Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders
| Status: | Recruiting |
|---|---|
| Healthy: | No |
| Age Range: | 7 - 50 |
| Updated: | 12/23/2018 |
| Start Date: | August 2016 |
| End Date: | December 2020 |
| Contact: | Andrea L Gropman, M.D. |
| Email: | agropman@childrensnational.org |
| Phone: | 202-476-3511 |
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.
(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.
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.
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.
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
We found this trial at
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sites
Boston Children's Hospital Boston Children's Hospital is a 395-bed comprehensive center for pediatric health care....
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Washington, District of Columbia 20010
Principal Investigator: Andrea L Gropman, M.D.
Phone: 202-476-3511
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