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Neurologic Injuries in Adults With Urea Cycle Disorders

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00472732
Recruitment Status : Completed
First Posted : May 14, 2007
Results First Posted : May 29, 2015
Last Update Posted : June 24, 2015
Office of Rare Diseases (ORD)
Rare Diseases Clinical Research Network
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
Andrea Gropman, Children's Research Institute

Brief Summary:
Urea cycle disorders (UCDs) are a group of rare inherited metabolism disorders. The purpose of this study is to evaluate how UCD-related neurologic injuries affect adults with one of the most common types of UCD.

Condition or disease
Brain Diseases, Metabolic, Inborn Urea Cycle Disorder Ornithine Transcarbamylase Deficiency

Detailed Description:

UCDs are a group of rare genetic diseases that affect how protein is broken down in the body. The cause of UCDs is a deficiency in one of eight enzymes responsible for removing ammonia, a waste product of protein metabolism, from the bloodstream. Normally, ammonia is converted into urea and then removed from the body in the form of urine. However, in people with UCDs, ammonia accumulates unchecked and is not removed from the body. Toxic levels of ammonia can build up and cause irreversible neurologic damage that can affect metabolism, cognition, sensation, and movement. This study will focus on the most common enzyme disorder among UCDs, ornithine transcarbamylase deficiency (OTCD), a disorder inherited from mothers. Using different types of magnetic resonance imaging (MRI), this study will evaluate how UCD-related neurologic injuries affect metabolism, cognition, sensation, and movement in adults with OTCD.

Participants in this study will attend an initial study visit that will include a review of medical history, current symptoms, impairments, and diet history; urine and blood collection; a physical exam; a full neurological exam; and cognitive and motor testing. During this visit, participants will undergo imaging studies and additional cognitive and motor testing over a 2- to 3-day period. This will include standard MRI studies and four sessions consisting of functional MRI (fMRI), diffusion tensor imaging, and 1H magnetic resonance spectroscopy. For the fMRI study, participants perform various motor and behavioral tasks while in the imaging scanner. Magnetic resonance spectroscopy (MRS) is used to study and evaluate the chemical makeup of specific brain areas. Diffusion tensor imaging is used to assess myelination of major brain pathways and their alteration in disease states. This study will involve one-time participation. There will be no follow-up visits for this study.

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Study Type : Observational
Actual Enrollment : 46 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Assessing Neural Mechanisms of Injury in Inborn Errors of Urea Metabolism Using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy
Study Start Date : March 2007
Actual Primary Completion Date : July 2009
Actual Study Completion Date : July 2010

Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD
Healthy males or females without known medical or metabolic disorder (control group)

Primary Outcome Measures :
  1. Concentration of Glutamine and Myoinositol by MRS [ Time Frame: one time measurement at study baseline ]

    Concentration based on area under curve on 1H MRS and quantitated by LCModel. A metabolite's tissue concentration is related to the integrated amplitude of the MRS signal it produces. Integrated amplitude is the area under the MRS signal curve. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocol we use selects 257 averages. This means, 257 free induction decays. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point.

    Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM).

  2. Functional MRI Activation in N-Back Tast [ Time Frame: one time measurement at study baseline ]
    Measure of blood oxygen level dependent (BOLD) signal of OTCD patients and healthy controls during an N-Back task comparing 2-back and 1-back conditions. This contrast was created for each participant using SPM and then entered into a group analysis in which we compare percent signal change between groups. Therefore, we never see BOLD signal change at the individual level, which is why we never see "scores" or numbers at the individual level and we cannot calculate a measure of dispersion for this data.

  3. Fractional Anisotropy [ Time Frame: one time measurement at study baseline ]
    Measure of white matter integrity in OTCD Patients and Controls in frontal white matter. Fractional anisotropy values fall on a scale of 0 to 1, with 0 meaning that the diffusion of water is isotropic and unrestricted, or equally restricted, in all directions and with 1 meaning that diffusion occurs along only one axis and is fully restricted along all other directions. Scores closer to 1 are associated with intact white matter while scores closer to 0 are associated with white matter damage.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD

Inclusion Criteria for Participants with OTCD:

  • Diagnosis of OTCD or heterozygote state of OTCD by metabolic or molecular means. Female participants must be clinically stable and heterozygous for OTCD. Male participants must be hemizygous for late onset OTCD.

Inclusion Criteria for Healthy Controls:

  • No known medical or metabolic disorder

Inclusion Criteria for All Participants:

  • IQ of at least 80
  • Willing to travel to study site
  • English-speaking
  • Age between 18 and 60 years

Exclusion Criteria for All Participants:

  • Currently being treated for an acute illness
  • History of neuropsychiatric drug use
  • Unable to undergo MRI scanning without being sedated
  • Unable to participate in neurocognitive and/or motor testing
  • Metal device in body that might interfere with MRI scanning
  • Pregnancy or breastfeeding

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 identifier (NCT number): NCT00472732

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United States, District of Columbia
George Washington University School of Medicine
Washington, District of Columbia, United States, 20037
Georgetown University
Washington, District of Columbia, United States, 20057
Sponsors and Collaborators
Andrea Gropman
Office of Rare Diseases (ORD)
Rare Diseases Clinical Research Network
National Center for Research Resources (NCRR)
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Study Chair: Andrea Gropman, MD Children's Research Institute

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Responsible Party: Andrea Gropman, MD, Children's Research Institute Identifier: NCT00472732     History of Changes
Other Study ID Numbers: RDCRN 5104
U54RR019453 ( U.S. NIH Grant/Contract )
First Posted: May 14, 2007    Key Record Dates
Results First Posted: May 29, 2015
Last Update Posted: June 24, 2015
Last Verified: May 2015
Keywords provided by Andrea Gropman, Children's Research Institute:
Urea Metabolism
Inborn Errors
Additional relevant MeSH terms:
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Brain Diseases
Urea Cycle Disorders, Inborn
Ornithine Carbamoyltransferase Deficiency Disease
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Metabolic Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Genetic Diseases, X-Linked