Definition
- The urea cycle:
- Is the sole source of endogenous production of arginine, ornithine, and citrulline;
- Is the principal mechanism for the clearance of waste nitrogen resulting from protein turnover;
- Is the principal mechanism for the metabolism of other nitrogenous metabolic compounds such as adenosine monophosphate;
- Includes enzymes that overlap with the nitric oxide production pathway (ASS1 and ASL).
The urea cycle comprises the following components:
- Five catalytic enzymes:
- Carbamoylphosphate synthetase I (CPS1)
- Ornithine transcarbamylase (OTC)
- Argininosuccinic acid synthetase (ASS1)
- Argininosuccinic acid lyase (ASL)
- Arginase (ARG1)
Clinical Characteristics of Urea Cycle Disorders (UCDs)
- N-acetyl glutamate synthetase (NAGS)
Clinical Characteristics of Urea Cycle Disorders
- Ornithine translocase (ORNT1; ornithine/citrulline carrier; solute carrier family 25, member 15)
- Citrin (aspartate/glutamate carrier; solute carrier family 25, member 13)
Severe Urea Cycle Defects (Neonatal Onset)
- Urea cycle disorders (UCDs) result from inherited deficiencies in any one of the six enzymes or two transporters of the urea cycle pathway, specifically:
- CPS1 (Carbamoylphosphate synthetase I)
- OTC (Ornithine transcarbamylase)
- ASS1 (Argininosuccinic acid synthetase)
- ASL (Argininosuccinic acid lyase)
- ARG1 (Arginase)
- NAGS (N-acetyl glutamate synthetase)
- ORNT1 (Ornithine translocase)
- Citrin (Aspartate/glutamate carrier)
Milder or Partial Urea Cycle Defects (Late Onset)
- The severity of urea cycle defects is influenced by:
- The position of the defective protein in the pathway
- The severity of the enzymatic deficiency
Specific Disorders within the Urea Cycle
- Severe deficiency or total absence of activity of CPS1, OTC, ASS1, ASL, or NAGS causes rapid ammonia accumulation due to the lack of effective alternative clearance mechanisms.
- Presentation:
- Typically occurs in the neonatal period due to liver immaturity
- Infants appear normal at birth but rapidly develop cerebral edema leading to symptoms such as:
- Lethargy, anorexia
- Hyperventilation or hypoventilation
- Hypothermia
- Seizures, neurological posturing
- Coma
Neurological Aspects of UCDs
- Failure to feed
- Loss of thermoregulation (hypothermia)
- Somnolence progressing to lethargy and coma
Survival and Intellectual Outcomes
- Early hyperventilation (respiratory alkalosis)
- Progression to hypoventilation and respiratory arrest as cerebral edema worsens
Causes and Prevalence of Urea Cycle Disorders (UCDs)
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