2025 – PAGE 352 – INBORN ERRORS OF METABOLISM & MISCELLANEOUS METABOLIC DISORDERS
UREA CYCLE DEFECTS
UREA CYCLE SUMMARY
IMAGE: (UREA CYCLE SUMMARY) www.pbrlinks.com/UREACYCLE1
SUMMARY: Ornithine → Citrulline → Arginosuccinate → Arginine → Ornithine, (OCAA) with ammonia being injected via carbamoyl phosphate synthetase and ornithine transcarbamylase.
Nitrogen waste presents as NH3 (ammonia) to the urea cycle.
- AMMONIA (NH4+) and Carbon Dioxide (CO2) combine with CARBAMOYL PHOSPHATE SYNTHETASE (CPS) to from CARBAMOYL PHOSPHATE. Then, ORNITHINE TRANSCARBAMYLASE (OTC) converts CARBAMOYL PHOSPHATE and ORNITHINE (a urea cycle end product) to CITRULLINE.
- PEARL: OTC deficiency is the disorder most likely to be tested because it’s the most common, and unlike the others, it’s X-linked (ornithine transcarbamylaX). If you’re finding this section overwhelming, focus on this disorder and note that without OTC, there can be NO CITRULLINE!
- ARGININOSUCCINIC SYNTHETASE (ASS) converts Citrulline into ARGININOSUCCINIC ACID (AKA ARGININOSUCCINATE in the image).
- ARGININOSUCCINATE LYASE converts Argininosuccinic Acid into ARGININE.
- ARGINASE converts Arginine into ORNITHINE AND UREA.
- ORNITHINE TRANSCARBAMYLASEthen works again with CARBAMOYL PHOSPHATE SYNTHETASE to catalyze the reaction between AMMONIA and ORNITHINE to create CITRULLINE!
UREA CYCLE DEFECTS INCLUDE…
Ornithine Transcarbamylase deficiency (OTC is the most common urea cycle defect and is X-linked), Citrullinemia, Argininosuccinic Aciduria, and Carbamoyl Phosphate Synthetase deficiency. Look for vomiting, lethargy, HYPOTONIA, and eventually coma. Labs should show a MASSIVE hyperammonemia (possibly greater than 500!) with a RESPIRATORY ALKALOSIS (look for an ABG). There is NO ketosis and usually NO lactic acidosis. If you are given a LOW ARGININE or a LOW BUN you will know it’s a urea cycle defect. To DIAGNOSE, check serum citrulline, arginine, argininosuccinic acid (ASA), and URINE Orotic acid. TREAT with increased caloric intake but protein restriction. Also give ammonia scavengers (Benzoate and Phenylbutyrate). A defect in the cycle prior to arginine production may also respond to treatment with arginine supplementation.
- PEARLS: LOW amino acid levels (Citrulline, ASA, Arginine) represent a lack of production. HIGH amino acid levels represent a build-up due to an enzyme defect that is further down in the pathway.
- MNEMONIC: Imagine a child riding a FLOPPY triCYCLE on the wet kitchen floor that has a ton of yellow AMMONIA cleaner on it that looks like UREAN.
- KEY: FLOPPY = Hypotonia. CYCLE = Urea cycle. AMMONIA = Hyperammonemia. UREAN = Urine to remind you of the Urea Cycle.
- MNEMONIC: All the –INE’s are part of the urea cycle (citrulline, arginine, ornithine, glutamine). Plus carbamoyl phosphate.