Urea Cycle Disorders Clinical Trial
— UCDOfficial title:
Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders
NCT number | NCT02935283 |
Other study ID # | UCD 5113 |
Secondary ID | |
Status | Recruiting |
Phase | |
First received | |
Last updated | |
Start date | August 2016 |
Est. completion date | December 2025 |
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.
Status | Recruiting |
Enrollment | 56 |
Est. completion date | December 2025 |
Est. primary completion date | July 2025 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 7 Years to 50 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
United States | Children's Research Institute | Washington | District of Columbia |
Lead Sponsor | Collaborator |
---|---|
Children's National Research Institute | Boston Children's Hospital |
United States,
Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase d — View Citation
Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol. 2010 Oct;3 — View Citation
Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, Rigas A, Hussain R, VanMeter J. Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Hum Brain Mapp. 2013 Apr;34(4):753-61. doi: 10 — View Citation
Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM. MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology. 2003 Jun;45(6):393-9. doi: 10.1007/s00234-003-0955-7. Epub 2003 May 8. — View Citation
Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. 2010 Jan;42(1):49-52. doi: 10.1016/j.pediatrneurol.2009.07.017. — View Citation
Pacheco-Colon I, Washington SD, Sprouse C, Helman G, Gropman AL, VanMeter JW. Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency. PLoS One. 2015 Jun 11;10(6):e0129595. doi: 10.1371/journal — View Citation
Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, Lemons C, Baumgartner M, Cederbaum S, Diaz GA, Feigenbaum A, Gallagher RC, Harding CO, Kerr DS, Lanpher B, Lee B, Lichter-Konecki U, McCandless SE, Merritt JL, Oster-Granite ML, Seashore MR, Stricker — View Citation
Shapiro E, Bernstein J, Adams HR, Barbier AJ, Buracchio T, Como P, Delaney KA, Eichler F, Goldsmith JC, Hogan M, Kovacs S, Mink JW, Odenkirchen J, Parisi MA, Skrinar A, Waisbren SE, Mulberg AE. Neurocognitive clinical outcome assessments for inborn errors — View Citation
Sprouse C, King J, Helman G, Pacheco-Colon I, Shattuck K, Breeden A, Seltzer R, VanMeter JW, Gropman AL. Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol Genet Metab. 2014 Sep-Oct;113(1- — View Citation
Waisbren SE, He J, McCarter R. Assessing Psychological Functioning in Metabolic Disorders: Validation of the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for Identification — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change in 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 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 | |
Primary | Change in 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. | baseline and 2 year follow up | |
Secondary | Change in behavioral testing results | correlation of the findings from neuroimaging with cognitive functioning that assesses executive function | baseline and 2 year follow up |
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