Genetic Research for Chiari Type 1 Malformation and Syringomyelia is Well Underway
By Chantelle Wolpert, Courtney Drake and Marcy Speer Phd, Duke University

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This is the third year of the ongoing genetic research study for Chiari type 1 malformation and Syringomyelia (CM1/S). Our research is aimed at determining whether or not there is a genetic component to CM1/S.

The response from individuals and families to this research study has been very enthusiastic. We are greatly encouraged by this outpouring of interest and support for this project, and we thank you for your interest and participation. Together we can continue to push forward the research efforts and begin to understand the causes of CM1/S.

Currently, more than 150 families have joined the research study. Of these families, several have more than one family member with CM1/S. A subset of these families are involved in the next phase of the research study which is funded by a research grant from the American Syringomyelia Alliance Project (ASAP). This phase of the study involves having a magnetic resonance imaging (MRI) study performed on each family member (with or without symptoms) to identify whether CM1/S is occurring in families. For instance, in some families a parent, as well as his or her child, may have CM1/S. In other families, a child may be diagnosed with CM1/S, yet neither of the parents have CM1/S.

What is the Goal of this Research?

Often, families that have a Chiari malformation and/or syringomyelia are concerned about other members of their family. Some of the greatest unanswered questions about this disorder include: "Can I pass this on to my children? Are my brothers and sisters at risk? Is it possible that CM1/S runs in our family?" Through this research study, we hope to answer these questions. Although our current data shows evidence for CM1/S "running" (or clustering) in some families, we cannot say how often this phenomenon occurs, or even whether it is truly due to genes or genetic factors. The current research is aimed at learning if CM1/S is indeed caused by factors inherited through the family, and, if so, what the exact genes involved are.

Why Genetic Research Now?

The time is favorable to conduct genetic research for CM1/syringomyelia for several reasons. Until recently, the technology simply did not exist to conduct such a detailed genetic research study. However, thanks to technological advances and funding from the American Syringomyelia Alliance Project (ASAP), researchers are able to take the next steps in determining whether there are gene(s) associated with CM1 and syringomyelia.

The recent advances in computing power and new statistical methods are also key in uncovering the genetic causes of CM1 and syringomyelia. New computers enable researchers to store vast amounts of information, a feat that would have been impossible only a few years ago. Powerful statistical tools allow the researchers to examine all of these data and to understand which genes seem to be at work in causing a disorder. Molecular advances are also a significant factor in our ability to perform genetic research in CM1/S. The Human Genome Project has produced genetic maps that enable genetic researchers to locate the gene (s) with greater ease. In addition, the advent and widespread use of magnetic resonance imaging (MRI) has enabled the medical

Lastly, the National Institutes of Health (NIH), through its National Institute for Neurological Disorders and Stroke, has issued a Program Announcement to encourage researchers to study syringomyelia. The issuance of this program announcement sends a strong signal to researchers like us that the federal government is committed to funding good scientific research that will lead to advances in syringomyelia.

Steps in the Research Process for Genetic Studies at the
Center for Human Genetics at Duke University Medical Center

Step 1. Gather preliminary data supporting the idea that CM1 and syringomyelia show familial aggregation ("familial clustering") in some individuals and families.

During this initial stage, we obtain detailed family histories and blood samples from study participants. In some families, more than one person is affected with CM1/S. This phenomenon is known as familial aggregation. When familial aggregation is found, it may indicate that there is a genetic basis to this disorder. This first step of the genetic research has already been accomplished thanks to all of the families that have generously participated in this study! With Dr. Milhorat, leader of the ASAP Medical Advisory Board, we investigated a familial aggregation in a large study of 364 CM1/S patients. Of these, 21 of the patients' families had two or more cases of CM1/S within the family, demonstrating that there is indeed familial aggregation of CM1/S.

Step 2. Provide scientific evidence that the familial aggregation actually indicates a genetic transmission.

The current research efforts are focusing on establishing that the familial aggregation is due to a genetic cause. For this step, we perform MRI studies on all family members in some of the families that already have more than one diagnosed patient with CM1/S, including some family members who do not have symptoms. By imaging several families, our hope is to provide evidence that CM1 and syringomyelia have a genetic component. This phase of the research is funded by the American Syringomyelia Alliance Project (ASAP), and we are well on the way to providing some answers to the fundamental research question: Is the genetic transmission of CM1 real? The funding from ASAP has been critically important in our ability to submit a grant application to the National Institutes of Health to continue this research. Completing this second step paves the way for step three.

Step 3. Locate the gene or genes associated with CM1 and syringomyelia.

After convincing ourselves and other scientists that there is good evidence that the familial clustering seen in some CM1/S families is due to the effect of a gene or genes, the next step is to start to look for the genes involved. We carefully study each region of each chromosome to find a region that contributes to CM1/S. Then, these regions are studied in detail. The next step is to start to look for the genes involved. From a molecular standpoint, the regions we identify for detailed study are large. Hunting for genes in these regions is the equivalent of searching an area the size of a state for a specific street or house. For this reason, we cannot predict how soon the gene(s) or genetic mechanisms will be found. However, we are hopeful that in the next several years researchers working together will be able to explain what changes occur on these chromosomes to cause some cases of CM1/syringomyelia.

Step 4. Characterize the gene(s) associated with CM1 and syringomyelia

Once the genes that play a role in causing CM1/S and syringomyelia are identified, it will be possible to understand how the gene found in people with CM1/S differs from the gene found in the general population. We will be able to look at the genetic sequence and see exactly where the change has occurred. A change in the sequence may cause a change in the gene's ability to function properly. Once a genetic change in CM1/S is identified, it is possible that direct genetic testing may be developed that would enable a person to see if he or she has the original copy of the gene or the changed copy.

Step 5. Understand how the gene(s) may cause CM1 and syringomyelia

The next step in the research is to learn the mechanism by which this changed gene causes CM1/S, and ultimately, why and how this condition becomes symptomatic. By examining the function of the original form of the gene, we can learn about its role in development. Then, we can understand why a different form of the gene causes a change in the developmental process, eventually leading to a Chiari malformation.

To date, we have:

 

• Talked with more than 150 families, obtained detailed family histories, and reviewed medical records.
• obtained more then 170 blood samples for DNA studies
• Performed and/or obtained and reviewed more than 35 magnetic resonance images (MRIs) to document diagnosis. The first scientific manuscript describing the results in our initial series of families is in preparation and should be submitted for review in August or September.
• Submitted a grant to the National Institutes of Health to expand this research. If funded, this grant will provide us with about $350,000/year for five years to investigate the genetic hypothesis about CM1/S. The chance for a first submission of a grant to be funded is low, so we are not expecting that it will be funded on this round. However, we will continue to update and resubmit this grant and we believe, given the NIH's commitment to Syringomyelia, that it will ultimately be funded. We will know the status of this application in November.
• Investigated a specific hypothesis about PAX3, a gene involved in early neural development. We studied PAX3 in a family in which a mother and child were both affected with CM1/S and who had physical characteristics similar to those found in Waardenburg syndrome, known to be caused by changes in the PAX3 gene. We found no changes in the PAX3 that could explain the occurrence of CM1/S in this family.

None of this work would have been possible without the support of ASAP and without the assistance and encouragement of Dr. Thomas Milhorat, head of the Medical Advisory Board of ASAP.

What does Participation in the Research Involve?

First, we take a detailed family history (pedigree), asking medical information about relatives within three degrees of relationship (cousins) of the patient with CM1/S. If the family includes two or more individuals reported to be affected with CM1/S diagnosed by MRI, we then collect the MRI scans and medical records to document the diagnosis. After the diagnosis is documented in the individuals reported to be affected, we may ask selected member (both affected and unaffected) of the family to agree to have MRI scans to determine whether they have CM1/S or not. In addition, we request blood samples to obtain DNA on selected family members.

The Research Team

Finding genes is a huge undertaking that involves the combined efforts of many people. Individuals with CM1 and syringomyelia and their family members are the most vital members of this team. Other members of the research team include neurosurgeons, geneticists, genetic counselors and laboratory technicians. In addition to all of the research participants and research personnel, we strive to work together with families and professionals from the continental United States, Canada and Europe. Members of our team at DUMC include Amy Franklin, Patient Coordinator; Courtney Drake, Intern; Chantelle Wolpert, MBA, Kristi Viles, B.S., laboratory research analyst; Dr. Timothy George, pediatric neurosurgeon, Dr. David Enterline, neuroradiologist; and Marcy Speer, study director. In addition, our medical and scientific guidance is spearheaded by Dr. Thomas Milhorat, Professor and Chair, Department of Neurosurgery at the State University of New York.

We Apologize for a Technical Glitch

We offer our sincerest apologies for not responding sooner to some of the individuals who contacted us via e-mail. Due to a computer problem within our system, some e-mail messages were re-routed to another part of Duke University Medical Center (DUMC). Upon receiving these re-routed e-mails we have tried to contact the senders. We sincerely apologize for this delay.

We are indebted to the individuals and families that are interested and participate in this very important study. Please know that we remain available to you and your family. Our toll free number is (800) 283-4316, Monday through Friday 8:30 a.m. to 4:30 p.m. eastern standard time (EST).

A Reminder

We would also like to take this opportunity to emphasize that our research is concentrated on studying genetic causes of Chiari type 1 and syringomyelia. With research as our primary focus, we are not in a position to communicate medical advice. If you are seeking specific information regarding clinical or surgical outcomes, or are interested in obtaining information about particular institutions or physicians, please contact ASAP directly.

Acknowledgements

This research is supported in part by grants from the Bobby Jones Open Fund, the National Institutes of Health (NS26630) and a generous research grant from the American Syringomyelia Alliance Project (ASAP).