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Systemic Biomarkers of Brain Injury From Hyperammonemia

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ClinicalTrials.gov Identifier: NCT04602325
Recruitment Status : Recruiting
First Posted : October 26, 2020
Last Update Posted : November 1, 2021
Sponsor:
Collaborator:
National Center for Advancing Translational Science (NCATS)
Information provided by (Responsible Party):
Nicholas Ah Mew, Children's National Research Institute

Study Description
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:

Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. High blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. The following aims are proposed:

Aim 1 of this study will be to determine the chronology of biomarkers of brain injury in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder.

Aim 2 will be to determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1).


Condition or disease
Urea Cycle Disorder Organic Acidemia Maple Syrup Urine Disease Glutaric Acidemia I Fatty Acid Oxidation Disorder Hypoxic-Ischemic Encephalopathy

Detailed Description:

Ammonia is a waste product of protein and amino acid catabolism and is also a potent neurotoxin. The onslaught of high blood ammonia levels on the brain can manifest as cytotoxic brain edema and vascular compromise leading to intellectual and developmental disabilities. In addition, clinical hyperammonemia recurs at varying intervals, which can increase the cumulative damage to the brain and the chance of irreversible coma and death during a hyperammonemia episode due to vascular compromise or brain herniation. The threshold of tolerance for elevated blood ammonia is very low and concentrations above 100 µM can cause brain dysfunction manifested as nausea, vomiting, lethargy, and abnormal behavior; higher concentrations can cause coma and even death. Failure to remove ammonia can be due to inherited defects of the urea cycle, some defects in amino acid catabolism, and degradation of fatty acids.

Aim 1 - To determine the chronology of biomarkers of brain injury - S100B, NSE, and UCHL1 - in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder. We hypothesized that elevations of S100B, NSE, and UCHL1 will parallel the rise in blood ammonia. These biomarkers will be measured concurrently to ammonia levels throughout hospitalizations for HA until normalization of patient's blood ammonia and mental status.

Aim 2 - To determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism in which the primary pathology is neurological injury, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1). We hypothesize that neuronal and astroglial injury in these disorders may also result in increased levels of S100B, NSE, and UCHL1.

Metabolic patients will be enrolled either during a hospitalization or in outpatient clinic, but outpatient enrollment is preferred. Metabolic patients typically have multiple laboratory tests performed at their outpatient visits. We will obtain the discarded blood samples from such laboratory tests in order to measure S100B, NSE, and UCHL1 levels at baseline (normal blood ammonia), which will provide data on biomarker levels following recovery from a hyperammonemic episode.

During hospitalization for metabolic decompensation or for hypoxic-ischemic encephalopathy, sequential measurements of S100B, NSE and UCHL1 levels will be obtained from discarded blood samples. We will obtain S100B, NSE, and UCHL1 levels from collected discarded blood samples at all subjects' next outpatient visit following their hospitalization, to determine if levels return to baseline.

Study Design
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Study Type : Observational
Estimated Enrollment : 24 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Systemic Biomarkers of Brain Injury From Hyperammonemia
Actual Study Start Date : July 9, 2020
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : May 2024

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort
Inherited Hyperammonemias

A clinical diagnosis of 1 of 7 diagnosed urea cycle disorders:

  1. N-acetylglutamate Synthetase Deficiency (NAGS)
  2. Carbamyl Phosphate Synthetase Deficiency (CPSD)
  3. Ornithine Transcarbamylase Deficiency (OTCD)
  4. Argininosuccinate Synthetase Deficiency (ASD)
  5. Argininosuccinate Lyase Deficiency (ALD)
  6. Arginase Deficiency (AD)
  7. Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH)

A clinical diagnosis of 1 of 2 organic acidemias:

  1. Propionic Acidemia (PA)
  2. Methylmalonic Acidemia (MMA)
Acute Metabolic Disorder + Neurological Sequelae

Acute metabolic disorder without hyperammonemia but with neurological sequelae:

  1. Maple Syrup Urine Disease (MSUD)
  2. Glutaric Acidemia (GA1)
Fatty Acid Oxidation Disorders

Acute metabolic disorder without hyperammonemia and without neurological sequelae:

  1. Medium Chain-Acyl CoA Dehydrogenase Deficiency
  2. Very Long Chain-Acyl CoA Dehydrogenase Deficiency
  3. Trifunctional Protein Deficiency
  4. Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency
  5. Carnitine Palmitoyltransferase I or II Deficiency
  6. Carnitine/Acylcarnitine Translocase Deficiency
  7. Primary Carnitine Transport Deficiency
Hypoxic-Ischemic Encephalopathy
Patients with hypoxic-ischemic encephalopathy


Outcome Measures
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Primary Outcome Measures :
  1. Biomarker Brain Injury Chronology [ Time Frame: 2 Years ]
    Determine the chronology of biomarkers of brain injury (S100B, NSE, and UCHL1) in response to a hyperammonemic (HA) brain insult in patients with an inherited hyperammonemic disorder


Secondary Outcome Measures :
  1. Brain Injury Protein Alterations [ Time Frame: 2 Years ]
    Determine if S100B, NSE, and UCHL1 are altered in patients with two other inborn errors of metabolism in which the primary pathology is neurological injury, Maple Syrup Urine Disease (MSUD) and Glutaric Acidemia (GA1)


Biospecimen Retention:   Samples Without DNA

Discarded blood samples will be obtained from such laboratory tests in order to measure S100B, NSE, and UCHL1 levels at baseline (normal blood ammonia), which will provide data on biomarker levels following recovery from a hyperammonemic episode.

During hospitalization for metabolic decompensation or for hypoxic-ischemic encephalopathy, sequential measurements of S100B, NSE and UCHL1 levels will be obtained from discarded blood samples.

S100B, NSE, and UCHL1 levels will again be obtained from collected discarded blood samples at all subjects' next outpatient visit following their hospitalization, to determine if levels return to baseline.


Eligibility Criteria
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Ages Eligible for Study:   7 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Eligible subjects will be recruited from the patient population at Children's National Hospital in Washington, DC. Study population will consist of those patients with inherited hyperammonemias, acute metablic disorders, fatty acid oxidation disorders, and hypoxic-ischemic encephalopathy.
Criteria

Inclusion Criteria:

  1. Inherited Hyperammonemias:

    1. A clinical diagnosis of 1 of 7 diagnosed urea cycle disorders:

      • N-acetylglutamate Synthetase Deficiency (NAGS)
      • Carbamyl Phosphate Synthetase Deficiency (CPSD)
      • Ornithine Transcarbamylase Deficiency (OTCD)
      • Argininosuccinate Synthetase Deficiency (ASD)
      • Argininosuccinate Lyase Deficiency (ALD)
      • Arginase Deficiency (AD)
      • Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH)

    2. A clinical diagnosis of 1 of 2 organic acidemias:

      • Propionic Acidemia (PA)
      • Methylmalonic Acidemia (MMA)

  2. Acute metabolic disorder without hyperammonemia, with neurological sequelae

    1. Maple Syrup Urine Disease (MSUD)
    2. Glutaric Acidemia (GA1)

  3. Acute metabolic disorder without hyperammonemia and without neurological sequelae

    • Fatty Acid Oxidation Disorders:
    • Medium Chain-Acyl CoA Dehydrogenase Deficiency
    • Very Long Chain-Acyl CoA Dehydrogenase Deficiency
    • Trifunctional Protein Deficiency
    • Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency
    • Carnitine Palmitoyltransferase I or II Deficiency
    • Carnitine/Acylcarnitine Translocase Deficiency
    • Primary Carnitine Transport Deficiency
  4. Hypoxic-Ischemic Encephalopathy

Exclusion Criteria:

  • Prior Solid-Organ Transplant
  • Use of any other investigational drug, biologic, or therapy or any clinical or laboratory abnormality or medical condition that, as determined by the investigator, may interfere with or obscure the biomarker measurements
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04602325


Contacts
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Contact: Katie Rice, MPH, CCRP 202-476-6191 krice3@childrensnational.org
Contact: Nicholas Ah Mew, MD 202-476-5863 nahmew@childrensnational.org

Locations
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United States, District of Columbia
Children's National Research Institute Recruiting
Washington, District of Columbia, United States, 20010
Contact: Katie Rice, MPH, CCRP       krice3@childrensnational.org   
Principal Investigator: Nicholas Ah Mew, MD         
Sponsors and Collaborators
Children's National Research Institute
National Center for Advancing Translational Science (NCATS)
Investigators
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Principal Investigator: Nicholas Ah Mew, MD Children's National Research Institute
Study Chair: Ljubica Caldovic, PhD Children's National Research Institute
More Information
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
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Responsible Party: Nicholas Ah Mew, MD, Children's National Research Institute
ClinicalTrials.gov Identifier: NCT04602325    
Other Study ID Numbers: 14021
R21TR003166-01 ( U.S. NIH Grant/Contract )
First Posted: October 26, 2020    Key Record Dates
Last Update Posted: November 1, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nicholas Ah Mew, Children's National Research Institute:
N-acetylglutamate Synthetase Deficiency
Carbamyl Phosphate Synthetase Deficiency
Ornithine Transcarbamylase Deficiency
Argininosuccinate Synthetase Deficiency
Argininosuccinate Lyase Deficiency
Arginase Deficiency
Hyperammonemia-Hyperornithinemia-Homocitrullinuria
 Medium Chain-Acyl CoA Dehydrogenase Deficiency
Very Long Chain-Acyl CoA Dehydrogenase Deficiency
Trifunctional Protein Deficiency
Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency
Carnitine Palmitoyltransferase I or II Deficiency
Carnitine/Acylcarnitine Translocase Deficiency
Primary Carnitine Transport Deficiency
Additional relevant MeSH terms:
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Brain Injuries
Brain Diseases
Brain Ischemia
Hypoxia-Ischemia, Brain
Urea Cycle Disorders, Inborn
Maple Syrup Urine Disease
Disease
Hyperammonemia
Pathologic Processes
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
 Wounds and Injuries
Hypoxia
Signs and Symptoms, Respiratory
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Hypoxia, Brain
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases