Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI

The purpose of this study is to use various types of MRI and cognitive testing to evaluate changes in the brain and cognitive function that occur in subjects with ornithine transcarbamylase deficiency (OTCD) relative to healthy individuals

Study Overview

• Status: Completed
• Conditions: Ornithine Transcarbamylase Deficiency
• Intervention / Treatment: Other: MRI scanning; Behavioral: Cognitive testing

Detailed Description

The overall goal of this project is to characterize metabolic, structural and cognitive changes in OTCD using 1H MRS, DTI, volumetric averaging and fMRI with cognitive testing of executive function measures to validate biomarkers for the effect of HA and its treatment on the brain.

The investigators will measure gln and mI in blood and brain (using 1H MRS) in affected participants, and mI in brain in controls, fractional anisotropy as a measure of white matter microstructural damage (by DTI) and brain activation pathways alterations with tasks probing working memory (fMRI). As a secondary outcome measure, the investigators will correlate the findings from neuroimaging with cognitive functioning. This protocol is based on the previous 5104 protocol, now includes children to evaluate the age and stage of disease on these indices in a cohort that is undergoing important developmental events against an age matched typically developing cohort.

• Study Type: Observational
• Enrollment (Actual): 49

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Males and females, ages 7-60 years with ornithine transcarbamylase deficiency Males and females, ages 7-60 years who are healthy controls without ornithine transcarbamylase deficiency

Description

Inclusion Criteria:

Subject inclusion criteria:

1. Patients with OTCD;
2. Age range: 7-60 years
3. Able to undergo neuroimaging safely (i.e. without presence of ferromagnetic devices)
4. Subject has a documented full scale IQ > 70

Control participant inclusion criteria:

1. Healthy males and females without metabolic disease aged 7-60 years
2. Subject has a documented full scale IQ > 70

Exclusion Criteria:

Subject exclusion criteria:

1. Mental retardation (i.e., Full Scale IQ< 70)
2. Age range <7 or >60 years
3. Presence of ferromagnetic device(s) that preclude safe imaging
4. Pregnant female

Control exclusion criteria:

1. Subjects with a documented history of an intellectual deficit (i.e., Full Scale IQ< 70)
2. Age range <7 or >60 years
3. Presence of ferromagnetic device(s) that preclude safe imaging
4. Pregnant female

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Subjects with OTCD; males and females ages 7-60 years with OTCD who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing	Other: MRI scanning; 1H MRS, DTI, FMRI; Other Names: MRI; Behavioral: Cognitive testing; Behavioral testing
Healthy controls; males and females ages 7-60 years who are healthy controls who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing	Other: MRI scanning; 1H MRS, DTI, FMRI; Other Names: MRI; Behavioral: Cognitive testing; Behavioral testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Glutamine and Myoinositol	Concentration based on area under curve on 1H Magnetic Resonance Spectroscopy(MRS) and quantitated by LCModel (a method that allows automatic quantitation of spectroscopy data). A metabolite's tissue concentration is related to the integrated amplitude, the area under the curve of the MRS signal, it produces. 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. 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
Functional Connectivity of Assessed by Resting-state fMRI	Investigation of differences in functional connectivity of OTCD patients compared to healthy controls, particularly in the default-mode network (DMN) and the set-maintenance network (SMN). Participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, identified the nodes that comprised each network in each group, and assessed internodal connectivity. For each subject, this analysis generated a correlation value, which reflected the strength of functional connectivity between each ROI pair.The correlation r-values were normalized using Fisher's r-to-Z-transform, generating z-scores. The DMN was composed of 1) anterior cingulate/medial prefrontal cortex (ACC/mPFC), 2) posterior cingulate cortex (PCC), and 3) bilateral inferior parietal lobule (IPL). The SMN was composed of 1)ACC, 2) bilateral superior frontal gyrus (SFG), and 3) bilateral anterior insula/frontal operculum (aI/fO).	Baseline
Fractional Anisotropy Assessed Using DTI	Fractional Anisotropy (FA) is a measure of the diffusion asymmetry within a voxel as defined by its eigenvalues. In our study, FA is being used as a measure of white matter integrity, because FA is very sensitive to small microstructural changes.Fractional anisotropy (FA) is a scalar value between zero and one (0-1) that describe anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychological Assessment	Testing consisted of the Wechsler Abbreviated Scale of Intelligence (WASI), Comprehensive Trail Making Test (CTMT) (range 17-87), and the Behavioral Rating Inventory of Executive Function (BRIEF) (range GEC: 70-210; BRI:39-82 ; MI:41-92). The WASI includes three measures of intelligence; including, performance IQ (sum of block design and matrices sub scales; range: 40-160), verbal IQ (sum of vocabulary and similarities sub scales; range 40-160), and total IQ (sum of all four subscales; range: 80-320). The CTMT measures simple attention and executive function, it consists of five dot to dots that increase with complexity and difficulty. Higher values indicate better outcomes for all scales.	Baseline

Collaborators and Investigators

• Sponsor: Andrea Gropman
• Collaborators: Children's National Research Institute
• Investigators: Principal Investigator: Andrea L Gropman, M.D., Children's National Research Institute

Publications and helpful links

General Publications

• 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.
• Prust MJ, Gropman AL, Hauser N. New frontiers in neuroimaging applications to inborn errors of metabolism. Mol Genet Metab. 2011 Nov;104(3):195-205. doi: 10.1016/j.ymgme.2011.06.020. Epub 2011 Jun 30.
• 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.
• Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S20-30. doi: 10.1016/j.ymgme.2010.01.017. Epub 2010 Feb 13.
• 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.
• Gropman AL, Sailasuta N, Harris KC, Abulseoud O, Ross BD. Ornithine transcarbamylase deficiency with persistent abnormality in cerebral glutamate metabolism in adults. Radiology. 2009 Sep;252(3):833-41. doi: 10.1148/radiol.2523081878. Epub 2009 Jun 30.
• 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.

Helpful Links

• Urea Cycle rare disease consortium

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: March 30, 2012
• First Submitted That Met QC Criteria: April 2, 2012
• First Posted (Estimated): April 3, 2012

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: February 10, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: MRI; cognitive function; Neuroimaging; hyperammonemia; Urea cycle; ornithine transcarbamylase deficiency
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Ornithine Carbamoyltransferase Deficiency Disease
• Other Study ID Numbers: UCRDC 5107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Final data is on the UCDC website