Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

NCT02935283 | Recruiting DMC

• 1 other identifier: UCD 5113
• Study Type: observational
• Target: 56
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Urea Cycle Disorders

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (1)

• Change in behavioral testing results

  baseline and 2 year follow up

Study Arms (4)

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; Behavioral: Behavioral

Normal controls

Healthy males or females without known medical or metabolic disorder (control group) who can undergo MRI and behavioral testing

Procedure: MRI; Behavioral: Behavioral

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; Behavioral: Behavioral

Distal UCD

Males and females with ASSD and ASLD who can undergo MRI and behavioral testing

Procedure: MRI; Behavioral: Behavioral

Interventions

MRI PROCEDURE

MRI, fMRI, 1H MRS, DTI

Distal UCD; HA recovery group; Normal controls; OTCD participants

Behavioral BEHAVIORAL

Battery of executive function tasks

Also known as: cognitive testing, Neuropsychological testing

Distal UCD; HA recovery group; Normal controls; OTCD participants

Eligibility Criteria

• Age: 7 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

• 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
• Ability to undergo MRI without sedation
• Ages 7 - 50 years
• Ability to provide informed consent or assent to the procedures
• Healthy controls (age and gender matched)
• Males and females with a UCD who are having an acute metabolic crisis, with ammonia levels between 100-300 µM
• 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
• Age range 7-30 years
• Able to undergo neuroimaging safely (i.e. without ferromagnetic devices)
• Sexually active female of childbearing potential must agree to urine pregnancy test
• Admitted to the hospital for treatment of HA at one of the 4 sites for this study
• Can be subjects who were originally enrolled in aim 1 who then have HA (they will cross over to aim 2)
• Confirmed diagnosis of arginosuccinate ASSD, and ASLD by genotype and/or enzyme analysis or healthy age and gender matched control
• Ability to undergo MRI without sedation
• Age 7 - 30 years

You may not qualify if:

• Inability to undergo MRI without sedation
• Metal implants, including orthodontic braces
• Other health conditions contra-indicated in MRI
• Medically unstable at time of scheduled research visit
• Unable to provide informed consent or assent to the procedures
• Ammonia level \> 300 µM, or \<100 µM
• Presence of coma and/or inability to maintain a patent airway
• Age \<7 or \>30 years
• Subject with ferromagnetic device that precludes safe MRI imaging
• Pregnant female
• Unstable medically, at risk for decompensations
• 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
• Inability to undergo MRI without sedation
• Metal implants, including orthodontic braces

Sponsors & Collaborators

• Children's National Research Institute: lead
• Boston Children's Hospital: collaborator

Study Sites (1)

Children's Research Institute

Washington D.C., District of Columbia, 20010, United States

RECRUITING

Related Publications (10)

• 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.pone.0129595. eCollection 2015.

  PMID: 26067829 RESULT

• 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(1-2):136-41. doi: 10.1016/j.ymgme.2014.05.007. Epub 2014 May 20.

  PMID: 24881970 RESULT

• 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: 10.1002/hbm.21470. Epub 2011 Nov 23.

  PMID: 22110002 RESULT

• 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;31(9):1719-23. doi: 10.3174/ajnr.A2122. Epub 2010 May 20.

  PMID: 20488904 RESULT

• 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.

  PMID: 20004862 RESULT

• 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 deficiency. Mol Genet Metab. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26.

  PMID: 18662894 RESULT

• 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 of metabolism and other rare conditions. Mol Genet Metab. 2016 Jun;118(2):65-9. doi: 10.1016/j.ymgme.2016.04.006. Epub 2016 Apr 14.

  PMID: 27132782 RESULT

• 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 of Individuals at Risk. JIMD Rep. 2015;21:35-43. doi: 10.1007/8904_2014_373. Epub 2015 Feb 25.

  PMID: 25712381 RESULT

• 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 T, Summar M, Waisbren S, Yudkoff M, Batshaw ML. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S97-105. doi: 10.1016/j.ymgme.2010.01.014. Epub 2010 Feb 10.

  PMID: 20188616 RESULT

• 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.

  PMID: 12736767 RESULT

MeSH Terms

Conditions

Urea Cycle Disorders, Inborn

Interventions

Neuropsychological Tests

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Psychological Tests; Behavioral Disciplines and Activities

Study Officials

• Andrea L. Gropman, M.D.

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrea L Gropman, M.D.

CONTACT

202-476-3511; agropman@childrensnational.org

Andrea L. Gropman, M.D.

CONTACT

202-476-3511

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Division of Neurogenetics and Developmental Pediatrics

Study Record Dates

• First Submitted: May 12, 2016
• First Posted: October 17, 2016
• Study Start: August 1, 2016
• Primary Completion: July 1, 2025
• Study Completion: December 1, 2025
• Last Updated: June 25, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR
• Time Frame: One year after study completion and available for 5 years

Locations

US (1)