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.

Study Start Date

August, 01 2016

Estimated Completion Date

December 2020

Interventions

  • Procedure: MRI
  • Behavioral: Behavioral

Study ID

Children's Research Institute -- UCD 5113

Status

Recruiting

Trial ID

NCT02935283

Study Type

Observational

Trial Phase

N/A

Enrollment Quota

56

Sponsor

Children's Research Institute

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

Gender

All

Ages

7 Years to 50 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Study Locations and Contact Information (6)

Study Location Distance Name Phone Email
Boston Childrens Hospital - Boston, Massachusetts 2.6 miles Gerard Berry MD 617-355-6394 gerard.berry@childrens.harvard.edu
Boston Childrens Hospital - Boston, Massachusetts 2.6 miles Gerard Berry MD 617-355-6394 gerard.berry@childrens.harvard.edu
Boston Childrens Hospital - Boston, Massachusetts 2.6 miles Gerard Berry MD 617-355-6394 gerard.berry@childrens.harvard.edu
Childrens Research Institute - Washington, District of Columbia 391.7 miles Andrea L Gropman MD 202-476-3511 agropman@childrensnational.org
Childrens Research Institute - Washington, District of Columbia 391.7 miles Andrea L Gropman MD 202-476-3511 agropman@childrensnational.org
Childrens Research Institute - Washington, District of Columbia 391.7 miles Andrea L Gropman MD 202-476-3511 agropman@childrensnational.org

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