Systemic Biomarkers of Brain Injury From Hyperammonemia

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).

Study Overview

• Status: Recruiting
• Conditions: Hypoxic-Ischemic Encephalopathy; Urea Cycle Disorder; Organic Acidemia; Fatty Acid Oxidation Disorder; Maple Syrup Urine Disease; Glutaric Acidemia I

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 Type: Observational
• Enrollment (Estimated): 24

Contacts and Locations

• Study Contact: Name: Katie Rice, MPH, CCRP; Phone Number: 202-476-6191; Email: krice3@childrensnational.org
• Study Contact Backup: Name: Nicholas Ah Mew, MD; Phone Number: 202-476-5863; Email: nahmew@childrensnational.org

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Research Institute
      • Principal Investigator: Nicholas Ah Mew, MD
      • Contact: Katie Rice, MPH, CCRP; Email: krice3@childrensnational.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 16 years (Child, Adult)
• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Inherited Hyperammonemias; 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) A clinical diagnosis of 1 of 2 organic acidemias: Propionic Acidemia (PA); Methylmalonic Acidemia (MMA)
Acute Metabolic Disorder + Neurological Sequelae; Acute metabolic disorder without hyperammonemia but with neurological sequelae: Maple Syrup Urine Disease (MSUD); Glutaric Acidemia (GA1)
Fatty Acid Oxidation Disorders; Acute metabolic disorder without hyperammonemia and without neurological sequelae: 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
Hypoxic-Ischemic Encephalopathy; Patients with hypoxic-ischemic encephalopathy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker Brain Injury Chronology	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	2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Injury Protein Alterations	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)	2 Years

Collaborators and Investigators

• Sponsor: Children's National Research Institute
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Nicholas Ah Mew, MD, Children's National Research Institute; Study Chair: Ljubica Caldovic, PhD, Children's National Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2020
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: October 20, 2020
• First Submitted That Met QC Criteria: October 20, 2020
• First Posted (Actual): October 26, 2020

Study Record Updates

• Last Update Posted (Actual): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Trifunctional Protein Deficiency; Ornithine Transcarbamylase Deficiency; N-acetylglutamate Synthetase Deficiency; Carbamyl Phosphate Synthetase 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; Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency; Carnitine Palmitoyltransferase I or II Deficiency; Carnitine/Acylcarnitine Translocase Deficiency; Primary Carnitine Transport Deficiency
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Genetic Diseases, Inborn; Craniocerebral Trauma; Trauma, Nervous System; Signs and Symptoms, Respiratory; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Hypoxia; Hypoxia, Brain; Brain Ischemia; Brain Injuries; Brain Diseases; Hypoxia-Ischemia, Brain; Urea Cycle Disorders, Inborn; Hyperammonemia; Maple Syrup Urine Disease
• Other Study ID Numbers: 14021; R21TR003166-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No