Urea Cycle Disorders (UCDs)

Urea Cycle Disorders (UCDs)

The urea cycle is a series of biochemical reactions that occur primarily in the liver, which converts toxic ammonia produced by the breakdown of protein and other nitrogen-containing molecules in the human body into urea for excretion. Urea cycle disorders (UCDs) are a group of disorders caused by genetic mutations that result in a deficiency in any one of the six enzymes or two of the amino acid transporters, which can lead to an excess accumulation of ammonia in the bloodstream, a condition known as hyperammonemia. Acute hyperammonemia can cause lethargy, somnolence, coma, and multi-organ failure, while chronic hyperammonemia can lead to headaches, confusion, lethargy, failure to thrive, behavioral changes, and learning and cognitive deficits. Common symptoms of both acute and chronic hyperammonemia also include seizures and psychiatric symptoms.

Diagnosis and Incidence
The diagnosis of UCDs is based on clinical observations, confirmed by biochemical and molecular genetic testing. A plasma ammonia concentration of 150 μmol/L or higher associated with a normal anion gap and a normal plasma glucose concentration is an indication for the presence of UCDs. Plasma quantitative amino acid analysis and measurement of urinary orotic acid can distinguish between the various types of UCDs. A definitive diagnosis of UCDs depends on either molecular genetic testing or measurement of enzyme activity. Molecular genetic testing is possible for all urea cycle defects. Studies suggest that the incidence of UCDs in the U.S. is about 1 in 35,000 live births.1 Table 1 shows estimates of the incidence for the individual disorders based on this overall incidence. Newborn screening data on over six million births and data from the large US and European longitudinal registries was used to determine how common these conditions are. Approximately 2,000 patients suffer from UCDs in the U.S.

Table 1: Distribution by Group and Overall Incidence of UCDs

*As of April 2013

Abbreviations: UCDC (Urea Cycle Disorders Consortium); E-IMD (European Registry and Network for Intoxication Type Metabolic Diseases); NUCDF (National Urea Cycle Disorders Foundation); UCDs (urea cycle disorders); NAGS (N-acetylglutamate synthase); CPSI (carbamoyl phosphate synthetase I); OTC (ornithine transcarbamylase); ASS/AS (argininosuccinic acid synthetase); ASL (argininosuccinate lyase); ARG (arginase); HHH (hyperornithinemia-hyperammonemia-homocitrullinuria syndrome)

Table Source: Marshall L. Summar, et al., The incidence of urea cycle disorders, Molecular Genetics and Metabolism, Volume 110, Issues 1–2, 2013, Pages 179-180.

Current Treatment Options for UCDs
The current treatment of UCDs consists of dietary management to limit ammonia production in conjunction with medications that provide alternative pathways for the removal of ammonia from the bloodstream. Dietary protein must be carefully monitored, and some restriction is necessary; too much dietary protein causes excessive ammonia production. However, if protein intake is too restrictive or insufficient calories are consumed, the body will break down lean muscle mass to obtain the amino acids or energy it requires, which can also lead to excessive ammonia in the bloodstream. Dietary management may also include supplementation with special amino acid formulas developed specifically for UCDs, which can be prescribed to provide approximately 50% of the daily dietary protein allowance. Some patients treated with sodium phenylbutyrate may also require individual branched-chain amino acid supplementation.

Medications for UCDs are primarily comprised of nitrogen scavenger drugs, which are substances that provide alternative excretion pathways for nitrogen by bypassing the urea cycle. The use of these alternative pathways for nitrogen removal is important for the management of acute episodes of hyperammonemia and are also included as part of a long-term treatment regimen for UCDs patients. Current nitrogen scavenger treatments for UCDs are based on phenylbutyrate or benzoate, which conjugate with glutamine or glycine, respectively, allowing for urinary excretion of nitrogen as phenylacetylglutamine or ippurate, respectively.

According to a 2016 study by Shchelochkov et al., published in Molecular Genetics and Metabolism Reports2, while nitrogen scavenging medications are effective in helping to manage UCDs, non-compliance with treatment is common. Reasons given for non-compliance include the unpleasant taste associated with some available medications, the frequency with which medication must be taken and the high cost of the medication.

Phenylbutyrate is available as both NaPB, which is marketed as BUPHENYL®, and glycerol phenylbutyrate (GPB), which is marketed as RAVICTI®. While a study provided by Horizon Therapeutics, Inc. in the RAVICTI® package insert involving 46 adults with UCDs demonstrated that BUPHENYL® and RAVICTI® were similarly effective in controlling the blood level of ammonia over a 24-hour period, many patients who take their medicine orally prefer RAVICTI®, as it is significantly more palatable than BUPHENYL®. However, the average annual cost of RAVICTI® is $950,000 (based on patient weight), which is often prohibitively expensive.3

In cases where dietary management or medication is not effective, patients with UCDs may require a liver transplant.

References:

  1. Peña-Quintana L, et al. Profile of sodium phenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. Patient Prefer Adherence. 2017 Sep 6;11:1489-1496.
  2. Shchelochkov et al. Molecular Genetics & Metabolism Reports 8 (2016) 43-47.
  3. Batshaw ML, Tuchman M, Summar M, Seminara J; Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014 Sep-Oct;113(1-2):127-30. Doi: 10.1016/j.ymgme.2014.08.001. Epub 2014 Aug 10. Review.
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