Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Description

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

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Study Overview

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Study Details

Study overview

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.

Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Condition
Urea Cycle Disorders
Intervention / Treatment

-

Contacts and Locations

Washington

Children's Research Institute, Washington, District of Columbia, United States, 20010

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

For general information about clinical research, read Learn About Studies.

Eligibility Criteria

  • 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)
  • 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)
  • 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
  • 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
  • 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.
  • 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

Ages Eligible for Study

7 Years to 50 Years

Sexes Eligible for Study

ALL

Accepts Healthy Volunteers

Yes

Collaborators and Investigators

Children's National Research Institute,

Andrea L. Gropman, M.D., PRINCIPAL_INVESTIGATOR, Children's National Research Institute

Study Record Dates

2025-12