Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

Study Overview
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Brief Summary
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Hyperammonemia, which can cause brain damage, occurs in many different kinds of inborn errors of metabolism. The investigators propose to determine if short-term (3 day) treatment with N-carbamylglutamate can diminish hyperammonemia by enhancing ureagenesis in these patients. The investigators propose here a short-term (3 day) trial. If it succeeds, the investigators would consider more extensive long-term studies of the drug.

Detailed Description
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To determine whether brief (3 day) treatment with N-carbamylglutamate can improve ureagenesis in adult healthy controls and patients with the following inborn errors of metabolism: N-acetylglutamate synthetase deficiency, propionic acidemia, methylmalonic acidemia, carbamylphosphate synthase deficiency, ornithine transcarbamylase deficiency and the syndrome of hyperammonemia, hypoglycemia and hyperinsulinemia (HHH Syndrome). To determine if such treatment improves other indicators of abnormal nitrogen metabolism such as elevated blood levels of glutamine, glycine and alanine.

Official Title
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Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate

Conditions
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Urea Cycle Disorders, Inborn, Inborn Errors of Metabolism, Propionic Acidemia, Methylmalonic Acidemia, Carbamyl Phosphate Synthetase Deficiency

Intervention / Treatment
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* Drug: N-carbamylglutamate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range: males or females, ages 3 years - 70 years Condition(s): N-acetylglutamate synthetase deficiency, propionic acidemia, methylmalonic acidemia, carbamylphosphate synthase deficiency, ornithine transcarbamylase deficiency and the syndrome of hyperammonemia, hypoglycemia and hyperinsulinemia. In addition, healthy volunteers will be studied (ages 18 years - 50 years). Exclusion Criteria: Acutely ill on day of study (fever, evidence of hyperammonemia - ataxia, worsening obtundation, focal neurologic signs, seizures, increased intracranial pressure, vomiting, signs of acute respiratory or enteric illness, headache, confusion, disorientation, acute personality change). Girls 11 years of age must have a negative urine/serum pregnancy test within 1 week prior to testing unless having a menstrual period during week of test Lactating females Hyperammonemia probably refractory to N-carbamylglutamate: other urea cycle disorders (UCD), lysinuric protein intolerance, mitochondrial disorders, congenital lactic acidemia, fatty acid oxidation defects or primary liver disease. Amount of blood necessary for study exceeds safe limits. Any investigational drug use within 30 days prior to enrollment. Parents/guardians or subjects who, in the opinion of the PI, may be non-compliant with study schedules or procedures. Subjects who do not meet all the enrollment criteria may not be enrolled. Any violations of these criteria will be reported in accordance with Institutional Review Board (IRB) Policies and Procedures.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N-carbamylglutamate (Carbaglu)<br> | Drug: N-carbamylglutamate<br>* N-carbamylglutamate: 200 mg/kg/day for 3 days, divided into 4 daily oral doses<br>* Other names: Carbaglu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of ureagenesis | Goal is to determine whether a 3 day trial of N-carbamylglutamate increases ureagenesis in patients with urea cycle defects and other inborn errors of metabolism. | 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ureagenesis, Urea cycle, Inborn errors of metabolism