Clinical trial NCT04602325: Systemic Biomarkers of Brain Injury From Hyperammonemia
Official title: Systemic Biomarkers of Brain Injury From Hyperammonemia
Study type: OBSERVATIONAL
Overall status: RECRUITING
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
Lead sponsor: Children's National Research Institute
Sponsor class: OTHER
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2020-10-26
Enrollment: 24
Sex: ALL
Minimum age (years): 7
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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

Primary outcomes:
measure: Biomarker Brain Injury Chronology
timeFrame: 2 Years
Secondary outcomes:
measure: Brain Injury Protein Alterations
timeFrame: 2 Years
Other outcomes:
Locations:
city: Washington
country: United States
facility: Children's National Research Institute
state: District of Columbia
Study officials:
affiliation: Children's National Research Institute
name: Nicholas Ah Mew, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's National Research Institute
name: Ljubica Caldovic, PhD
role: STUDY_CHAIR
References: