CPS1 deficiency is one of the rarest urea cycle disorders (UCDs), affecting roughly 1 in 800 000 to 1 in 1 000 000 people worldwide. The enzyme carbamoyl phosphate synthetase I is the first and most critical step in the urea cycle — the liver's mechanism for converting toxic ammonia from protein metabolism into harmless urea, which is excreted in urine. When CPS1 is absent or severely reduced, ammonia accumulates rapidly and can cause brain damage, coma, or death.
Most severe cases present in newborns, but milder late-onset forms are increasingly recognised in older children and adults — some of whom reach adulthood before diagnosis. Adults with late-onset CPS1 deficiency frequently need to manage weight, often after years of unknowingly avoiding high-protein foods. This guide is for them — and for parents managing older children with the condition.
Always work with a metabolic dietitian and your treating physician. CPS1 deficiency is life-threatening if mismanaged. This article provides general education, not medical advice.
The urea cycle is a sequence of six enzymatic reactions, all occurring in liver cells. CPS1 catalyses the very first reaction: combining ammonia, bicarbonate, and two molecules of ATP to produce carbamoyl phosphate. Without this step, the entire downstream cycle stalls and ammonia piles up.
Ammonia is neurotoxic at elevated concentrations. Even short periods of hyperammonemia — plasma ammonia above 80–100 µmol/L in adults — can cause cerebral oedema, altered consciousness, and irreversible neurological damage. Prolonged or severe elevation (above 200 µmol/L) is a medical emergency.
The CPS1 gene sits on chromosome 2q35. Pathogenic variants are typically missense mutations, deletions, or splice-site changes — over 200 variants have been described. Inheritance is autosomal recessive, meaning both copies of the gene must be abnormal for the disorder to manifest.
Every gram of protein you eat contains nitrogen. When protein is metabolised, nitrogen is released as ammonia. The urea cycle converts that ammonia to urea. In CPS1 deficiency, that conversion fails. This means:
Paradoxically, many adults with late-onset CPS1 deficiency carry excess weight. Reasons include:
Excess weight worsens metabolic health, increases cardiovascular risk, and can worsen insulin resistance — which in turn complicates nitrogen handling. Achieving a healthy weight reduces these risks and can improve liver function relevant to urea cycle efficiency.
In most metabolic conditions, 0.5 kg/week is considered a safe maximum. For CPS1 deficiency, the upper limit is even more conservative — most metabolic dietitians target 0.25–0.3 kg per week, with frequent ammonia monitoring. Losing weight faster causes muscle catabolism that releases more nitrogen than the impaired urea cycle can handle.
Standard protein recommendations (1.2–2 g/kg/day) are unsafe in CPS1 deficiency. Protein intake is prescribed in grams per day by your metabolic team, typically 0.5–0.8 g/kg ideal body weight per day of natural protein, often supplemented with essential amino acid (EAA) formulas to prevent deficiency while minimising waste nitrogen.
South African metabolic formula options are limited — most families import from the UK (Vitaflo, Nutricia). Ask your metabolic dietitian about GEMS or medical aid coverage for therapeutic formulas under the metabolic chronic condition benefit.
Since protein is severely restricted, calories must come predominantly from fat and carbohydrates:
| Food Type | Role | SA Examples |
|---|---|---|
| Complex carbohydrates | Primary energy — prevents muscle catabolism | Brown rice, sweet potato, samp, pap (moderate portions) |
| Low-GI starchy veg | Sustained energy, vitamins | Butternut, beetroot, carrots, gem squash |
| Healthy fats | Calorie density without nitrogen | Avocado, olive oil, nuts (within protein budget) |
| Fruit | Carbohydrates, micronutrients | Banana, mango, pawpaw, granadilla |
| Low-protein bread/pasta | Protein-free energy | Loprofin speciality products (via some SA pharmacies) |
Exercise is beneficial for metabolic health — but must be approached carefully in CPS1 deficiency. Key principles:
| Test | Frequency | Target / Action |
|---|---|---|
| Plasma ammonia | Monthly minimum (more during weight loss phase) | Below 80 µmol/L; if elevated, reduce catabolism urgently |
| Plasma amino acids | Every 3 months | Essential amino acids within normal range |
| Liver function tests | Every 6 months | Baseline surveillance — CPS1 is liver-based |
| Body weight | Weekly | Loss no faster than 0.25–0.5 kg/week |
| Plasma urea | Monthly | Low urea paradoxically indicates inadequate urea cycle activity |
All patients with CPS1 deficiency should carry an emergency protocol. During illness, surgery, or any period of reduced oral intake: stop all natural protein, begin emergency high-carbohydrate intake, increase nitrogen scavengers per your metabolic team's sick-day plan, and contact your metabolic unit immediately. In South Africa: Charlotte Maxeke Academic Hospital (Johannesburg) and Tygerberg Hospital (Cape Town) both have metabolic units.