Carbamoyl phosphate synthetase I deficiency

Overview

Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare genetic metabolic disorder that impacts the body's ability to process and remove ammonia. Ammonia is a toxic waste product created when proteins are broken down. Normally, the liver converts ammonia into a less harmful substance called urea, which is then excreted from the body in urine. This conversion process is known as the urea cycle [PMID:31747864].

In individuals with CPS1 deficiency, a crucial enzyme in the urea cycle, carbamoyl phosphate synthetase I, does not function correctly. This leads to a build-up of ammonia in the blood, a condition known as hyperammonaemia. High ammonia levels can be very harmful, particularly to the brain, and can cause severe health problems if not managed promptly.

While this condition is rare, its early recognition and management are vital for improving outcomes. It is part of a group of conditions known as urea cycle disorders.

Symptoms & clinical features

Symptoms of CPS1 deficiency can vary in severity but often appear shortly after birth, within the first few days of life. These symptoms are primarily caused by the toxic effects of high ammonia levels on the brain and other organs. Newborns may seem normal at birth but quickly start to show signs of illness.

Common early symptoms include feeding difficulties, such as poor suckling or refusal to feed, vomiting, and lethargy (unusual sleepiness or lack of energy). As ammonia levels rise, infants may develop more severe symptoms like irritability, seizures, abnormal muscle tone (either floppiness or stiffness), and increasing somnolence, potentially progressing to coma. In some cases, respiratory distress can also occur [PMID:24269134].

Less commonly, some individuals with milder forms may present later in childhood or even adulthood, often triggered by stress, illness, or high protein intake. These later-onset symptoms can also include episodes of confusion, headaches, behavioural changes, and aversion to protein-rich foods.

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Affected organs

The primary organ affected by Carbamoyl phosphate synthetase I deficiency is the liver, where the urea cycle normally takes place. However, the most significant and damaging effects of high ammonia levels are typically seen in the brain. The brain is particularly vulnerable to ammonia toxicity, which can lead to swelling, neurological dysfunction, and long-term developmental issues if not promptly addressed.

Other body systems can also be indirectly affected by the severe metabolic disturbance. For example, the toxic effects can lead to electrolyte imbalances and can sometimes impact the kidneys, though not as a direct primary effect of the enzyme deficiency itself.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of CPS1 deficiency varies. Infants with complete absence or severe reduction of enzyme activity often experience severe symptoms within the first few days of life, which can be life-threatening if not diagnosed and treated urgently. These early-onset cases carry a significant risk of severe neurological damage due to prolonged hyperammonaemia.

For individuals with residual enzyme activity, symptoms might be milder or appear later, often triggered by metabolic stress, infections, or excessive protein intake. Despite a later onset, these individuals are still at risk of acute metabolic crises that can lead to coma and permanent neurological damage. The long-term outlook depends heavily on the timeliness and effectiveness of management, with early diagnosis and strict adherence to treatment protocols being crucial for improving outcomes [PMID:31747864]. The exact prevalence of CPS1 deficiency is not well established due to its rarity.

Genetic causes

Carbamoyl phosphate synthetase I deficiency is caused by pathogenic variants in the *CPS1* gene. This gene provides the instructions for making the carbamoyl phosphate synthetase I enzyme. This enzyme is crucial for the very first step of the urea cycle, a series of biochemical reactions that occur mainly in the liver.

The carbamoyl phosphate synthetase I enzyme's main job is to combine ammonia with bicarbonate to form carbamoyl phosphate. This is an essential step in converting toxic ammonia into urea, which can then be safely removed from the body. When variants in the *CPS1* gene lead to a non-functional or deficient enzyme, this critical first step of the urea cycle is impaired.

Without sufficient functional carbamoyl phosphate synthetase I, ammonia cannot be effectively processed and builds up in the bloodstream, leading to hyperammonaemia and the associated clinical symptoms observed in CPS1 deficiency.

• CPS1
  carbamoyl-phosphate synthase 1
  The CPS1 gene provides instructions for producing carbamoyl-phosphate synthase 1, an enzyme critical for the first step of the urea cycle in the body's nitrogen waste removal pathway.

Inheritance pattern

Carbamoyl phosphate synthetase I deficiency is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of the altered *CPS1* gene - one from each parent - to develop the condition.

Individuals who inherit only one copy of the altered gene are known as carriers. Carriers typically do not show symptoms of the condition themselves because their single working copy of the *CPS1* gene is usually sufficient to produce enough functional enzyme. When two carriers have children together, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered gene copies and develop CPS1 deficiency. There is a 50% (2 in 4) chance their child will be a carrier, and a 25% (1 in 4) chance their child will inherit two working copies of the gene and not be affected or a carrier.

Diagnosis & testing

Diagnosis of Carbamoyl phosphate synthetase I deficiency is usually suspected based on clinical symptoms, especially in a newborn presenting with acute hyperammonaemia without an obvious cause. Initial blood tests may show elevated ammonia levels and characteristic abnormalities in amino acids and organic acids. Further specific laboratory tests, such as plasma amino acid analysis and urine organic acid analysis, can help differentiate CPS1 deficiency from other urea cycle disorders.

Definitive diagnosis is confirmed through genetic testing, which identifies pathogenic variants in the *CPS1* gene. This testing is crucial for confirming the diagnosis, guiding management, and enabling genetic counselling for the family. In the UK, genetic testing for suspected urea cycle disorders, including CPS1 deficiency, may be accessed through the NHS Genomic Medicine Service (GMS) pathways. Healthcare professionals, such as paediatricians or clinical geneticists, can refer eligible patients for genomic testing, often using specific R-codes from the National Genomic Test Directory.

Management & lifestyle

The management of Carbamoyl phosphate synthetase I deficiency focuses on preventing and treating hyperammonaemia and providing adequate nutrition. Acute hyperammonaemic crises require emergency medical intervention, often including intravenous ammonia-scavenging medications and sometimes dialysis to rapidly reduce ammonia levels [PMID:24269134].

Long-term management typically involves a strict, lifelong, protein-restricted diet to limit the production of ammonia. This diet needs careful monitoring by a specialist dietitian to ensure adequate growth and development. Medications that help remove ammonia (ammonia scavengers) may also be prescribed. Regular monitoring of ammonia levels and growth parameters is essential.

Patients with CPS1 deficiency are managed by a multi-disciplinary team, including metabolic specialists, dietitians, and genetic counsellors. In the UK, care pathways within the NHS Genomic Medicine Service ensure access to specialist metabolic centres and ongoing support. Genetic counselling is vital for affected individuals and their families to understand the condition, its inheritance, and reproductive risks.

UK care pathway

In the UK, individuals suspected of having Carbamoyl phosphate synthetase I deficiency, or other rare genetic conditions, typically enter a care pathway through the NHS Genomic Medicine Service (GMS). If a clinician suspects a genetic condition based on symptoms, they may refer the patient for genomic testing. These tests are guided by the National Genomic Test Directory, which uses specific R-codes to indicate eligibility for testing, for example, R148 for 'Urea cycle disorders'.

Following a diagnosis, individuals are usually referred to specialist metabolic centres, often associated with a paediatric or adult clinical genetics service. Here, a team of experts, including clinical geneticists, metabolic consultants, and specialist dietitians, will coordinate care. Genetic counsellors play a key role in explaining the condition, its inheritance, and implications for family planning.

Related conditions

Carbamoyl phosphate synthetase I deficiency is one of several conditions known as urea cycle disorders. These disorders all result from defects in different enzymes involved in the urea cycle, leading to the accumulation of ammonia in the body. Other related urea cycle disorders include Ornithine Transcarbamylase (OTC) deficiency, Argininosuccinic Aciduria, and Citrullinaemia.

While all urea cycle disorders share the common feature of hyperammonaemia and its associated symptoms, the specific enzyme defect and the pattern of biochemical abnormalities can help distinguish between them. For instance, OTC deficiency is X-linked, whereas CPS1 deficiency is autosomal recessive. Accurate diagnosis differentiating these conditions is crucial for appropriate management and prognosis.

Frequently asked questions

References

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