Systemic Biomarkers of Brain Injury From Hyperammonemia

NCT ID: NCT04602325

Last Updated: 2024-02-07

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 24 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-07-09
• Study Completion Date: 2027-05-31

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).

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.

Conditions

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

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

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)

No interventions assigned to this group

Acute Metabolic Disorder + Neurological Sequelae

Acute metabolic disorder without hyperammonemia but with neurological sequelae:

1. Maple Syrup Urine Disease (MSUD)

2. Glutaric Acidemia (GA1)

No interventions assigned to this group

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

No interventions assigned to this group

Hypoxic-Ischemic Encephalopathy

Patients with hypoxic-ischemic encephalopathy

No interventions assigned to this group

Eligibility 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

• Minimum Eligible Age: 7 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Center for Advancing Translational Sciences (NCATS)

NIH

Sponsor Role: collaborator

Children's National Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Nicholas Ah Mew

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nicholas Ah Mew, MD

Role: PRINCIPAL_INVESTIGATOR

Children's National Research Institute

Ljubica Caldovic, PhD

Role: STUDY_CHAIR

Children's National Research Institute

Locations

Children's National Research Institute

Washington D.C., District of Columbia, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Katie Rice, MPH, CCRP

Role: CONTACT

krice3@childrensnational.org

202-476-6191

Nicholas Ah Mew, MD

Role: CONTACT

nahmew@childrensnational.org

202-476-5863

Facility Contacts

Katie Rice, MPH, CCRP

Role: primary

krice3@childrensnational.org

Other Identifiers

R21TR003166-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

14021

Identifier Type: -

Identifier Source: org_study_id