific community and patients regarding FSHD research.

"Mr. Chairman, we request that an amount of not less than five (5) million and not more than ten (10) million dollars be earmarked for FSHD research. We know that this Committee does not like to earmark. The record of five years indicates that the NIH ignores Congressional direction and scientific opportunities. Earmarking appears the only way to get the NIH’s attention.

"I am submitting a longer statement from the FSH Society for the record.

"Mr. Chairman, again, thank you for providing this opportunity to testify before your Subcommittee."

Both Representatives Farr and Cunningham thanked Ms. Conron for her excellent and profoundly moving testimony and assured the witness that everything possible would be done to help honor the request. The following is the longer version and written testimony presented by Mr. Perez and Ms. Conron on behalf of the members of the FSH Society for the record on April 29, 1999 to the U.S. House of Representatives:

"Mr. Chairman, it is a great pleasure to submit this testimony to you today.

"My name is Daniel Paul Perez, of Lexington, Massachusetts, and I am testifying today as President of the Facioscapulohumeral Society and as an individual who has this disorder.

"As a chief patient activist for the tens of thousands of individuals living with Facioscapulohumeral Disease (FSHD) in the United States, I will continue to argue the case of wanting to live life free from disease.

"My testimony is about the profound and devastating effects of a disease known as Facioscapulohumeral Disease which is also known as FSH Muscular Dystrophy or FSHD, and the urgent need for NIH funding for research on this disorder. In past years (1994, 1995, 1997, 1998) and again this year we will submit testimony before both House and Senate Committees which states that NIH and Congress could help bring about a significant research and scientific discovery program which, with modest investments, would benefit hundreds of thousands of people worldwide.

"The FSH Society has previously informed the members of this Committee of the United States Congress on the need and rationale for research on FSHD. We have updated you on the most recent developments in clinical medicine with respect to FSHD, kept you abreast of the latest breakthroughs in the molecular genetics of the disease and given you insight into the difficulty of living a lifetime with this disease.

"Thanks largely to your efforts, Mr. Porter, NIH research funding continues to grow to its current level of 14 billion annually. Our gratitude fuels our hope for promising research solutions for FSHD. Ironically, I must in all candor express our frustration that promising FSHD research support and programs have yet to appear from the NIH, even in light of Congressional mandates and report language for such. While NIH has seen a funding increase of 30 percent in the past decade, FSHD research through the NIH has not benefited at all. In fact, research funding has gone down, not up. Since the FSH Society first testified before Congress in 1994, FSHD research has decreased from between $300-500,000 to between $100-250,000. During this time, Congressional directives to NIH regarding the state of FSHD research have been either ignored or responded to in an untimely manner. We have met with NIH officials, testified before the Institute of Medicine Committee and taken the path indicated to put forth our goals and the situation has only gotten worse.

"FSHD is a neuromuscular disorder that is inherited in an autosomal dominant fashion and has an estimated frequency of one in twenty thousand (1/20,000). Autosomal dominant means that there is a fifty percent chance that a child will inherit the disease from an affected parent. The prevalence could be as much as three times greater than the estimated frequency stated in the literature due to an undetermined number of sub-clinical cases. The major consequence of inheriting this disease is that of a progressive and severe loss of skeletal muscle, with the usual pattern of initial noticeable weakness of facial, scapular and upper arm muscles and subsequent developing weaknesses of other skeletal muscles. FSHD can be extremely severe and in some forms can lead to an early death. FSHD can happen to anyone of us.

"In 1997, the FSH Society submitted testimony to Chairman John Porter before the U.S. House of Representatives and to Senator Arlen Specter before the U.S. Senate requesting appropriations for research on FSHD and the need for Congressional input to the NIH to initiate research in this area.

"Report language was issued on July 22, 1997 stating: ‘Facioscapulohumeral disease– The Committee has heard compelling testimony about facioscapulohumeral (FSH) disease, which causes a progressive and severe loss of skeletal muscle. FSH research includes aspects such as molecular genetics, neurological function and muscular dystrophy involving multiple NIH Institutes. The Committee encourages NIH to take steps to stimulate research in this area and requests NIH to develop a plan for enhancing NIH research into FSH disease, including an assessment of whether an intramural research program in this area would be beneficial.’

"In 1998 the FSH Society again submitted testimony to Chairman John Porter before the U.S. House of Representatives and to Senator Arlen Specter before the U.S. Senate requesting appropriations for research on FSHD and the need for Congressional input to the NIH to initiate research in this area.

"By this time, NIH responded to the 1997 Congressional language, a year late: ‘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.’

"One month after our 1998 testimony before the U.S. House of Representatives, NIH issued a program announcement that covered, in part, FSHD. PA-98-044 is a response to the 1997 testimony and is over one year late. On March 20, 1998, the NIH issued PA Number: PA-98-044, titled: "Pathogenesis and Therapy of the Muscular Dystrophies." PA-98-044 was sponsored jointly by NINDS and NIAMS and the support mechanisms for grants in this area were the investigator-initiated research project grant (R01) and the program project grant (P01). We were disappointed with the diffusion of our efforts by this program announcement covering not just FSHD but all of the muscular dystrophies.

"Additionally in 1998, we testified before the Institute of Medicine (IOM) responding to its four-part directive from Congress on priority setting for research at the NIH. We were forced to submit the IOM testimony from the back of the auditorium as it was not wheelchair accessible. We testified before the IOM Committee regarding the area of report language: ‘… We find that the NIH response did not directly address the questions asked by the committee regarding the development of a plan for research in the area of FSHD research and regarding the possibility of intramural research in the area of FSHD research. The response we received did, in fact, dilute our efforts to accelerate and enhance research directly on FSHD by opening up a program announcement to all of the muscular dystrophies when in fact the request was for FSHD research.’

"In 1998, report language appeared in three sections of the U.S. House and U.S. Senate Appropriations budget under NIH, NIAMS and NINDS. The report language is as follows:

‘The Committee was pleased with the Institutes’ response to last year’s request which encouraged NIH to stimulate research in the area of facioscapulohumeral disease (FSHD). However, the committee notes that NIAMS has not responded in developing a plan for enhancing FSHD research, and has not addressed the question of whether an intramural program in this area would be beneficial. Therefore, the Committee urges NIAMS to conduct a research planning conference in the near future in order to explore scientific opportunities in FSHD research, both intramurally and extramurally.’

"No response was heard from NIH in 1998 for the 1998 language. FSHD researchers expressed disbelief both with the lack of funds and with the grants turned down. In 1998, NINDS and NIAMS funded no less than $100,000 and no more than $250,000 on direct FSHD research.

"This year NINDS asked for our input on a draft document titled, ‘Neuroscience at the New Millennium’ outlining priorities for NINDS 2000-2001. There was not one mention of FSHD nor was there any program that explicitly and suitably covered research on FSHD. My comments to Dr. Fischbach, Director of NINDS, and Dr. Varmus, Director of NIH, were:

‘I have some comments after having reviewed your document "Neuroscience at the New Millennium - Priorities and Plans for the National Institute of Neurological Disorders and Stroke Fiscal Years 2000-2001." It is clear to me, if not completely black and white, that the formulation of the plan does not account for or even give consideration to FSHD and is not adequate with respect to FSHD.

‘Of the greatest concern to me is no direct mention of FSHD in any of the sentences, clauses or paragraphs in the document I received, "Neuroscience at the Millennium," despite strong Congressional report language on the issue. I do not see the scope expanding to cover diseases such as FSHD for which there is no known gene—and for which there may never be a gene per se. Where in this program is FSHD covered?

‘The NINDS plan is not consistent with recent congressional mandates and report language which instruct NINDS for more involvement in FSHD research. Despite repeated meetings and work with the various institutes at NIH, and assurances the responsibility and jurisdiction with respect to FSHD research is shared across institutes, NINDS does not reflect this in the current document.

‘Both the House and Senate Appropriations Reports have language for this fiscal year and the last fiscal year that instructs and authorizes NINDS and NIAMS for plans and priorities with respect to FSHD.’

"In 1999 to date, NINDS has only one newly issued grant in its portfolio that is directly titled for FSHD. When we called NIAMS, the secretary who answered incorrectly informed us that NIAMS does not do research in muscular dystrophy. In 1999 to date, NIAMS has no grants presently issued with FSHD in their title. NIAMS states that it is beginning the process of organizing the research conference for the spring of 2000 but we have absolutely no indication of movement in this area. NIAMS again points us towards the MDA which has recently started gene therapy trials in limb-girdle muscular dystrophy. FSHD is not limb-girdle muscular dystrophy. NIH must understand that FSHD requires their attention. NIH must understand that FSHD may be the only muscular dystrophy for which the putative gene has not been identified.

"FSHD researchers still express incredulity with the lack of funds and rejection of grants submitted by the top laboratories in the world. In 1999, NIAMS currently has funded $0 (zero) on direct FSHD research.

"Mr. Chairman, it is ironic that with FSHD being a primary neurological disease which is almost exclusively musculoskeletal in its effects, it can not gain support from the very institutes that have ‘neurology’ and ‘musculoskeletal’ in their names.

"Mr. Chairman, we know that the Committee is overwhelmed in hearing from patient groups such as ours. We know that you trusted that the Institute of Medicine (IOM) and the NIH would set its priorities correctly. The truth is that we have come before Congress to testify year after year, given testimony in a wheelchair from the back of the room at the IOM, worked hard to have NIH take a more active, deliberate and responsible role, and yet the NIH is not listening to the Congress, the scientific community and the patients on this issue.

"Mr. Chairman, this is a clear and disturbing trend.

"Although FSHD research may have benefited indirectly from NIH funding of the Human Genome Project, direct funding of FSHD research by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) at NIH has been minimal.

"The total NIH funding for directly titled FSHD research currently for the fiscal year 1999 (FY99) is approximately three hundred thousand dollars.

"FSH Muscular Dystrophy has a prevalence of 5-10/100,000 persons, Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, has a prevalence of 1-2/100,000 persons and Charcot-Marie-Tooth (CMT Type 1, 2, 3) has a prevalence of 1/15,000 persons. Even though FSHD may have a greater prevalence in the population than CMT and be similar in magnitude to ALS, it has received far, far significantly less from NIH funding sources.

"Mr. Chairman, there presently is very little funding of FSHD from NIH—perhaps three hundred thousand dollars. I re-iterate, this is clearly inadequate given the recent advances and the high likelihood of making significant progress in the very near future. With a budget of 14 billion dollars, NIH is spending such a miniscule amount on FSHD research. This tiny amount is utterly unconscionable and defies logic and reason given the prevalence of FSHD and the cost of doing molecular genetics research in 1999.

"Mr. Chairman, we ask the Subcommittee to earmark a dollar amount to FSHD research. We request that an amount of not less than five (5) million and not more than ten (10) million dollars be earmarked for FSHD research. We know that this Committee does not approve of earmarking. However, the record of five years indicates that NIH ignores Congressional direction as well as scientific opportunities. Earmarking appears to be the only way to get NIH’s attention.

"The FSHD community demands that the Congress of the United States of America take action on funding research on FSHD. We are asking today for a promise to people living with FSHD which commits to funding FSHD research in the following areas:

"Additionally, the FSHD community is requesting that Congress ask NIH to research and make recommendations on the following:

"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.

"This is the United States of America and, in a country as great as ours with all of its technical means and ability, it should be absolutely clear that the number one priority for individuals with FSHD and the one absolutely commanding imperative for the federal government is to initiate and accelerate in any way possible, research on FSHD. With modest funding and a clear direction from Congress to the NIH to support research on FSHD, significant progress can be made in conquering and eliminating this and other devastating diseases.

"Mr. Chairman, again, thank you for providing this opportunity to testify before your Subcommittee." •

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" (the hyperlink to PA-98-044 is http://www.nih.gov/grants/guide/pa-files/PA-98-044.html). 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).

The National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) encourage investigator-initiated research grant applications to study the pathogenesis and therapy of the various forms of muscular dystrophy in children and adults. Responses to this program announcement may include studies in appropriate animal models or preclinical or clinical studies in patients with facioscapulohumeral dystrophy (FSH), limb-girdle muscular dystrophy (LGMD), myotonic dystrophy, congenital muscular dystrophy (CMD), Emery-Dreifuss muscular dystrophy (EMD), Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or other forms of muscular dystrophy.

Some possible areas of research that are specific to facioscapulohumeral muscular dystrophy include the continuation of the sequencing of the entire 4q35 region, and the investigation of the position effect hypothesis and its basis in chromatin structure.

As program announcements are usually three years in duration, both the NIH and the FSH Society encourage both researchers and clinicians working on FSHD to apply and continue to apply for these grants. •

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Grewal PK, Bolland DJ, Todd LC, Hewitt JE. High-resolution mapping of mouse chromosome 8 identifies an evolutionary chromosomal breakpoint. Mamm Genome 1998 Aug;9(8):603-7

Lemmers RJ, van der Maarel SM, van Deutekom JC, van der Wielen MJ, Deidda G, Dauwerse HG, Hewitt J, Hofker M, Bakker E, Padberg GW, Frants RR. Inter- and intrachromosomal sub-telomeric rearrangements on 4q35: implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis. Hum Mol Genet 1998 Aug;7(8):1207-14

Birch JG. Orthopedic management of neuromuscular disorders in children. Semin Pediatr Neurol 1998 Jun;5(2):78-91

Cacurri S, Piazzo N, Deidda G, Vigneti E, Galluzzi G, Colantoni L, Merico B, Ricci E, Felicetti L. Sequence homology between 4qter and 10qter loci facilitates the instability of subtelomeric KpnI repeat units implicated in facioscapulohumeral muscular dystrophy. Am J Hum Genet 1998 Jul;63(1):181-90

Funakoshi M, Goto K, Arahata K. Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy. Neurology 1998 Jun;50(6):1791-4

Lunt PW. 44th ENMC International Workshop: Facioscapulohumeral Muscular Dystrophy: Molecular Studies 19-21 July 1996, Naarden, The Netherlands. Neuromuscul Disord 1998 Apr;8(2):126-30

Delaporte C. Personality patterns in patients with myotonic dystrophy. Arch Neurol 1998 May;55(5):635-40

Zatz M, Marie SK, Cerqueira A, Vainzof M, Pavanello RC, Passos-Bueno MR. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am J Med Genet 1998 May 1;77(2):155-61

Kissel JT, McDermott MP, Natarajan R, Mendell JR, Pandya S, King WM, Griggs RC, Tawil R. Pilot trial of albuterol in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology 1998 May;50(5):1402-6

Butefisch CM, Lang DF, Gutmann L. The devastating combination of Charcot-Marie-Tooth disease and facioscapulohumeral muscular dystrophy. Muscle Nerve 1998 Jun;21(6):788-91

Eggers S, Zatz M. How the magnitude of clinical severity and recurrence risk affects reproductive decisions in adult males with different forms of progressive muscular dystrophy. J Med Genet 1998 Mar;35(3):189-95

Eggers S, Zatz M. Social adjustment in adult males affected with progressive muscular dystrophy. Am J Med Genet 1998 Feb 7;81(1):4-12

Tawil R, Figlewicz DA, Griggs RC, Weiffenbach B. Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis. FSH Consortium. Ann Neurol 1998 Mar;43(3):279-82

Spuler S, Engel AG. Unexpected sarcolemmal complement membrane attack complex deposits on nonnecrotic muscle fibers in muscular dystrophies. Neurology 1998 Jan;50(1):41-6

Okinaga A, Matsuoka T, Umeda J, Yanagihara I, Inui K, Nagai T, Okada S. Early-onset facioscapulohumeral muscular dystrophy: two case reports. Brain Dev 1997 Dec;19(8):563-7

Funakoshi M, Goto K, Kim BY, Arahata K. [Facioscapulohumeral muscular dystrophy]. [Article in Japanese] Nippon Rinsho 1997 Dec;55(12):3181-5

Kimura T, Moriwaki T, Sawada J, Naka T, Hazama T, Nakata T. [A family with facioscapulohumeral muscular dystrophy and hereditary long QT syndrome]. [Article in Japanese] Rinsho Shinkeigaku 1997 Aug;37(8):690-2

Felice KJ, Grunnet ML. Autosomal dominant centronuclear myopathy: report of a new family with clinical features simulating facioscapulohumeral syndrome. Muscle Nerve 1997 Sep;20(9):1194-6

Rudnik-Schoneborn S, Glauner B, Rohrig D, Zerres K. Obstetric aspects in women with facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, and congenital myopathies. Arch Neurol 1997 Jul;54(7):888-94

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 1997 Jul;149(1):73-9

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 1997 Jun;34(6):476-9

Sansone V, Boynton J, Palenski C. Use of gold weights to correct lagophthalmos in neuromuscular disease. Neurology 1997 Jun;48(6):1500-3

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 1997 Jun;8(6):394-8

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 1997 May;36(5):333-9

Milanov I, Ishpekova B. Differential diagnosis of scapuloperoneal syndrome. Electromyogr Clin Neurophysiol 1997 Mar;37(2):73-8

Ohya K, Tachi N, Kozuka N, Kon S, Kikuchi K, Chiba S. Detection of the mutation in facioscapulohumeral muscular dystrophy patients. Acta Paediatr Jpn 1997 Feb;39(1):92-6

Fisher J, Upadhyaya M. Molecular genetics of facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 1997 Jan;7(1):55-62

Fowler WM Jr, Abresch RT, Koch TR, Brewer ML, Bowden RK, Wanlass RL. Employment profiles in neuromuscular diseases. Am J Phys Med Rehabil 1997 Jan-Feb;76(1):26-37

Speer MC, Pericak-Vance MA, Stajich JM, Sarrica J, Jordan M, Roses AD, Vance JM, Gilbert JR. Further exclusion of FSHD1B from the telometric region of 10q. Neurogenetics 1997 1:151-52.

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 1997 Jan;48(1):46-9

The FSH-DY Group. A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. Neurology 1997 Jan;48(1):38-46

Researcher(s): Alexandra Belayew, Jan Gabriels, Marie Claire Beckers, Stephane Plaisance, Astrid De Vriese

Address: Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000-Leuven, Belgium

Interest(s): Molecular genetics

Update: This work was done in collaboration with Jane Hewitt in Nottingham, Rune Frants and Silvere van der Maarel in Leiden, George Padberg in Nijmegen, in addition to people from my group in Leuven.

FSHD is genetically linked to a region (D4Z4) close to the telomere on the long arm of chromosome 4. In non affected individuals, this chromosome region comprises 10 to 100 tandem copies of a DNA element named 3.3 kb repeat. FSHD is associated with chromosome deletions leaving only 1-8 such repeats in D4Z4. Members of the 3.3 kb family are not only found in the D4Z4 region, but also on several different chromosomes. Their number is estimated to about 500 in the whole genome, and their function is presently unknown, although they are often associated with heterochromatin, a chromosome structure that blocks gene activity.

A few 3.3 kb elements from the D4Z4 loci of non-affected individuals have been cloned and sequenced and the sequences made available in computer databases by the groups of Drs J Hewitt and K Arahata. The sequences are very rich in the DNA bases G and C, which makes them difficult to determine. Their analyses showed a complex pattern with several smaller repeated motifs known to occur also elsewhere in the genome. In addition, the 3.3 kb elements were found to putatively encode a large protein with two homeodomains. Such domains can bind DNA regulatory elements, and are known in proteins that activate genes involved in early embryo development. However, no promoter that might drive expression of this putative homeo gene was identified in the 3.3 kb elements.

Two years ago, we cloned, by serendipity, other members of the 3.3 kb repeat family not coming from the D4Z4 region. We have identified among the later some genes with a functional promoter and encoding proteins with two homeodomains: we named those genes DUX1, DUX2, DUX3 (for DoUble homeoboX). Alignment of the DUX genes with the known sequences of 3.3 kb repeats derived from D4Z4 loci of non-affected individuals identified in some of these a homologous promoter. It was not detected earlier because it is inside the region that putatively encodes a large protein with two homeodomains. Moreover promoters usually comprise a TATAA sequence that was changed here into a TACAA sequence. Interestingly, a shorter protein with the same two homeodomains is putatively encoded just after this promoter: we named this putative protein DUX4.

In the present study, we investigated whether the 3.3 kb repeats actually present in the D4Z4 locus after the partial deletion linked to FSHD could still include such putative DUX4 genes. To facilitate this study, we needed DNA from a patient with very few 3.3 kb repeats left in his D4Z4 locus. One patient followed by Dr. G. Padberg had only two such elements; its D4Z4 locus had been cloned by the group of Dr. R. Frants and was used as starting material. We determined the complete locus sequence and found that the two 3.3 kb elements were identical, and contained the putative DUX4 gene. In addition, their sequences were nearly identical to those determined previously in non-affected individuals. We then showed that the promoter was active when it was introduced in muscle cells grown in vitro, and that a DUX4 protein could be made in vitro. This is the first demonstration that a putative gene is present in the 3.3 kb repeats of the D4Z4 locus.

In collaboration with Dr J. Hewitt, we made the following hypothesis: in non-affected individuals, the many 3.3 kb repeats in the D4Z4 locus would be covered by heterochromatin and inactive. Deletions of most of the locus observed in patients would destabilize heterochromatin and allow activation of the DUX4 genes in some cells; the resulting DUX4 protein would be toxic to muscle cells. This hypothesis would fit, among others, with the known genetic dominance of FSHD and with the heterogeneity of the symptoms. We want to stress that this is only a hypothesis and that a lot of studies will still be needed to evaluate it.

Abstract of recent publication: Gene 1999 Aug 5;236(1):25-32; Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gabriels J, Beckers M, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A; Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

Facioscapulohumeral muscular dystrophy (FSHD) is linked to the polymorphic D4Z4 locus on chromosome 4q35. In non-affected individuals, this locus comprises 10-100 tandem copies of members of the 3.3kb dispersed repeat family. Deletions leaving 1-8 such repeats have been associated with FSHD, for which no candidate gene has been identified. We have determined the complete nucleotide sequence of a 13.5kb EcoRI genomic fragment comprising the only two 3.3kb elements left in the affected D4Z4 locus of a patient with FSHD. Sequence analyses demonstrated that the two 3.3kb repeats were identical. They contain a putative promoter that was not previously detected, with a TACAA instead of a TATAA box, and a GC box. Transient expression of a luciferase reporter gene fused to 191bp of this promoter, demonstrated strong activity in transfected human rhabdomyosarcoma TE671 cells that was affected by mutations in the TACAA or GC box. In addition, these 3.3kb repeats include an open reading frame (ORF) starting 149bp downstream from the TACAA box and encoding a 391 residue protein with two homeodomains (DUX4). In-vitro transcription/translation of the ORF in a rabbit reticulocyte lysate yielded two (35)S Cys/ (35)S Met labeled products with apparent molecular weights of 38 and 75kDa on SDS-PAGE, corresponding to the DUX4 monomer and dimer, respectively. In conclusion, we propose that each of the 3.3kb elements in the partially deleted D4Z4 locus could include a DUX4 gene encoding a double homeodomain protein.

Researcher(s): Mayana Zatz, Maria Rita Passos-Bueno, Suely K. Marie, Rita de Cassia M. Pavanello, Maria Tonini, Maria Cerqueira

Address: Departmento de Biologia, Instituto de Biosciencias, Universidade de Sao Paulo, Rua de Matao 227 - sala 211, 05508-900, Sao Paulo, SP, Brazil

Interest(s): Molecular genetics, clinical and occupational and genetic testing

Update: Our group is focused on the following aspects of FSHD: molecular analysis of FSHD, genotype-phenotype correlations, genetic testing and genetic counseling.

Abstract from recent publication: American Journal of Medical Genetics 1998 May 1;77(2):155-61; The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Zatz M, Marie SK, Cerqueira A, Vainzof M, Pavanello RC, Passos-Bueno MR Departamento de Biologia, Instituto de Biociencias, Universidade de Sao Paulo, Brazil

We investigated 52 families of patients with facioscapulohumeral muscular dystrophy (FSHD1), including 172 patients (104 males and 68 females). Among 273 DNA samples which were analyzed with probe p13E-11, 131 (67 males and 64 females) were shown to carry an EcoRI fragment smaller than 35 kb; 114 among them were examined clinically and neurologically. Results of the present investigation showed that: a) there is no molecular evidence for autosomal or X-linked recessive inheritance of FSHD1; b) an excess of affected males, which is explained by a significantly greater proportion of females than males among asymptomatic cases and a significantly greater proportion of affected sons than daughters observed in the offspring of asymptomatic mothers; c) the penetrance of the FSHD1 gene until age 30 was estimated as 83% for both sexes but was significantly greater for males (95%) than for females (69%); d) new mutations occur significantly more frequently in females than males among somatic/germinal mosaic cases; and e) severely affected cases originated more often through new mutations or were transmitted through maternal than through paternal lines including somatic/germinal mothers. These observations have important implications for understanding the molecular mechanisms responsible for FSHD1 and for genetic and prognostic counseling according to the gender of the affected patient.

Researcher(s): Peter J. Bridge

Address: Molecular Diagnostic Laboratory, Alberta Children’s Hospital, 1820 Richmond Road, S.W., Calgary, Alberta, Canada T2T 5C7

Interest(s): Molecular genetics, clinical and genetic testing

Researcher(s): Robert Korneluk, Alasdair Hunter, Nancy Carson

Address: Department of Genetics, Children’s Hospital of Eastern Ontario (CHEO), 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1

Interest(s): Molecular genetics, clinical and genetic testing

• • •

Researcher(s): David Picketts, Christopher Storbeck

Address: Ottawa General Hospital, Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6

Interest(s): Molecular genetics and cellular biology

Researcher(s): Peter Lunt

Address: Bristol Royal Hospital for Sick Children, Clinical Genetics Service, St. Michael’s Hill, Bristol BS2 8BJ, England

Interest(s): Molecular genetics and clinical

• • •

Researcher(s): Philip Jardine

Address: Children’s Centre, Frenchay Hospital, Bristol BS16 1LE, England

Interest(s): Molecular genetics and clinical

Researchers: Peter S. Harper, Meena Upadhyaya, Mike Osborn, David N. Cooper

Address: Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, England

Interest(s): Molecular genetics, clinical and genetic testing

Update: Our main research interests include: 1.) Study of methylation status of DNA sequences within the FSHD region, specifically targeting known genes or repeat sequences; 2.) to investigate the prevalence of subtelomeric exchanges between homologous 4q35 and 10q26 loci in both normal individuals and FSHD patients and to ascertain their possible role in the etiology of the disorder; 3.) to search for potential differences in the expression levels of muscle specific 4q35 located transcribed sequences in both FSHD patients and control subjects. Our institute is also involved in the molecular testing for FSHD

Researcher(s): Robin B. Fitzsimons

Address: Institute of Opthamology, Moorefield Eye Hospital, Department of Clinical Opthamology, City Road, London EC1V 2PD, England

Interest(s): Molecular genetics, clinical and genotype-phenotype correlations

• • •

Researcher(s): Michael Rose

Address: King’s Neurosciences Centre, Mapother House, De Crespigny Park, Denmark Hill, London SE5 8AZ, England

Interest(s): Clinical

Researcher(s): Jane Hewitt, Pam Grewal, Daniel Bolland

Address: Division of Genetics, Queen’s Medical Centre, Nottingham University, Nottingham, N97 2UH, England

Interest(s): Molecular genetics and mouse models

Update: We have recently moved from Manchester to Nottingham University and have spent the last few months setting up our new laboratory here. We are continuing our comparative mapping approach to identify candidate genes which might be involved in FSHD. We are concentrating on the mouse and the Japanese puffer fish (Fugu rubripes). The Fugu genome is much smaller than human but contains a similar number of genes. We hope that this will make it easier to find genes!

We are also continuing to investigate the evolution of the FSHD-associated repeat because we think this will help us to understand its normal function and why the deletion causes FSHD.

Abstracts of recent publications: Gene 1998 Aug 17;216(1):13-9; FRG1, a gene in the FSH muscular dystrophy region on human chromosome 4q35, is highly conserved in vertebrates and invertebrates. Grewal PK, Todd LC, van der Maarel S, Frants RR, Hewitt JE; School of Biological Sciences, The University of Manchester, 3.239 Stopford Building, Oxford Rd, Manchester M13 9PT, UK.

The human FRG1 gene maps to human chromosome 4q35 and was identified as a candidate for facioscapulohumeral muscular dystrophy. However, FRG1 is apparently not causally associated with the disease and as yet, its function remains unclear. We have cloned homologues of FRG1 from two additional vertebrates, the mouse and the Japanese puffer fish Fugu rubripes, and investigated the genomic organization of the genes in the two species. The intron/exon structure of the genes is identical throughout the protein coding region, although the Fugu gene is five times smaller than the mouse gene. We have also identified FRG1 homologues in two nematodes: Caenorhabditis elegans and Brugia malayi. The FRG1 protein is highly conserved and contains a lipocalin sequence motif, suggesting it may function as a transport protein.

Gene 1999 Feb 4;227(1):79-88; Recent amplification of the human FRG1 gene during primate evolution. Grewal PK, van Geel M, Frants RR, de Jong P, Hewitt JE

School of Biological Sciences, The University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK.

There is evidence of multiple copies of the FSHD Region Candidate Gene 1 (FRG1) in humans. Analysis of human FRG1 ESTs showed many of them to be non-processed pseudogenes dispersed throughout the genome. To determine when the amplification of FRG1 occurred, we used a PCR-based approach to identify FRG1 sequences from great apes, chimpanzee, gorilla and orang-utan, and an Old World monkey, Macaca mulatta. In common with humans, multiple copies of FRG1 were detected in the great apes. However, in Macaca mulatta, only two FRG1 loci were identified, one presumed to be the homologue of the human chromosome 4q gene. This is strikingly similar to the distribution of a dispersed 3.3-kb repeat family in primates. A member of this family, D4Z4, maps to the subtelomeric region of 4q, in close proximity to FRG1. We propose that an ancestral duplication of distal 4q included FRG1. This duplication is present in Macaca mulatta whose divergence from hominoids is thought to have occurred at least 33 million years ago. We propose that this telomeric region then underwent further amplification and dispersion events in the great ape lineage, with copies of FRG1 and the 3.3-kb repeats being localized in heterochromatic regions.

Mammalian Genome 1998 Aug;9(8):603-7; High-resolution mapping of mouse chromosome 8 identifies an evolutionary chromosomal breakpoint. Grewal PK, Bolland DJ, Todd LC, Hewitt JE; School of Biological Sciences, The University of Manchester, 3.239 Stopford Building, Oxford Rd., Manchester M13 9PT, UK.

The central region of mouse Chromosome (Chr) 8, containing the myodystrophy (myd) locus, is syntenic with human Chr 4q28-qter. The human neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD) maps to Chr 4q35, and myd has been proposed as a mouse homolog of FSHD. We have employed a comparative mapping approach to investigate this relationship further by extending the mouse genetic map of this region. We have ordered 12 genes in a single cross, 8 of which have human homologs on 4q28-qter. The results confirm a general relationship between the most distal genes on human 4q and the most proximal genes in the mouse 8 syntenic region. Despite chromosomal rearrangements of syntenic groups in this region, conservation of gene order is maintained between the group of genes in the human telomeric region of 4q35 and MMU8. Furthermore, this conserved telomeric HSA4q35 syntenic group maps proximal to the myd mutation and is flanked by genes with homologs on HSA8p22. At the proximal boundary of the MMU8 linkage group we have identified a single 300-kb YAC containing the genes Frgl and Pcml, which have human homologs on 4q35 and 8p22, respectively. Thus, this YAC spans an evolutionary chromosomal breakpoint. As well as providing clues about chromosomal evolution, this map of the FSHD syntenic mouse region should prove invaluable in the isolation of candidate genes for this disease.

Researcher(s): Claude Diaz, Annie Barois, Jean Pouget

Address: Association Française contre les Myopathies (AFM) 1, rue l’Internationale BP59 — 91002 Evry cedex, France

Interest(s): Molecular genetics, clinical, research and medical school education

Update: The Association Française contre les Myopathies (AFM) recently issued a new monograph (copyright May 1999) on facioscapulohumeral muscular dystrophy (Dystrophie Musculaire Facio-Scapulo-Humerale) in its "Myoline" series on neuromuscular disorders. The monograph (100 pages, 3 ring bound ) is available in French and is a comprehensive training manual covering the various aspects FSHD. It is a collection of information and articles for use in the training of medical professionals. Chapters cover the following aspects of FSHD: definition of muscular dystrophy, history of FSHD, epidemiology, physiology and patho-physiology, clinical description of FSHD and associated clinical features, genetics, differential diagnosis issues, methods for quantitatively tracking and treating the disease clinically, occupational and vocational issues, researchers, diagnostic criteria, psychosocial development, and counseling and mental health issues. In