In carbamoyl phosphate synthetase I (CPS I) deficiency, which of the following is the expected finding?

Explanation

## CPS I Deficiency: The First Step Block **Key Point:** Carbamoyl phosphate synthetase I (CPS I) catalyzes the first committed step of the urea cycle. Its deficiency prevents ammonia fixation and results in severe hyperammonemia with normal or low orotic acid (because carbamoyl phosphate is never formed to enter pyrimidine synthesis). ### The CPS I Reaction $$\text{NH}_3 + \text{CO}_2 + 2 \text{ ATP} + \text{Glutamine} \xrightarrow{CPS I} \text{Carbamoyl phosphate} + \text{ADP} + \text{Pi}$$ ### Metabolic Consequences of CPS I Deficiency 1. **Ammonia accumulation**: CPS I is the primary mechanism for ammonia fixation in the liver. Without it, ammonia cannot enter the urea cycle → severe hyperammonemia 2. **No carbamoyl phosphate formation**: The substrate for the entire urea cycle is absent 3. **Normal orotic acid levels**: Since carbamoyl phosphate is not produced, there is no substrate to be shunted into pyrimidine synthesis. Orotic acid remains normal or low 4. **Citrulline deficiency**: Downstream products of the urea cycle are not formed ### Comparison of Urea Cycle Defects | Enzyme Deficiency | Ammonia | Orotic Acid | Citrulline | Argininosuccinate | Distinctive Feature | | --- | --- | --- | --- | --- | --- | | **CPS I** | ↑↑↑ | Normal/Low | ↓ | ↓ | No orotic aciduria | | **OTC** | ↑↑↑ | ↑↑↑ | ↓ | ↓ | Orotic aciduria (pathognomonic) | | **Argininosuccinate synthetase** | ↑ | Normal | ↑↑ | Normal | Citrullinemia | | **Argininosuccinate lyase** | ↑ | Normal | Normal | ↑↑ | Argininosuccinic aciduria | | **Arginase** | ↑ | Normal | Normal | Normal | Argininemia | **High-Yield:** CPS I and OTC deficiencies are the most severe and present in the neonatal period. The key distinguishing feature is orotic acid: elevated in OTC deficiency, normal/low in CPS I deficiency. **Mnemonic:** **COMA** — **C**arbamoyl phosphate synthetase I, **O**TC, **M**itochondrial, **A**mmonia (the two most severe defects that cause neonatal hyperammonemia and encephalopathy).