U01.01.106 Ornithine transcarbamylase deficiency

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder, characterized by impaired ammonia elimination and the buildup of toxic metabolites. Its understanding is crucial for the USMLE Step 1 due to its biochemical and clinical implications.

Etiology

Genetic Basis:
- Inheritance Pattern: X-linked recessive.
- Contrast: Other urea cycle enzyme deficiencies are autosomal recessive.
Pathophysiology:
- Defective OTC enzyme leads to reduced elimination of ammonia.
- Excess carbamoyl phosphate is shunted into the pyrimidine synthesis pathway, forming orotic acid.

Clinical Presentation

Often evident in the first few days of life but may have late-onset forms.
Key Symptoms:
- Poor feeding, vomiting.
- Lethargy progressing to encephalopathy due to hyperammonemia.

Key Laboratory Findings

Parameter	Change	Notes
Orotic acid	↑ in blood and urine	Due to excess carbamoyl phosphate.
Blood Urea Nitrogen (BUN)	↓	Impaired urea cycle function.
Ammonia levels	↑	Causes neurological toxicity.
Megaloblastic anemia	Absent	Differentiates from orotic aciduria.

Differential Diagnosis

Condition	Key Feature	Differentiation
Orotic aciduria	Megaloblastic anemia	Absent in OTC deficiency.
Other urea cycle defects	No orotic acid buildup	Autosomal recessive inheritance.

Points to Remember

Inheritance: OTC deficiency is X-linked recessive.
Metabolic Pathway: Excess carbamoyl phosphate diverted to pyrimidine synthesis causes orotic acid accumulation.
Differentiation: Unlike orotic aciduria, megaloblastic anemia is absent in OTC deficiency.
Early Signs: Hyperammonemia symptoms like lethargy, vomiting, and encephalopathy may appear within days after birth.

USMLE Step 1 Pearls

Focus on the enzyme deficiency’s impact on the urea cycle and its clinical manifestations.
Correlate laboratory findings with the clinical picture, emphasizing orotic acid accumulation without anemia.
Recognize the inheritance pattern (X-linked) to differentiate from other urea cycle disorders.

Recommended References

Murray RK et al., Harper’s Illustrated Biochemistry.
Nelson DL, Cox MM, Lehninger Principles of Biochemistry.
OnlineMedEd and First Aid for the USMLE Step 1 resources.

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