Carbamoyl phosphate synthetase 1 deficiency (CPSID) is a rare inherited disorder characterized by complete or partial lack of the carbamoyl phosphate synthetase (CPS) enzyme. This is one of five enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the CPSI enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Affected children may experience vomiting, refusal to eat, progressive lethargy, and coma. CPSID is inherited as an autosomal recessive genetic disorder.[rx]
The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.[rx]
Carbamoyl Phosphate Synthetase 1 Deficiency, also known as CPS1 deficiency, is a rare genetic disorder that affects the body’s ability to produce a substance called urea. Urea plays a crucial role in removing excess nitrogen from the body, so when CPS1 deficiency occurs, it can lead to a buildup of harmful ammonia in the blood. In this article, we will provide simple explanations for various aspects of CPS1 deficiency, including its types, causes, symptoms, diagnosis, treatment options, and medications.[rx]
Types of CPS1 Deficiency
CPS1 deficiency can be classified into two main types: neonatal onset and late-onset.
- Neonatal Onset CPS1 Deficiency: This is the most severe form of the condition and is usually apparent shortly after birth. Babies with neonatal onset CPS1 deficiency may show symptoms like poor feeding, vomiting, seizures, and lethargy.
- Late-Onset CPS1 Deficiency: This form of CPS1 deficiency becomes noticeable later in life, often during childhood or adolescence. Symptoms may include confusion, behavioral changes, and episodes of extreme tiredness.
Causes of CPS1 Deficiency
CPS1 deficiency is caused by mutations in the CPS1 gene, which provides instructions for making the CPS1 enzyme. This enzyme is essential for the urea cycle, a process that helps remove ammonia from the body. When CPS1 enzyme activity is reduced or absent due to genetic mutations, ammonia buildup occurs.[rx]
CPSID is inherited as an autosomal recessive genetic disorder and is caused by mutations in the CPSI gene. Mutations in the CPSI gene result in production of an abnormal carbamoyl phosphate synthetase enzyme.[rx]
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.[rx]
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.[rx]
Symptoms of CPS1 Deficiency
The symptoms of CPS1 deficiency can vary in severity, but they all stem from the accumulation of ammonia in the body. Here are some common symptoms:
- Vomiting: People with CPS1 deficiency may experience recurrent episodes of vomiting.
- Lethargy: Fatigue and a lack of energy are common symptoms, especially in infants.
- Poor Feeding: Babies may have difficulty feeding and may not gain weight properly.
- Seizures: In severe cases, seizures can occur due to high ammonia levels.
- Confusion: Individuals with late-onset CPS1 deficiency may experience confusion and behavioral changes.
- Respiratory Issues: Breathing problems can occur in severe cases.
- Coma: If ammonia levels become extremely high, it can lead to a coma and be life-threatening.
- Intellectual Disabilities: Prolonged exposure to elevated ammonia levels can result in intellectual and developmental issues.
- Growth Problems: Children with CPS1 deficiency may have growth delays.
- Liver Damage: Elevated ammonia can harm the liver over time.
The symptoms of CPSID are caused by the accumulation of ammonia in the blood. The severe form of CPSID occurs within 24-72 hours after birth, regardless of exposure to dietary protein. This form of CPSID is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting, and irritability. Shortly thereafter, affected infants may also experience seizures, respiratory distress, and abnormal movements and postures, The symptoms are mostly attributable to the swelling of the brain (cerebral edema) caused by hyperammonemia.[rx]
In neonatal cases, untreated CPSID progresses to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases and even with effective treatment, the disorder may potentially result in neurological abnormalities, including developmental delays and intellectual disability. The neurological abnormalities are more severe in infants who are in hyperammonemic coma for a prolonged period (days). If left untreated, the disorder will typically results in death of the patient.[rx]
Those with the milder form of CPSID show symptoms later during infancy, childhood, or adulthood. Symptoms are often triggered by a secondary illness such as a viral infection or other stress. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, vomiting, and/or diminished muscle tone (hypotonia). Patients with the milder form of CPSID may still experience hyperammonemic coma and life-threatening complications.[rx]
Diagnosing CPS1 Deficiency
A diagnosis of CPSID involves a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, which is the main criterion for a diagnosis of urea cycle disorders including CPSID. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, liver disease, and fatty acid oxidation disorders. [rx]Urea cycle disorders can be differentiated from these disorders through the examination of urine for elevated levels of, or abnormal, organic acids. In urea cycle disorders, urinary organic acids are normal except for the presence of orotic acid in OTCD. Genetic sequencing of the CPSI gene is the main form of diagnosis at this time (typically combined with sequence of the other urea cycle enzymes). Measurement of CPSID1 enzyme activity on cells obtained from a liver biopsy can confirm the diagnosis but is rarely employed currently.[rx]
Diagnosing CPS1 deficiency is essential to provide appropriate treatment. Several diagnostic tests can help identify the condition:
- Blood Ammonia Levels: A simple blood test measures ammonia levels in the blood. Elevated levels may indicate CPS1 deficiency.
- Genetic Testing: Genetic tests can identify mutations in the CPS1 gene, confirming the diagnosis.
- Urine Organic Acid Analysis: This test can detect abnormal substances in the urine that are associated with CPS1 deficiency.
- Liver Function Tests: These tests assess liver health, which can be affected by high ammonia levels.
- Imaging: Brain imaging may be necessary if neurological symptoms are present to rule out other causes.
Treatment for CPS1 Deficiency
Treatment is very complex and should be coordinated by a metabolic specialist at a center experienced in the care of urea cycle patients. Therapy is based on reducing plasma ammonia concentration, preventing excess ammonia from being formed, and reducing the amount of nitrogen in the diet while supplying enough for growth.[rx]
Reduction of plasma ammonia concentration is accomplished by dialysis and several different methods are available.
The nitrogen scavenger drugs sodium phenylacetate and sodium benzoate provide an alternative pathway for removing excess nitrogen. Intravenous and oral forms of these medications are available (Ammonul and Ucephan). Phenylbutyrate (Buphenyl) has a less offensive odor than the other medications but is available as oral therapy only.[rx]
Dietary restrictions in individuals with CPSID are aimed at limiting the amount of protein intake. Children with CPSID are placed on a low-protein, high calorie diet, supplemented by essential amino acids. Treatment may also include citrulline or arginine, to maintain a normal rate of protein formation (synthesis).[rx]
Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can sometimes prevent coma and severe neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications. In many centers liver transplantation is offered as a more permanent solution to severe CPSID.[rx]
Consensus treatment guidelines are available online at the NIH sponsored urea cycle disorders consortium website.[rx]
http://rarediseasesnetwork.epi.usf.edu/ucdc/
Seizures are treated with phenobarbital or carbamazepine. Valproic acid and intravenous steroids should be avoided, as it can increase blood ammonia levels. Prednisone and other similar steroid compounds should also be avoided because they will trigger a protein catabolic state and hyperammonemia. Inhaled steroids are somewhat safer if necessary.[rx]
Managing CPS1 deficiency primarily involves reducing ammonia buildup and providing nutritional support. Treatment options include:
- Protein-Restricted Diet: Reducing protein intake can help decrease ammonia production. Patients may need a special low-protein diet.
- Medications: Medications like sodium benzoate and sodium phenylbutyrate can help remove excess ammonia from the body.
- Hemodialysis: In severe cases, hemodialysis may be necessary to lower ammonia levels quickly.
- Liver Transplant: In cases of severe liver damage or unmanageable ammonia levels, a liver transplant may be considered.
- Regular Monitoring: Patients require frequent monitoring of ammonia levels and overall health.
- Supportive Care: Supportive therapies may be needed to address specific symptoms or complications.
Medications for CPS1 Deficiency
Several medications can be prescribed to manage CPS1 deficiency:
- Sodium Benzoate: This medication helps the body excrete excess ammonia.
- Sodium Phenylbutyrate: It reduces ammonia levels and promotes its elimination.
- Arginine: Arginine supplements can support the urea cycle and help reduce ammonia buildup.
- Citrulline: Citrulline may be used to improve urea cycle function.
- Phenylacetate: Sometimes used in combination with other medications to lower ammonia levels.
- Antibiotics: Antibiotics like rifaximin can help decrease ammonia-producing bacteria in the gut.
- Anti-Seizure Medications: These may be prescribed if seizures are a symptom.
Conclusion
Carbamoyl Phosphate Synthetase 1 Deficiency is a rare genetic disorder that affects the body’s ability to eliminate ammonia. It can lead to a range of symptoms, from vomiting and poor feeding in infants to confusion and seizures in older individuals. Early diagnosis and appropriate treatment are crucial to manage the condition effectively. Treatment may involve dietary restrictions, medications, and, in severe cases, liver transplantation. Regular monitoring and a supportive healthcare team can significantly improve the quality of life for individuals with CPS1 deficiency. If you suspect you or a loved one may have CPS1 deficiency, consult a healthcare professional for proper evaluation and guidance.
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