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  • Updated 05.06.2020
  • Released 11.28.1994
  • Expires For CME 05.06.2023

Carbamoyl phosphate synthetase I deficiency


This article includes discussion of carbamoyl phosphate synthetase I deficiency, carbamoyl phosphate synthetase 1 deficiency (CPS1D), carbamylphosphate synthetase 1 deficiency, congenital hyperammonemia type 2, and CPS1 deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Carbamoyl phosphate synthetase I deficiency (CPS1D) is an inherited urea cycle defect that causes hyperammonemia, neurologic sequelae, and most importantly, intellectual disability and early death. Complete enzyme deficiency almost invariably results in hyperammonemic coma within the first days of life (≤ 28 days; neonatal-/early-onset), whereas partial deficiency can present with hyperammonemia at any age (> 28 days; late-onset). Biochemical markers include elevated plasma glutamine and reduced or absent L-arginine and L-citrulline concentrations on amino acid analysis. Diagnosis is established by enzyme analysis of liver tissue, or genetic analysis, or both. Treatment consists of a protein-restricted diet, ammonia scavenger drugs, and substitution with L-citrulline or L-arginine. Liver transplantation cures recurrent hyperammonemic episodes, but will not restore irreversible neurologic sequelae.

Currently, international networks for rare metabolic diseases (UCDC, E-IMD, JUCDC) aim to more completely describe the natural history, especially the initial and evolving clinical phenotype, of urea cycle disorders such as carbamoyl phosphate synthetase I deficiency. Furthermore, they want to determine if the natural disease course can be favorably modulated by diagnostic and therapeutic interventions. These networks collect systematic data to improve the clinical knowledge, develop guidelines, and provide patients and professionals with reliable data on disease manifestation, complications, as well as long-term outcomes of urea cycle disorders. They include the Urea Cycle Disorders Consortium (UCDC), established in 2006, the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD), established in 2011, and the Japanese Urea Cycle Disorders Consortium (JUCDC), established in 2012 (90).

Key points

• Carbamoyl phosphate synthetase I deficiency is a rare urea cycle disorder that causes hyperammonemia, neurologic sequelae, and intellectual disability.

• Disease manifestations occur most often within the first days of life (early onset ≤ 28 days) and less commonly after the neonatal period (late onset > 28 days).

• Neurologic outcome depends on noninterventional parameters, eg, intrinsic disease severity (reflected by onset type and initial peak plasma ammonium concentration during first metabolic decompensation). The impact of interventional parameters, eg, diagnostic and therapeutic interventions, on clinical outcome remains to be elucidated.

• Therapy is based on principles of acute and long-term management involving diet and antihyperammonemic pharmacotherapy.

Historical note and terminology

Carbamoyl phosphate synthetase 1 deficiency was first reported in 1962 (80). The nomenclature distinguishes this mitochondrial urea cycle enzyme from carbamoyl phosphate synthetase 2, which is cytosolic and involved in pyrimidine synthesis.

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