Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Urea Cycle Disorders Clinical Trial

— UCD  

Official title:

Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02935283
• Other study ID #: UCD 5113
• Status: Recruiting
• Start date: August 2016
• Est. completion date: December 2025

Study information

• Verified date: February 2023
• Source: Children's National Research Institute
• Contact: Andrea L Gropman, M.D.
• Phone: 202-476-3511
• Email: agropman[@]childrensnational.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• 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

Related Conditions & MeSH terms

• Urea Cycle Disorders
• Urea Cycle Disorders, Inborn

Intervention

Procedure:
• MRI
MRI, fMRI, 1H MRS, DTI

Behavioral:
• Behavioral
Battery of executive function tasks

Locations

Country	Name	City	State
United States	Children's Research Institute	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Children's National Research Institute	Boston Children's Hospital

Country where clinical trial is conducted

United States, 

References & Publications (10)

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

Outcome

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