Neurologic Injuries in Adults With Urea Cycle Disorders

Assessing Neural Mechanisms of Injury in Inborn Errors of Urea Metabolism Using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy

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.

Study Overview

• Status: Completed
• Conditions: Brain Diseases, Metabolic, Inborn; Ornithine Transcarbamylase Deficiency; Urea Cycle Disorder

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.

• Study Type: Observational
• Enrollment (Actual): 46

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Georgetown University
    • Washington, District of Columbia, United States, 20037
      • George Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Glutamine and Myoinositol by MRS	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).	one time measurement at study baseline
Functional MRI Activation in N-Back Tast	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.	one time measurement at study baseline
Fractional Anisotropy	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.	one time measurement at study baseline

Collaborators and Investigators

• Sponsor: Andrea Gropman
• Collaborators: National Center for Research Resources (NCRR); Rare Diseases Clinical Research Network; Office of Rare Diseases (ORD)

Publications and helpful links

General Publications

• Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004 Jan;55(1):80-6. doi: 10.1002/ana.10794.
• Kurihara A, Takanashi Ji, Tomita M, Kobayashi K, Ogawa A, Kanazawa M, Yamamoto S, Kohno Y. Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency. Brain Dev. 2003 Jan;25(1):40-4. doi: 10.1016/s0387-7604(02)00153-5.
• McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet. 2000 Aug 14;93(4):313-9. doi: 10.1002/1096-8628(20000814)93:43.0.co;2-m.

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (ACTUAL): July 1, 2009
• Study Completion (ACTUAL): July 1, 2010

Study Registration Dates

• First Submitted: May 11, 2007
• First Submitted That Met QC Criteria: May 11, 2007
• First Posted (ESTIMATE): May 14, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): June 24, 2015
• Last Update Submitted That Met QC Criteria: May 28, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: UCD; Ammonia; Inborn Errors; OTCD; Urea Metabolism
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Amino Acid Metabolism, Inborn Errors; Brain Diseases; Metabolic Diseases; Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn
• Other Study ID Numbers: RDCRN 5104; U54RR019453 (U.S. NIH Grant/Contract)