Brain Diseases, Metabolic, Inborn, Ornithine Transcarbamylase Deficiency, Urea Cycle Disorder
Conditions
Keywords
UCD, OTCD, Ammonia, Urea Metabolism, Inborn Errors
Brief summary
Urea cycle disorders (UCDs) are a group of rare inherited metabolism disorders. The purpose of this study is to evaluate how UCD-related neurologic injuries affect adults with one of the most common types of UCD.
Detailed 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. Participants in this study will attend an initial study visit that will include a review of medical history, current symptoms, impairments, and diet history; urine and blood collection; 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 2- to 3-day period. This will include standard MRI studies and four sessions consisting of functional MRI (fMRI), 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 one-time participation. There will be no follow-up visits for this study.
Interventions
None listed
Sponsors
Office of Rare Diseases (ORD)
Rare Diseases Clinical Research Network
National Center for Research Resources (NCRR)
Andrea Gropman
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
for Participants with OTCD: * Diagnosis of OTCD or heterozygote state of OTCD by metabolic or molecular means. Female participants must be clinically stable and heterozygous for OTCD. Male participants must be hemizygous for late onset OTCD. Inclusion Criteria for Healthy Controls: * No known medical or metabolic disorder Inclusion Criteria for All Participants: * IQ of at least 80 * Willing to travel to study site * English-speaking * Age between 18 and 60 years
Exclusion criteria
for All Participants: * Currently being treated for an acute illness * History of neuropsychiatric drug use * Unable to undergo MRI scanning without being sedated * Unable to participate in neurocognitive and/or motor testing * Metal device in body that might interfere with MRI scanning * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of Glutamine and Myoinositol by MRS | one time measurement at study baseline | 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 protocol we use 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). |
| Functional MRI Activation in N-Back Tast | one time measurement at study baseline | Measure of blood oxygen level dependent (BOLD) signal of OTCD patients and healthy controls during an N-Back task comparing 2-back and 1-back conditions. This contrast was created for each participant using SPM and then entered into a group analysis in which we compare percent signal change between groups. Therefore, we never see BOLD signal change at the individual level, which is why we never see scores or numbers at the individual level and we cannot calculate a measure of dispersion for this data. |
| Fractional Anisotropy | one time measurement at study baseline | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Female Carriers of Ornithine Transcarbamylase Deficiency (OTCD Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD | 24 |
| Healthy Males or Females Without Known Medical or Metabolic di Healthy males or females without known medical or metabolic disorder (control group) | 22 |
| Total | 46 |
Baseline characteristics
| Characteristic | Female Carriers of Ornithine Transcarbamylase Deficiency (OTCD | Total | Healthy Males or Females Without Known Medical or Metabolic di |
|---|---|---|---|
| Age, Customized Age | 32.55 years | 32.46 years | 32.38 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 44 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 38 Participants | 15 Participants |
| Region of Enrollment United States | 24 participants | 46 participants | 22 participants |
| Sex: Female, Male Female | 17 Participants | 36 Participants | 19 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 24 | 0 / 22 |
| serious Total, serious adverse events | 0 / 24 | 0 / 22 |
Outcome results
Primary
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 protocol we use 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).
Time frame: one time measurement at study baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OTCD Patients | Concentration of Glutamine and Myoinositol by MRS | Glutamine in PWM | 2.13 mM | Standard Deviation 1.22 |
| OTCD Patients | Concentration of Glutamine and Myoinositol by MRS | Myoinositol in PCGM | 3.78 mM | Standard Deviation 0.82 |
| OTCD Patients | Concentration of Glutamine and Myoinositol by MRS | Myoinositol in PWM | 2.27 mM | Standard Deviation 0.77 |
| OTCD Patients | Concentration of Glutamine and Myoinositol by MRS | Glutamine in PCGM | 4.97 mM | Standard Deviation 2.08 |
| Healthy Controls | Concentration of Glutamine and Myoinositol by MRS | Myoinositol in PCGM | 4.50 mM | Standard Deviation 0.43 |
| Healthy Controls | Concentration of Glutamine and Myoinositol by MRS | Glutamine in PCGM | 3.66 mM | Standard Deviation 1.36 |
| Healthy Controls | Concentration of Glutamine and Myoinositol by MRS | Glutamine in PWM | 1.09 mM | Standard Deviation 0.75 |
| Healthy Controls | Concentration of Glutamine and Myoinositol by MRS | Myoinositol in PWM | 2.86 mM | Standard Deviation 0.38 |
Comparison: The null hypothesis predicted that the concentration of myoinositol in posterior cingulate gray matter will be the same in OTCD patients as in controls.p-value: 0.003t-test, 2 sided
Comparison: The null hypothesis predicted that the concentration of myoinositol in parietal white matter will be the same in OTCD patients as in controls.p-value: <0.001t-test, 2 sided
Comparison: The null hypothesis predicted that the concentration of glutamine in posterior cingulate gray matter would be the same for OTCD patients as for controls.p-value: 0.001t-test, 2 sided
Comparison: The null hypothesis predicted that the concentration of glutamine in parietal white matter would be the same for OTCD patients as for controls.p-value: <0.001t-test, 2 sided
Primary
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.
Time frame: one time measurement at study baseline
Population: Five OTCD Patients and four healthy controls were excluded due to excessive head motion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OTCD Patients | Fractional Anisotropy | 0.247 units on a scale | Standard Deviation 0.016 |
| Healthy Controls | Fractional Anisotropy | 0.274 units on a scale | Standard Deviation 0.015 |
Comparison: The null hypothesis predicted that fractional anisotropy, a marker of white matter integrity, would be the same for OTCD patients as for controls.p-value: <0.001t-test, 2 sided
Primary
Functional MRI Activation in N-Back Tast
Measure of blood oxygen level dependent (BOLD) signal of OTCD patients and healthy controls during an N-Back task comparing 2-back and 1-back conditions. This contrast was created for each participant using SPM and then entered into a group analysis in which we compare percent signal change between groups. Therefore, we never see BOLD signal change at the individual level, which is why we never see scores or numbers at the individual level and we cannot calculate a measure of dispersion for this data.
Time frame: one time measurement at study baseline
Population: Five OTCD patients and one healthy control were excluded due to excessive head motion.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OTCD Patients | Functional MRI Activation in N-Back Tast | Dorsolateral prefrontal cortex (BA 10) | 0.21 percent signal change |
| OTCD Patients | Functional MRI Activation in N-Back Tast | Dorsolateral prefrontal cortex (BA 46) | 0.22 percent signal change |
| OTCD Patients | Functional MRI Activation in N-Back Tast | Anterior cingulate cortex (BA 32) | 0.515 percent signal change |
| Healthy Controls | Functional MRI Activation in N-Back Tast | Dorsolateral prefrontal cortex (BA 10) | 0.04 percent signal change |
| Healthy Controls | Functional MRI Activation in N-Back Tast | Dorsolateral prefrontal cortex (BA 46) | 0.15 percent signal change |
| Healthy Controls | Functional MRI Activation in N-Back Tast | Anterior cingulate cortex (BA 32) | 0.28 percent signal change |
Comparison: Two-way between-group t-tests restricted to the prefrontal cortex were performed to compare activation during for the 2-Back\> 1-Back contrast between OTCD patients and controls.p-value: <0.05t-test, 2 sided