Systemic Biomarkers of Brain Injury From Hyperammonemia

NCT04602325 | Recruiting

• 2 other identifiers: 14021R21TR003166-01
• Study Type: observational
• Target: 24
• Locations: 1 country
• Sites: 1

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).

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Brain Injury Protein Alterations

  2 Years

Study Arms (4)

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

Eligibility Criteria

• Age: 7 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Children's National Research Institute: lead
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (1)

Children's National Research Institute

Washington D.C., District of Columbia, 20010, United States

RECRUITING

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.

MeSH Terms

Conditions

Urea Cycle Disorders, Inborn; Maple Syrup Urine Disease; Glutaric Acidemia I; Hypoxia-Ischemia, Brain; N-acetyl glutamate synthetase deficiency; Carbamoyl-Phosphate Synthase I Deficiency Disease; Ornithine Carbamoyltransferase Deficiency Disease; Citrullinemia; Argininosuccinic Aciduria; Hyperargininemia; HHH syndrome; Medium chain acyl CoA dehydrogenase deficiency; VLCAD deficiency; Trifunctional Protein Deficiency With Myopathy And Neuropathy; Carnitine-Acylcarnitine Translocase Deficiency

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Brain Ischemia; Cerebrovascular Disorders; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mitochondrial Diseases; Genetic Diseases, X-Linked

Study Officials

• Nicholas Ah Mew, MD

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

• Ljubica Caldovic, PhD

  Children's National Research Institute

  STUDY CHAIR

Central Study Contacts

Katie Rice, MPH, CCRP

CONTACT

202-476-6191; krice3@childrensnational.org

Nicholas Ah Mew, MD

CONTACT

202-476-5863; nahmew@childrensnational.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: October 20, 2020
• First Posted: October 26, 2020
• Study Start: July 9, 2020
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): May 1, 2027
• Last Updated: February 7, 2024

Record last verified: 2024-02

Locations

US (1)