Systemic Biomarkers of Brain Injury From Hyperammonemia

Sponsor

Children's National Research Institute (Other)

Overall Status

Recruiting

CT.gov ID

NCT04602325

Collaborator

National Center for Advancing Translational Science (NCATS) (NIH)

Enrollment

Location

45.7

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

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	Intervention/Treatment	Phase
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

Study Type:

Observational

Anticipated Enrollment :

24 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Systemic Biomarkers of Brain Injury From Hyperammonemia

Actual Study Start Date :

Jul 9, 2020

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

May 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

Biomarker Brain Injury Chronology [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

Brain Injury Protein Alterations [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

7 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 without hyperammonemia, with neurological sequelae
Maple Syrup Urine Disease (MSUD)
Glutaric Acidemia (GA1)
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

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

Locations

	Site	City	State	Country	Postal Code
1	Children's National Research Institute	Washington	District of Columbia	United States	20010

Sponsors and Collaborators

Children's National Research Institute
National Center for Advancing Translational Science (NCATS)

Investigators

Principal Investigator: Nicholas Ah Mew, MD, Children's National Research Institute
Study Chair: Ljubica Caldovic, PhD, Children's National Research Institute