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CompletedNCT01569568Updated Mar 8, 2024Results posted

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

An observational study in Ornithine Transcarbamylase Deficiency, sponsored by Andrea Gropman. Completed. Open to participants aged 7 Years to 60 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-03-08.

Sponsored by Andrea Gropman · Observational

Study type
Observational
Model
Cohort
Time perspective
Prospective
Enrollment
49
Ages
7 Years to 60 Years
Sex
All
01

Study summary

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

Read the 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.

02

Conditions studied

  • Ornithine Transcarbamylase Deficiency

Keywords

  • Neuroimaging
  • MRI
  • Urea cycle
  • hyperammonemia
  • cognitive function
  • ornithine transcarbamylase deficiency
03

In context

Ornithine Carbamoyltransferase Deficiency Disease

35 studies on the registry are indexed under Ornithine Carbamoyltransferase Deficiency Disease; 11 are open to participants now.

This study's enrollment of 49 is below the median of 66 across 20 observational studies indexed under Ornithine Carbamoyltransferase Deficiency Disease.

Browse Ornithine Carbamoyltransferase Deficiency Disease studies →

Lead sponsor

Andrea Gropman is the lead sponsor of 3 studies on the registry; 1 is open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
7 Years to 60 Years
Sexes eligible
All
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

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

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
05

Study design

Observational model
Cohort
Time perspective
Prospective
Enrollment
49 participants (actual)

Groups and cohorts

  • 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 · Behavioral: Cognitive 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 · Behavioral: Cognitive testing

Interventions

  • OtherMRI scanning

    1H MRS, DTI, FMRI

    Also known as: MRI

  • BehavioralCognitive testing

    Behavioral testing

06

What researchers measure

Primary outcomes

  1. 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).

    Time frame: Baseline

  2. 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).

    Time frame: Baseline

  3. 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.

    Time frame: Baseline

Secondary outcomes

  1. 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.

    Time frame: Baseline

07

Results

Posted Apr 14, 2017

Participant flow

Participant flow — Overall Study
MilestoneSubjects With OTCDHealthy Controls
Started2029
Completed2027
Not completed02
Withdrew: Physician decision02

Outcome measures

PrimaryConcentration 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).

Time frame:
Baseline
Reported as:
Mean · mM
Concentration of Glutamine and Myoinositol
mMSubjects With OTCDHealthy Controls
Concentration of glutamine in PWM2.61 ± 1.071.66 ± 0.93
Concentration of myoinositol in PWM2.23 ± 0.842.69 ± 0.48
Concentration of glutamine in PCGM5.22 ± 1.703.62 ± 0.91
Concentration of myoinositol in PCGM3.80 ± 0.804.37 ± 0.46
Statistical analysis
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = 0.001 (This is an uncorrected p-value. A priori threshold is 0.05.)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = 0.011 (This is an uncorrected p-value. A priori significance threshold is 0.05.)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = 0.004 (This is an uncorrected p-value. A priori threshold was 0.05.)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = 0.046 (This is an uncorrected p-value. A priori threshold was 0.05.)
PrimaryFunctional 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).

Time frame:
Baseline
Reported as:
Mean · z-scores
Functional Connectivity of Assessed by Resting-state fMRI
z-scoresSubjects With OTCDHealthy Controls
DMN: ACC/mPFC & left IPL connectivity-0.86 ± 0.700.18 ± 0.30
DMN: ACC/mPFC & PCC connectivity-0.10 ± 0.700.12 ± 0.40
DMN: ACC/mPFC & right IPL connectivity-0.26 ± 0.530.07 ± 0.34
DMN: PCC & left IPL connectivity0.69 ± 0.630.69 ± 0.31
DMN: PCC & right IPL connectivity0.66 ± 0.420.64 ± 0.30
DMN: left IPL & right IPL connectivity0.75 ± 0.690.70 ± 0.34
SMN: ACC & left aI/fO connectivity0.19 ± 0.390.28 ± 0.41
SMN: ACC & left SFG connectivity0.28 ± 0.350.44 ± 0.29
SMN: ACC & right aI/fO connectivity0.21 ± 0.300.44 ± 0.29
SMN: ACC & right SFG connectivity0.29 ± 0.370.59 ± 0.23
SMN: left aI/fO & left SFG connectivity0.10 ± 0.350.22 ± 0.38
SMN: left aI/fO & right aI/fO connectivity0.71 ± 0.430.80 ± 0.35
SMN: left aI/fO & right SFG connectivity0.05 ± 0.330.11 ± 0.33
SMN: left SFG & right SFG connectivity0.70 ± 0.430.68 ± 0.28
SMN: right aI/fO & left SFG connectivity0.02 ± 0.220.25 ± 0.21
SMN: right aI/fO & right SFG connectivity0.04 ± 0.260.27 ± 0.35
Statistical analysis
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = <0.001 (Our a priori threshold for statistical significance was 0.05.)We ran a 2 (Group) x 6 (ROI Pair) ANOVA to assess functional connectivity between the nodes of the DMN, using age as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.024 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.040 (This is an uncorrected p-value. A priori significance threshold is 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.008 (This is an uncorrected p-value. A priori significance threshold was 0.05)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.470 (This is an uncorrected p-value. A priori significance threshold was 0.05)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.829 (This is an uncorrected p-value. A priori significance threshold was 0.05)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.801 (This is an uncorrected p-value. A priori significance threshold was 0.05)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = <0.001 (Our a priori threshold for statistical significance was 0.05.)We ran a 2 (Group) x 6 (ROI Pair) ANOVA to assess functional connectivity between the nodes of the SMN, using age as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.550 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.113 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.039 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.005 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.426 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.256 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.853 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.003 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
  • Subjects With OTCD vs Healthy Controls · ANOVA · p = 0.023 (This is an uncorrected p-value. A priori significance threshold was 0.05.)We ran a series of post-hoc one-way ANOVAs to localize the main effect found. Age was used as a covariate.
PrimaryFractional 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.

Time frame:
Baseline
Reported as:
Mean · units on a scale
Fractional Anisotropy Assessed Using DTI
units on a scaleSubjects With OTCDHealthy Controls
Fractional Anisotropy Assessed Using DTI0.25 ± 0.0030.3 ± 0.008
SecondaryNeuropsychological 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.

Time frame:
Baseline
Reported as:
Mean · units on a scale
Neuropsychological Assessment
units on a scaleSubjects With OTCDHealthy Controls
WASI - Verbal IQ107.33 ± 14.52107.77 ± 18.59
WASI - Performance IQ98.5 ± 13.14112.59 ± 14.54
WASI - Full IQ103.28 ± 14.02111.22 ± 16.89
Trails - Composite48 ± 1547 ± 12
Brief - Behavioral Regulation Index (BRI)55.59 ± 9.4946.73 ± 8.90
Brief - Metacognition Index (MI)60.45 ± 11.7547.38 ± 8.22
Brief - Global Executive Composite Score (GEC)59.05 ± 10.3746.88 ± 7.67
Statistical analysis
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = .929 (Equal variance is not assumed. Two tailed t-test WASI verbal IQ between cases and controls)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = .002 (Equal variance not assumed. Comparison WASI performance IQ cases and controls)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = .094 (Equal variance not assumed. Comparison of WASI full IQ cases and controls)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = .853 (Equal variance not assumed. Comparison of CTMT global composite score between cases and controls)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = .001 (Equal variance not assumed. Comparison of BRIEF BRI cases and controls)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = <.001 (Equal variances not assumed. Comparison of BRIEF MI cases and controls)
  • Subjects With OTCD vs Healthy Controls · t-test, 2 sided · p = <0.001 (Equal variances not assumed. Comparison of BRIEF GEC between cases and controls.)

Adverse events

Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Subjects With OTCD—0/20 (0%)0/20 (0%)
Healthy Controls—0/29 (0%)0/29 (0%)

Baseline characteristics

Age, Continuous
Age, Continuous(years)Subjects With OTCDHealthy ControlsTotal
Mean30.3 ± 19.425.8 ± 14.628.05 ± 17.02
Sex: Female, Male
Sex: Female, Male(Participants)Subjects With OTCDHealthy ControlsTotal
Female171936
Male3811
08

Study locations

No study locations are listed for this record.

09

References and documents

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. PubMed 22110002 ↗
  • 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. PubMed 21778100 ↗
  • 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. PubMed 20488904 ↗
  • 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. PubMed 20207564 ↗
  • 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. PubMed 20004862 ↗
  • 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. PubMed 19567648 ↗
  • 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. PubMed 18662894 ↗

Individual participant data

Plan to share: Yes — Final data is on the UCDC website

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 8, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01569568
Lead sponsor
Andrea Gropman
Collaborators
Children's National Research Institute
Responsible party
Andrea Gropman (MD, Children's National Research Institute) — Sponsor-investigator
First posted
Apr 3, 2012
Start date
Sep 2010
Primary completion
Aug 2014
Completion
Aug 2014
Results posted
Apr 14, 2017
Last update
Mar 8, 2024

Study contacts

Andrea L Gropman, M.D.
principal investigator · Children's National Research Institute

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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