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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.
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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 |
| Jeffrey M. Stajich, PA-C |
Physician Assistant |
| Heidi Cope, MS, CGC |
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
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
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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. 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
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).
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CM Research Newsletters
 News About Chiari Research, Spring 2012
To obtain a print copy through the mail please call 1-(877) 825-1694,
or e-mail
chiari@chg.duhs.duke.edu to receive a copy.
CHG CM1/S research information contact:
CM Patient Coordinator
Phone: (toll free)(877) 825-1694
Phone: (919) 684-0767
E-mail: chiari@chg.duhs.duke.edu
NTD Support Groups and Information Sources
American Syringomyelia Alliance Project (ASAP)
The ASAP national network, founded in 1988, offers support, networking,
and information for individuals with syringomyelia.
PO Box 1586
Longview, TX 75606-1586
Phone: (toll free) (800) 272-7282
Phone: (903) 236-7079
Fax (903) 757-7456
Canadian Syringomyelia Network
69 Penny Crescent
Markham, Ontario L3P 5X7
Contact Person: Barbara Forrestall, Chair and Founder
Phone: (905) 471-8278
Fax: (905) 882-8367
E-mail: barb@csn.ca
National Organization for Rare Disorders
PO Box 8923
New Fairfield, CT 06812-8923
Phone: (800) 999-6673 toll-free; (203) 746-6518
National Institute of Neurological Disorders and Stroke (NIH-NINDS)
Federal Building, Room 814
7550 Wisconsin Avenue
Bethesda, MD 20892
Phone: (301) 496-5821
Fax: (301) 402-0302
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