About Urea Cycle Disorders (UCDs)

The basics:

The History and Discovery of Urea Cycle Disorders (UCDs)

The urea cycle was first described in 1932 by Hans Krebs and Kurt Henseleit, who identified it as the metabolic pathway by which excess nitrogen is converted into urea in the liver and excreted in the urine. The first clinical recognition of a urea cycle disorder occurred in the early 1960s when patients, often infants, presented with unexplained hyperammonemia (elevated ammonia in the blood), a hallmark of a defect in this metabolic process.

What Are Urea Cycle Disorders?

Urea Cycle Disorders (UCDs) are a group of rare, inherited metabolic conditions caused by mutations in any of the genes responsible for the urea cycle. The urea cycle is essential for removing ammonia—a toxic byproduct of protein metabolism—from the bloodstream. When any enzyme in the cycle is deficient or defective, ammonia accumulates in the body, leading to a condition known as hyperammonemia, which is potentially life-threatening.

The key enzymes and transporters involved include:

• Carbamoyl phosphate synthetase I (CPS1)
• Ornithine transcarbamylase (OTC)
• Argininosuccinate synthetase (ASS1)
• Argininosuccinate lyase (ASL)
• Arginase (ARG1)
• N-acetylglutamate synthase (NAGS)
• Ornithine translocase (SLC25A15)

Each of these enzyme deficiencies corresponds to a different type of UCD.

Clinical Presentation and Diagnosis

Symptoms of UCDs can appear shortly after birth (neonatal onset) or later in life (late onset), depending on the severity of the enzyme deficiency. Common early symptoms include:

• Poor feeding
• Vomiting
• Lethargy
• Irritability
• Rapid breathing

As ammonia levels rise, more serious symptoms develop, such as:

• Confusion
• Seizures
• Coma
• Brain swelling
• Death (if untreated)

Diagnosis is typically made through newborn screening and confirmed with blood and urine tests (to detect elevated ammonia, glutamine, and other biomarkers), genetic testing, and enzyme assays.

Treatment and Crisis Management

Immediate treatment during a metabolic crisis focuses on reducing ammonia levels as quickly as possible. This may involve:

• Intravenous glucose and lipid infusions to suppress protein breakdown
• Ammonia-scavenging drugs such as sodium benzoate, sodium phenylacetate, or glycerol phenylbutyrate (Ravicti®)
• Hemodialysis in severe hyperammonemia
• Intravenous arginine or citrulline (depending on the specific UCD)

Dietary management is crucial: patients require a low-protein diet supplemented with medical foods and special amino acid formulas that provide essential nutrients without excessive nitrogen.

Advances in Medical Treatment

In recent years, UCD treatment has advanced significantly. Pharmaceutical therapies like Ravicti® and Buphenyl® are now standard for long-term ammonia management. Research is ongoing in the fields of:

• Gene therapy, particularly for OTC deficiency, the most common UCD
• Liver cell therapy
• Enzyme replacement therapy

Liver Transplantation

For patients with severe UCDs, especially those experiencing recurrent metabolic crises or poor metabolic control, liver transplantation may be considered. A successful transplant can restore normal urea cycle function and eliminate the need for dietary and medication-based ammonia control. However, this option carries risks and is usually reserved for severe cases.

Living with UCDs

UCDs are lifelong conditions. With early diagnosis and careful metabolic management, many individuals with UCDs can lead relatively normal lives. Success depends on:

• Prompt treatment of metabolic decompensations
• Lifelong dietary adherence
• Regular monitoring of ammonia and amino acid levels
• Access to metabolic specialists and multidisciplinary care

Resources of Information:

• Brusilow, S. W., & Maestri, N. E. (1996). Urea cycle disorders: diagnosis, pathophysiology, and therapy. Advances in Pediatrics, 43, 127–170.

• Häberle, J., et al. (2012). Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases, 7, 32. https://doi.org/10.1186/1750-1172-7-32

• Summar, M. L., et al. (2008). Diagnosis and management of urea cycle disorders: a consensus statement from the UCD Consortium. Molecular Genetics and Metabolism, 94(3), 227–231.

• Tuchman, M., et al. (2002). Late onset ornithine transcarbamylase deficiency: clinical, biochemical, and molecular findings. Pediatrics, 109(2), 256–261.

• Batshaw, M. L., MacArthur, R. B., & Tuchman, M. (2001). Alternative pathway therapy for urea cycle disorders: twenty years later. Journal of Pediatrics, 138(1 Suppl), S46–S54.

• Mendelsohn, N. J., et al. (2006). Long-term efficacy and safety of glycerol phenylbutyrate for UCDs. Molecular Genetics and Metabolism Reports, 8, 43–49.

• National Urea Cycle Disorders Foundation. https://www.nucdf.org

• ClinicalTrials.gov – Search “urea cycle disorder” for ongoing trials and gene therapy updates.

Other Links:

OTC - https://cureOTCD.com