Genetics and Chiari Malformations and Syringomyelia

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Chiari type 1 malformations (CM1) occur in the region where the brain and the spinal cord join. In this disorder, the portions of the brain called the cerebellum and/or brainstem lie lower than usual. Often, a portion of the cerebellum called the cerebellar tonsils protrudes out of the base of the skull into the spinal canal. This protrusion causes pressure in the brain, contributing to the symptoms people experience. The cause of CM1 is not known. Some CM1 cases are believed to be present at birth. There are many symptoms associated with CM1. These symptoms may include headaches, especially at the base of the skull, dizziness, double vision, weakness in the arms, and/or difficulty walking. When symptoms are present, they are often vague or nonspecific. As a result, the diagnosis of CM1 is often delayed until more severe symptoms present themselves or after current symptoms persist for some time.

Syringomyelia is a condition characterized by a syrinx (fluid-filled cyst) in the spinal cord. In some instances, syringomyelia is caused by an injury. However, there are also some cases that are congenital (present at birth). Often, patients with CM1 are also diagnosed with syringomyelia.

The Center for Human Genetics, in collaboration with Dr. Thomas Milhorat and colleagues of North Shore University Hospital/Manhasset NY and the American Syringomyelia Alliance Project, is investigating the hereditary basis of Chiari type I malformations with or without syringomyelia. Our research is aimed at learning if CM1/S is indeed caused by factors inherited through the family and, if so, which genes are involved. Although our current data show evidence for CM1/S "running" (or clustering) in some families, we cannot say how often this phenomenon occurs or even whether this is truly due to inherited factors called genes.

CM1/S Research Review

Step 1 of the CM1/S research study involved gathering preliminary data that supported the idea that CM1 and syringomyelia show familial aggregation (or "familial clustering") in some individuals and families. More than 150 families joined the initial phase of the CM1/S research study and provided detailed family histories and blood samples. Together with Dr. Thomas Milhorat, leader of the American Syringomyelia Alliance Project (ASAP) Medical Advisory Board, we reported familial aggregation in a large study of 364 CM1/S patients. Of these study participants, 21 of the patients' families had two or more cases of CM1/S within the family. Thanks to all of the families who generously participated in the study, we successfully accomplished the first step of the genetic research: showing familial aggregation of CM1/S.

We have continued Step 1 of the CM1/S research study by expanding the number of families in our data set who have two or more members diagnosed with CM/S. We continue to hunt for genes that may cause CM1/S through large-scale genome screening and candidate gene analysis in the laboratory. We are actively recruiting new families for this phase of our research.

Step 2 of the research study involved providing scientific evidence that familial aggregation means a gene causing CM1/S is being passed down from generation to generation. While focusing on families in which two or more members were diagnosed with CM1/S, this phase of our research involved performing MRIs on appropriate first-degree relatives (parents, siblings and children) to determine if these individuals had CM1/S regardless of symptoms. Although the MRI portion of this research phase is complete, the data continues to be analyzed and combined with DNA data by our research scientists. This analysis continues in the hopes of increasing the probability of finding evidence that CM1 and/or syringomyelia are linked to regions on a chromosome(s). We are well on the way to answering the fundamental question, "Is the genetic transmission of this ma lformation real?"

Completion of this second step will pave the way to the remaining steps: locating the gene or genes associated with CM1/S, characterizing the CM1/S gene(s), understanding how the gene(s) may cause CM1/S, and determining if a CM1/S genetic test is feasible or useful.

A separate sub-study now underway is an MRI review study in which we have begun to review multiple skull measurements among CM1 patients to define characteristic skull size and shape among individuals with CM1. This study will hopefully aid in a more detailed classification of the disorder.

There has been an overwhelming response from individuals and families about this research study. We are greatly encouraged by this outpouring of interest and support for this research project. Together we can continue to push forward the research efforts and begin to understand the causes and natural progression of CM1/S.

CHG CM1/S Study Team
Allison Ashley-Koch, PhD Co-Principal Investigator and Genetic Epidemiologist
Simon Gregory, PhD Co-Principal Investigator and Molecular Geneticist
David Enterline, MD Neuroradiologist
Timothy George, MD Pediatric Neurosurgeon
Deborah Siegel Study Coordinator

Collaborators

Thomas H. Milhorat, MD
Principal Investigator, Professor and Chair, Department of Neurosurgery at North Shore University Hospital, Manhasset, New York

Bermans Iskandar, MD
Neurosurgeon, University of Wisconsin Medical School

Ulrich Batzdorf, MD
Neurosurgeon, University of California Los Angeles (UCLA)

Richard Ellenbogen, MD
Neurosurgeon, University of Washington School of Medicine

John Oro, MD
Neurosurgeon, University of Missouri


CHG Publications on CM1/S

As CHG researchers and collaborators continue to define the genetic causes of CM1/S, they publish their findings in leading academic journals and share their knowledge with colleagues at meetings and conferences.

CM1/S Research Publications

CM1/S Study Participation

The Duke Center for Human Genetics is actively recruiting families who have TWO OR MORE family members with Chiari malformations, with or without syringomyelia. These family members must be related to each other by blood, and BOTH must be willing to participate. At the current time, we are NOT accepting families in which the only diagnosed members are a parent and child. These study guidelines may be updated periodically and we encourage you to visit our web site in the future.

Study participation by at least two diagnosed family members involves these steps:

* Contact our patient coordinator.
* Answer questions about family and medical history.
* Complete a medical questionnaire.
* Provide a photo of yourself.
* Allow Center for Human Genetics researchers to review medical records and MRI to confirm the diagnosis of Chiari malformation.
* Provide a blood sample to the researchers.
* Potentially ask other first-degree family members (parents, siblings, children) to participate in the study.

If your family meets these criteria and you want to receive study participation information, please contact the patient coordinator via e-mail (Note: Please include "Chiari" in the e-mail subject.

CM1/S Patient Coordinator
Phone: (toll free) 1-877-385-2626
E-mail: chiari@chg.duhs.duke.edu

This research has been supported in part by grants from the Bobby Jones Open Fund, the National Institutes of Health HD33400, NS26630 and a generous research grant from the American Syringomyelia Alliance Project (ASAP).