Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders (UCD)

February 11, 2023 updated by: Andrea Gropman, Children's National Research Institute
In proximal urea cycle disorders (UCD), particularly ornithine transcarbamylase deficiency (OTCD), hyperammonemia (HA) causes increased brain glutamine (Gln) which perturbation is thought to be at the core of the neurological injury. In contrast, in distal UCD such as citrullinemia (argininosuccinate synthetase deficiency; (ASSD) and argininosuccinic aciduria (argininosuccinate lyase deficiency); (ASLD) cognitive impairment and neuropsychiatric disease are common even in the absence of acute HA. As a consequence, both citrulline and argininosuccinate (ASA) or their metabolic products have been implicated as neurotoxic. In this project the investigators will use state-of- the-art neuroimaging and neuropsychological methods to investigate whether patients with OTCD have chronically elevated brain Gln and reduced myo-inositol (mI) levels that correlate with regional brain structural abnormalities and neurocognitive dysfunction. The researchers will further investigate whether during an acute episode of HA elevated brain Gln and decreased mI levels correlate with the magnitude of cytotoxic edema and whether a Gln/mI ratio threshold can be identified at which the cytotoxic edema is followed by cell loss. Finally, the researchers will investigate whether regions of brain damage in ASSD and/or ASLD are distinct from those in OTCD and compare brain Gln levels in ASSD and ASLD in the absence of HA to those in OTCD. The investigators will also seek to determine if brain citrulline and ASA can be identified in the brains of patients with distal UCD and whether they correlate with brain abnormalities seen in MRI and neuropsychological testing. This project will elucidate the chronology of brain pathology both in acute hyperammonemia and chronic UCD and whether, proximal and distal UCD differ in their pathophysiology of brain damage.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

This study will be separated into three sections. The first study will study longitudinal changes in OTCD. The second section will study the recovery of OTCD participants from a hyperammonemic episode over time. The third section will be a longitudinal study of the distal urea cycle disorders. In all cases, participants in this study will attend an initial study visit that will include a review of medical history, current symptoms, impairments, and diet history; 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 1-2-day period. This will include standard MRI studies and four sessions consisting of functional MRI (fMRI) (CNMC only), 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 multiple time point participation. The study will be conducted at Children's National Medical Center and Boston Children's Hospital.

Study Type

Observational

Enrollment (Anticipated)

56

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
        • Recruiting
        • Children's Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

7 years to 50 years (ADULT, CHILD)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Participants have a urea cycle disorder or are healthy controls ages 7-30 years, male and female. Participants who have had a recent hyperammonemic episode are eligible for a more detailed analysis.

Description

Inclusion Criteria:

Inclusion criteria for group 1:

  1. Confirmed diagnosis of ornithine transcarbamylase deficiency (OTCD) by genetic analysis (genotype) and/or enzyme analysis with at least a single episode of HA hyperammonemic (HA) encephalopathy
  2. Ability to undergo MRI without sedation
  3. Ages 7 - 50 years
  4. Ability to provide informed consent or assent to the procedures
  5. Healthy controls (age and gender matched)

Inclusion criteria for group 2:

  1. Males and females with a UCD who are having an acute metabolic crisis, with ammonia levels between 100-300 µM
  2. Subjects must be awake, and not comatose and able to maintain patent airway on their own and in the opinion of the examining physician, medically stable without risk for acute decompensation and must continue to be stable based on visual contact, vital sign measurement and voice contact with subjects while in the scanner
  3. Age range 7-30 years
  4. Able to undergo neuroimaging safely (i.e. without ferromagnetic devices)
  5. Sexually active female of childbearing potential must agree to urine pregnancy test
  6. Admitted to the hospital for treatment of HA at one of the 4 sites for this study
  7. Can be subjects who were originally enrolled in aim 1 who then have HA (they will cross over to aim 2)

Inclusion criteria for group 3

  1. Confirmed diagnosis of arginosuccinate ASSD, and ASLD by genotype and/or enzyme analysis or healthy age and gender matched control
  2. Ability to undergo MRI without sedation
  3. Age 7 - 30 years
  4. Able to provide informed consent or assent to the procedures

Exclusion Criteria:

Exclusion Criteria for group 1:

  1. Inability to undergo MRI without sedation
  2. Metal implants, including orthodontic braces
  3. Other health conditions contra-indicated in MRI
  4. Medically unstable at time of scheduled research visit
  5. Unable to provide informed consent or assent to the procedures

Exclusion criteria for group 2:

  1. Ammonia level > 300 µM, or <100 µM
  2. Presence of coma and/or inability to maintain a patent airway
  3. Age <7 or >30 years
  4. Subject with ferromagnetic device that precludes safe MRI imaging
  5. Pregnant female
  6. Unstable medically, at risk for decompensations
  7. Combative, or severely neurologically compromised irrespective of ammonia level and showing declining medical status in the scanner based on visual, voice contact and electronic HR monitoring.

Subjects must be awake, and not comatose and able to maintain patent airway on their own

Exclusion criteria for group 3:

  1. Inability to undergo MRI without sedation
  2. Metal implants, including orthodontic braces
  3. Other health conditions contra-indicated for MRI
  4. Medically unstable at time of scheduled research visit
  5. Unable to provide informed consent or assent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
OTCD participants
Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD who can undergo MRI and behavioral testing
Procedure: MRI
MRI, fMRI, 1H MRS, DTI
Behavioral: Behavioral
Battery of executive function tasks
Other Names:
  • cognitive testing, Neuropsychological testing
Normal controls
Healthy males or females without known medical or metabolic disorder (control group) who can undergo MRI and behavioral testing
Procedure: MRI
MRI, fMRI, 1H MRS, DTI
Behavioral: Behavioral
Battery of executive function tasks
Other Names:
  • cognitive testing, Neuropsychological testing
HA recovery group
Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD or participants with CPS-1 who have had a recent hyperammonemic episode who can undergo MRI and behavioral testing
Procedure: MRI
MRI, fMRI, 1H MRS, DTI
Behavioral: Behavioral
Battery of executive function tasks
Other Names:
  • cognitive testing, Neuropsychological testing
Distal UCD
Males and females with ASSD and ASLD who can undergo MRI and behavioral testing
Procedure: MRI
MRI, fMRI, 1H MRS, DTI
Behavioral: Behavioral
Battery of executive function tasks
Other Names:
  • cognitive testing, Neuropsychological testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Concentration of Glutamine and Myoinositol by MRS
Time Frame: baseline and 2year follow up

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 protocols used 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).
baseline and 2year follow up
Change in Fractional Anisotropy
Time Frame: baseline and 2 year follow up
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.
baseline and 2 year follow up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in behavioral testing results
Time Frame: baseline and 2 year follow up
correlation of the findings from neuroimaging with cognitive functioning that assesses executive function
baseline and 2 year follow up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's National Research Institute

Collaborators

Boston Children's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2016

Primary Completion (ANTICIPATED)

July 1, 2025

Study Completion (ANTICIPATED)

December 1, 2025

Study Registration Dates

First Submitted

May 12, 2016

First Submitted That Met QC Criteria

October 13, 2016

First Posted (ESTIMATE)

October 17, 2016

Study Record Updates

Last Update Posted (ESTIMATE)

February 14, 2023

Last Update Submitted That Met QC Criteria

February 11, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UCD 5113

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be kept on UCD website and released after study completion

IPD Sharing Time Frame

One year after study completion and available for 5 years

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • CSR

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Urea Cycle Disorders

Clinical Trials on MRI

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Peru

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe