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Genetic Analysis of the Chiari I Malformation

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ClinicalTrials.gov Identifier: NCT00004738
Recruitment Status : Completed
First Posted : February 28, 2000
Last Update Posted : July 28, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Brief Summary:

The purpose of this study is to better understand the genetic factors related to the Chiari I malformation. In people with this abnormality, the lower part of the skull is smaller than normal. As a result, the lowest part of the brain, called the cerebellar tonsils, protrudes out of the hole at the bottom of the skull into the spinal canal. This study will try to discover the location of the genes responsible for the malformation.

Candidates for this study are: 1) Patients with Chiari I malformation who also have a family member with the abnormality or a family member with syringomyelia (a cyst in the spinal cord that is often associated with the Chiari I malformation). 2) Family members of patients with the Chiari I malformation.

Participants will have a medical history and physical and neurologic examinations. They will undergo magnetic resonance imaging (MRI) of the brain and cervical (neck) spinal cord to measure the size of the head and determine the presence of the Chiari I malformation and syringomyelia. A small blood sample (about 2 tablespoons) will be drawn for DNA studies relating to the Chiari I malformation.


Condition or disease
Syringomyelia Type I Arnold Chiari Malformation

Detailed Description:

Objectives: The goal of this study is to establish family pedigrees and undertake genetic linkage analysis that will identify gene loci associated with the Chiari I malformation and underdevelopment of the bone forming the posterior cranial fossa.

Study Population: Patients and family members of patients with the Chiari I malformation. Because the research institutions are located in the United States and Russia, subjects will be recruited predominantly from these countries.

Design: Human subjects will undergo 1) neurologic examinations, 2) head and cervical MRI scans to evaluate for the Chiari I malformation, syringomyelia, and maldevelopment of the posterior fossa, and 3) isolation and analysis of genomic DNA from whole blood for linkage analysis.

Outcome Measures: Pedigrees will be established based on the MRI findings. The Chiari I phenotype will be defined as the caudal portion of the cerebellar tonsils lying greater than or equal to 2 mm below the foramen magnum and underdevelopment of the bone of the posterior fossa will be defined as 1) obliteration of the CSF pathways in the inferior portion of the posterior fossa, 2) posterior fossa volume to supratentorial volume ratio of less than or equal to 15%, or 3) abnormal shortening of the bones of the skull base. Genetic analysis of the genomic DNA will be performed with DNA polymorphic markers to identify chromosomal loci linked to the small posterior fossa phenotype. A lod score of 3.0 (equivalent to 1000:1 odds in favor of linkage) will be taken as proof that the Chiari I gene maps to the same genetic region of the human genome as a given DNA marker.

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Study Type : Observational
Actual Enrollment : 152 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Genetic Analysis of the Chiari I Malformation
Actual Study Start Date : February 14, 2000


Group/Cohort
Chiari 1 Phenotype
The "Chiari I-small Posterior Fossa" phenotype will be defined by an underdeveloped posterior fossa with the Chiari I malformation.
Normal Phenotype
Normal ratio volume of posterior fossa to volume of neural elements
Underdeveloped Posterior Fossa Phenotype
The "Underdeveloped Posterior Fossa" phenotype will be defined by an underdevelopedposterior fossa without the Chiari I malformation.



Primary Outcome Measures :
  1. Genetic Analysis [ Time Frame: ongoing ]
    Establish family pedigrees and undertake genetic linkage analysis that will identify geneloci associated with the Chiari I malformation andunderdevelopment of the bone forming the posterior cranial fossa. Genetic analysis of the genomic DNA will be performed with DNApolymorphic markers to identify chromosomal loci linked to the Chiari I and small posterior fossa phenotype.


Secondary Outcome Measures :
  1. lod score [ Time Frame: ongoing ]
    A lod score of 3.0 (equivalent to 1000:1 odds in favor of linkage) will be taken as proof that the Chiari I gene maps to the same genetic region of the human genome as a given DNA marker.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients and family members of patients with the Chiari I malformation. Because the research institutions are located in the United States and Russia, subjects will be recruited predominantly from these countries.
Criteria
  • INCLUSION CRITERIA:

To be eligible for entry into the study, a candidate must meet the following criteria:

Patient with a confirmed diagnosis of Chiari I malformation who has a family member with syringomyelia or Chiari I malformation, or

Family member of a patient with a confirmed diagnosis of Chiari I malformation, AND

There are at least two family members diagnosed with Chiari I malformation.

If an adult, able to give informed consent; if a minor, has an adult who is legally responsible for the subject and who is able to give consent.

EXCLUSION CRITERIA:

A candidate will be excluded if he/she:

Has a contraindication to MRI scanning.

Is unable to comprehend the risks of the testing.

Is less than one year of age.

Cannot undergo MRI scanning without sedation.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00004738


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Russian Federation
Kazan State Medical University
Tartar Republic, Russian Federation
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: John D Heiss, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
Additional Information:
Publications:
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Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT00004738    
Other Study ID Numbers: 000089
00-N-0089
First Posted: February 28, 2000    Key Record Dates
Last Update Posted: July 28, 2020
Last Verified: July 24, 2020
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
Arnold Chiari Malformation
Skeletal Dysplasia
Syringomyelia
Genetics
Chiari I Malformation
Additional relevant MeSH terms:
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Arnold-Chiari Malformation
Syringomyelia
Congenital Abnormalities
Neural Tube Defects
Nervous System Malformations
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases