Introduction

Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare hereditary disorder. It is estimated to occur in one in every 150-200,000 births. It is classified as a urea cycle disorder and is characterized by elevated ammonia levels in the body. This can result in a fatal medical emergency in newborns, causing severe brain injuries, comas, or even death in severe cases.

In this article, we will learn about this rare disorder. However, before we get into this you should be familiar with the urea cycle. Let's read on to know more.

Understanding urea cycle and urea cycle disorders?

The human body is a complex machine that performs basic life processes using chemical substances known as biomolecules. These act as the foundation for all basic life processes. They coordinate the various processes that occur within cells, defining the characteristics of living things and facilitating their growth, adaptation, and evolution (Benjafield JG, 2013).

Biomolecules can be classified into four major categories: carbohydrates, lipids, proteins, and nucleic acids.Each of these biomolecule types serves a distinct purpose in the functioning of living organisms.Proteins, fats, and carbohydrates (known as macronutrients) are all components of a complex metabolic cycle that is necessary for life. Food that contains these nutrients undergoes chemical breakdown during digestion, allowing the body to absorb and use the fundamental components.

Proteins are the most diverse and versatile biomolecules, performing a wide range of functions inside cells. They are large, complex molecules composed of a chain of amino acids bound together by peptide bonds.They carry out most of the work in cells and are important for the organisation, operation, and control of the body's organs and tissues.

Protein must be consumed on a daily basis because your body does not store it in the same way that fats or carbohydrates are stored. Proteins and other nitrogenous substances are continuously degraded and synthesized. They exist in a state of balance between anabolism (formation) and catabolism (breakdown).

Proteins, when metabolized in the body, produce nitrogenous waste products such as ammonia, urea, uric acid, and creatinine.These are excreted through urine or feces.

The urea cycle occurring in the liver is the only pathway capable of metabolizing waste nitrogen (a byproduct of protein metabolism). It consists primarily of five catalytic enzymes, including carbamoyl phosphate synthetase 1 (CPS1). Mutations (alterations) in any of the enzymes involved can cause urea cycle disorders. Normally, urea is excreted through urine. In urea cycle disorders, nitrogen accumulates as ammonia, a highly toxic substance, resulting in hyperammonemia. 

What is carbamoyl phosphatase synthetase 1 deficiency?

A CPS1 deficiency occurs when the CPS1 enzyme, which is involved in the urea cycle and detoxifies ammonia, is absent completely or partially. This results in elevated levels of ammonia in the bloodstream, which is toxic in nature. CPS1 deficiency can manifest in two forms: the neonatal lethal and the less severe late-onset form.

Infants with carbamoyl phosphate synthetase I deficiency usually show signs of hyperammonemia (elevated levels of ammonia in the blood) in the first few days of life. If a person with this condition makes it through the newborn period and then gets infections or other stressful events later on, they may experience the symptoms of CPS1D again. Additionally, they might have an intellectual disability and delayed development. In some cases, it can manifest later in life in a milder form.

What clinical implications does it have?

The clinical picture of CPS1D disorder varies depending on whether the enzyme is completely or partially absent. In the case of complete absence, symptoms show up within 24 to 72 hours of childbirth (neonatal period). The symptoms appear due to the accumulation of ammonia in the blood and result in a severe form, which is described as:

• Refusal to feed
• Lack of appetite
• Lethargy
• Vomiting, irritability

Affected infants may eventually exhibit the following symptoms:

• Seizures
• Respiratory distress
• Abnormal movements and postures
• Cerebral edema (swelling of brain)

If left untreated, CPS1D can progress to coma due to high blood ammonia levels. Despite successful treatment, the disorder may still lead to neurological problems like intellectual disabilities and developmental delays.

In milder cases, symptoms may appear later in infancy, childhood, or adulthood. A secondary illness, such as a viral infection or another stressor, is usually what causes the symptoms to appear. Symptoms associated with milder forms include:

• Not being able to grow and gain weight at the expected rate
• Avoidance of protein from the diet
• Inability to coordinate voluntary movements (ataxia)
• Vomiting
• Diminished muscle tone (hypotonia)
• An affected person may go into a hyperammonemic coma and have other problems that could be life-threatening

What are the underlying causes of CPS1 deficiency?

We learned that it is a genetic disorder in the last section. It is inherited as an autosomal recessive genetic disorder caused by CPS1 gene mutations.The production of the CPS1 enzyme is directed by this particular gene.Recessive genetic disorders occur when an individual receives two copies of a defective gene for the same trait, one from each parent. A person will be a carrier for the disease but will not exhibit any symptoms if they inherit one healthy gene and one disease gene. With each pregnancy, the likelihood of having a child who is a carrier like both parents increases by half. There is a 25% chance that a child will inherit normal genes from both parents and be genetically normal for that trait. Both men and women are at the same risk.

How can a CPS1 deficiency be diagnosed?  

Anyone, from newborns to adults, who show any of the above symptoms should be checked for urea cycle disorders. Basically, the diagnosis includes:

• An in-depth medical history of the patient and their family
• Identification of characteristic findings
• Specialised tests to verify the disorder
• Genetic sequencing of the CPS1 gene

The following are some of the preliminary laboratory tests that must be carried out in order to make the diagnosis:

• Plasma ammonia, plasma amino acids
• Urine orotic acid
• Tests for liver function (AST, ALT, bilirubin, and alkaline phosphatase)
• Arterial or venous blood gas
• Blood glucose
• Depending on the clinical indication, blood, urine, and/or CSF cultures

Blood tests can reveal high levels of ammonia in the blood, which is the primary criterion for diagnosing urea cycle disorders such as CPS1D. However, elevated blood ammonia levels can also be a sign of other conditions such as fatty acid oxidation disorders, liver disease, and congenital lactic acidosis. These can be distinguished from urea cycle disorders by looking for abnormal or elevated levels of organic acids (orotic acid) in the urine. 

How to manage and treat CPS1 deficiency?

The treatment process for the carbamoyl phosphate synthetase 1 deficiency is complex. In order to prevent brain impairment and the related morbidity and death, hyperammonemia needs to be treated immediately. The main steps of immediate care are:

• Protein intake should be discontinued (but not for more than 36-48 hours, as this can 
• promote endogenous protein breakdown and interfere with metabolic control)
• Provide intravenous fluids containing dextrose and intralipids
• Provide ammonia-scavenger medications 

Prepare for a possible hemodialysis

The treatment of a hyperammonemic crisis in a patient with CPS I deficiency is based on the following principles:

Facilitate the elimination of waste nitrogen

Hemodialysis and medications that facilitate ammonia excretion are the two primary methods of promoting ammonia detoxification.

Hemodialysis is far more efficient than other dialysis techniques (hemofiltration, peritoneal dialysis) and is the most efficient way to quickly get rid of extra ammonia. The decision to hemodialyze is critical for preventing or reducing irreversible CNS damage.

Ammonia scavenger medications include sodium benzoate and sodium phenylacetate. These work by removing nitrogen from glycine and glutamine, two compounds that contribute to hyperammonemia.

Reverse catabolism or increase caloric intake

The goal is to limit the amount of protein intake and stop or reverse catabolism by making sure that the affected individual gets enough calories from other sources. All proteins should be stopped for a while. It is important to maintain the recommended calorie intake for neonates and infants with CPS I deficiency during a hyperammonemic crisis. Strict intake and output records must be kept.

Manage the underlying precipitant

In patients with urea cycle disorders, a metabolic decompensation is frequently the result of an underlying illness, such as dehydration or infection, which induces a state of catabolism. It is important to do diagnostic research and provide treatment targeted at the underlying precipitant.

Conclusion

Carbamoyl Phosphate Synthetase 1 (CPS1) deficiency is a rare genetic disorder that disrupts the urea cycle, causing ammonia accumulation in the bloodstream. This condition can cause serious neurological damage and metabolic disturbances, especially in newborns and young children. Early detection through newborn screening and prompt treatment, including dietary management and ammonia scavengers, are critical for improving outcomes. Targeting CPS1D 

is still a major challenge. Ongoing research into gene therapy and novel treatments provides hope for better management of this challenging disorder.