Genetic Analysis of the Chiari I Malformation

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.

Study Overview

• Status: Completed
• Conditions: 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.

• Study Type: Observational
• Enrollment (Actual): 152

Contacts and Locations

Study Locations

• Russian Federation
  • Kazan, Russian Federation
    • Kazan State Medical University
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Family Members; At least 2 family members of a patient with a confirmed diagnosis of Chiari I malformation.
Patients; Patient with a confirmed diagnosis of Chiari I malformation who has a family member with syringomyelia or Chiari I malformation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Family Pedigree/Genetic Linkage	Establish family pedigrees and undertake genetic linkage analysis that will identify gene loci associated with the Chiari I malformation andunderdevelopment of the bone forming the posterior cranial fossa.	ongoing
Genetic Analysis	Genetic analysis of the genomic DNA will be performed with DNA polymorphic markers to identify chromosomal loci linked to the Chiari I and small posterior fossa phenotype.	Genetic Analysis ongoing

Collaborators and Investigators

• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: John D Heiss, M.D., National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2001

Study Registration Dates

• First Submitted: February 26, 2000
• First Submitted That Met QC Criteria: February 26, 2000
• First Posted (Estimated): February 28, 2000

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 17, 2024

More Information

Terms related to this study

• Keywords: Genetics; Natural History; Skeletal Dysplasia; Syringomyelia; Arnold Chiari Malformation
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Nervous System Malformations; Neural Tube Defects; Congenital Abnormalities; Syringomyelia; Arnold-Chiari Malformation
• Other Study ID Numbers: 000089; 00-N-0089

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No