Carbamoyl phosphate synthetase 1, or CPS1, is an enzyme located within the mitochondria, the powerhouses of our cells. This protein is most abundant in the mitochondria of liver cells, where it performs its primary duties. It is also present in smaller quantities within the cells lining the small intestine, contributing to other metabolic processes there. This enzyme is a ligase, meaning its function is to join two molecules together.
Role in the Urea Cycle
The body’s metabolism of proteins, a necessary process for growth and repair, produces ammonia as a byproduct. Ammonia is toxic, and its accumulation can be harmful, so the body has a specialized system to dispose of it called the urea cycle. This multi-step process, occurring primarily in the liver, converts ammonia into a much less toxic substance called urea, which is then safely eliminated from the body through urine.
CPS1 initiates the very first step of the urea cycle. It takes ammonia and bicarbonate, a common substance in the body, and uses energy from ATP to convert them into a molecule called carbamoyl phosphate. This reaction is not just the first step; it is also the rate-limiting step of the entire cycle. This means the speed at which CPS1 works dictates the overall pace of the entire urea cycle, much like the first step in an assembly line dictates the overall speed. The activity of CPS1 itself is regulated by the availability of its substrates and other cellular signals, ensuring the urea cycle operates according to the body’s needs for nitrogen disposal.
Consequences of CPS1 Deficiency
When CPS1 does not function correctly, the urea cycle cannot begin, leading to a serious condition known as CPS1 deficiency. The immediate and most dangerous consequence is the rapid buildup of ammonia in the bloodstream, a state called hyperammonemia. The brain is particularly vulnerable to the toxic effects of high ammonia concentrations.
This neurotoxicity manifests in a range of severe symptoms, especially in newborns who often show signs within the first few days of life. Initial symptoms can include:
- Sleepiness or lethargy
- Poor appetite
- Vomiting
- Problems regulating breathing
- Problems regulating body temperature
As ammonia levels continue to rise, the situation can quickly escalate to include seizures, abnormal body movements, and ultimately, coma. Without prompt and aggressive treatment to lower ammonia levels, the damage to the central nervous system can be permanent, leading to developmental delays and intellectual disability in survivors, or it can be fatal.
Even individuals who survive a neonatal hyperammonemic episode may experience recurrent crises throughout their lives. These episodes can be triggered by stressors such as infections or an inappropriate diet that produces more ammonia than their compromised urea cycle can handle. In some cases, individuals may have a less severe form of the disorder where symptoms do not appear until later in life, but the underlying risk from high ammonia levels remains.
Genetic Basis of the Deficiency
CPS1 deficiency is a hereditary disorder rooted in the body’s genetic blueprint. The instructions for making the carbamoyl phosphate synthetase 1 enzyme are encoded in a specific gene, known as the CPS1 gene. This gene is located on the long arm of chromosome 2. These mutations alter the genetic instructions, resulting in the production of a CPS1 enzyme that is misshapen and non-functional, or preventing the enzyme from being produced at all.
The inheritance pattern for this condition is described as autosomal recessive. This means that for an individual to have CPS1 deficiency, they must inherit two mutated copies of the CPS1 gene—one from each parent. A person who inherits only one mutated copy is considered a carrier; they typically do not show any signs or symptoms of the disorder because their one functional copy of the gene can produce enough of the enzyme to manage ammonia levels effectively.
Diagnosis and Management
Diagnosing CPS1 deficiency often begins shortly after birth. Many newborn screening programs include tests that can detect abnormalities suggestive of a urea cycle disorder. When a newborn displays symptoms like lethargy or seizures, doctors will promptly order blood tests to measure ammonia levels. A significantly elevated ammonia level is a strong indicator of a urea cycle defect, and further analysis can pinpoint the exact enzyme deficiency. To confirm the diagnosis definitively, genetic testing is performed to identify mutations in the CPS1 gene.
Management of CPS1 deficiency is a lifelong endeavor focused on preventing hyperammonemia and its neurological effects. The primary treatment is a strict low-protein diet, which aims to limit the intake of nitrogen from food sources, thereby reducing the amount of ammonia the body produces. This dietary restriction must be carefully managed to ensure the individual still receives adequate nutrition for growth and development.
To supplement dietary control, patients are often prescribed medications known as ammonia scavengers. These compounds, such as sodium phenylbutyrate and sodium benzoate, work by providing an alternative pathway for the body to remove nitrogen waste, bypassing the defective urea cycle. In severe cases where dietary and medical management are insufficient, a liver transplant may be considered a curative measure, as it provides a new liver with functional CPS1 enzymes.