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Ornithine Carbamoyltransferase Deficiency

Pathophysiology description

2026-02-23
Falcon MONDO:0010703 Model: Edison Scientific Literature 29 citations

Pathophysiology description OTCD is an X-linked urea-cycle disorder caused by loss-of-function variants in OTC, a mitochondrial hepatocyte enzyme catalyzing carbamoyl phosphate + ornithine → citrulline. Blockade of ureagenesis causes episodic or persistent hyperammonemia. The brain detoxifies ammonia primarily via astrocytic glutamine synthetase, increasing glutamine (glutaminosis). Glutamine accumulation drives astrocyte osmotic swelling, cerebral edema, intracranial hypertension, seizures, coma, and potentially herniation/death; mitochondrial dysfunction, oxidative stress, and neurotransmitter disturbances amplify injury. Biomarker patterns include hyperammonemia, elevated glutamine (and often alanine), low citrulline (variable in DBS), and elevated urinary orotic acid. (yilmaz2023genetictherapyapproaches pages 1-2, lo2023thefunctionalimpact pages 1-3, redant2021managementoflate pages 1-3, ribas2022hyperammonemiaininherited pages 5-6, matsumoto2019ureacycledisorders—update pages 4-5)

Gene/protein annotations (HGNC) - OTC (X-linked; mitochondrial enzyme; hepatocyte expression) (yilmaz2023genetictherapyapproaches pages 1-2)

Cell type involvement (CL) - Hepatocyte (CL:0000182) — primary site of ureagenesis defect (yilmaz2023genetictherapyapproaches pages 1-2) - Astrocyte (CL:0000127) — ammonia→glutamine detoxification, swelling, edema (zielinska2022dysregulationofastrocytic pages 1-2, redant2021managementoflate pages 1-3)

Anatomical locations (UBERON) - Liver (UBERON:0002107) — primary site of defective ammonia detoxification (yilmaz2023genetictherapyapproaches pages 1-2) - Brain (UBERON:0000955) — site of ammonia neurotoxicity and edema (redant2021managementoflate pages 1-3)

Chemical entities (CHEBI) - Ammonia (CHEBI:16134); glutamine (CHEBI:28300); citrulline (CHEBI:16349); ornithine (CHEBI:15729); carbamoyl phosphate (CHEBI:17674); orotic acid (CHEBI:30845) (supported as key metabolites/biomarkers in text) (ribas2022hyperammonemiaininherited pages 5-6, matsumoto2019ureacycledisorders—update pages 4-5, hu2024indepthanalysisof pages 1-2)

  1. Limitations of this report (evidence availability)
  2. A MONDO identifier for OTCD was not present in the retrieved excerpts; therefore it is not asserted.
  3. Several mechanistic sections rely on peer-reviewed reviews that cite primary studies without listing PMIDs in the excerpt text; PMIDs are therefore not consistently recoverable from the tool context alone, though DOIs and full citations are provided.

References

  1. (OpenTargets Search: Ornithine carbamoyltransferase deficiency,Ornithine transcarbamylase deficiency-OTC): Open Targets Query (Ornithine carbamoyltransferase deficiency,Ornithine transcarbamylase deficiency-OTC, 8 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (NCT05345171 chunk 2): Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency. Ultragenyx Pharmaceutical Inc. 2022. ClinicalTrials.gov Identifier: NCT05345171

  3. (yilmaz2023genetictherapyapproaches pages 1-2): Berna Seker Yilmaz and Paul Gissen. Genetic therapy approaches for ornithine transcarbamylase deficiency. Biomedicines, 11:2227, Aug 2023. URL: https://doi.org/10.3390/biomedicines11082227, doi:10.3390/biomedicines11082227. This article has 30 citations.

  4. (lo2023thefunctionalimpact pages 1-3): Russell S. Lo, Gareth A. Cromie, Michelle Tang, Kevin Teng, Katherine Owens, Amy Sirr, J. Nathan Kutz, Hiroki Morizono, Ljubica Caldovic, Nicholas Ah Mew, Andrea Gropman, and Aimée M. Dudley. The functional impact of 1,570 individual amino acid substitutions in human otc. American journal of human genetics, 110 5:863-879, May 2023. URL: https://doi.org/10.1016/j.ajhg.2023.03.019, doi:10.1016/j.ajhg.2023.03.019. This article has 28 citations and is from a highest quality peer-reviewed journal.

  5. (NCT03767270 chunk 1): Safety, Tolerability and PK/PD Evaluation of Intravenous Administration of MRT5201 in Patients With OTC Deficiency. Translate Bio, Inc.. 2019. ClinicalTrials.gov Identifier: NCT03767270

  6. (matsumoto2019ureacycledisorders—update pages 4-5): Shirou Matsumoto, Johannes Häberle, Jun Kido, Hiroshi Mitsubuchi, Fumio Endo, and Kimitoshi Nakamura. Urea cycle disorders—update. Journal of Human Genetics, 64:833-847, May 2019. URL: https://doi.org/10.1038/s10038-019-0614-4, doi:10.1038/s10038-019-0614-4. This article has 261 citations and is from a peer-reviewed journal.

  7. (hu2024indepthanalysisof pages 4-7): Qingyang Hu, Haiming Chen, Tianyi Liu, Xue-Tao Dong, Xuejiao Hu, Wenxin Yan, and Zhong Li. In-depth analysis of otc a208t case induced by otc gene mutation and research on the prediction and simulation of the impact on protein function. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1450859, doi:10.3389/fped.2024.1450859. This article has 2 citations.

  8. (ribas2022hyperammonemiaininherited pages 5-6): Graziela Schmitt Ribas, Franciele Fátima Lopes, Marion Deon, and Carmen Regla Vargas. Hyperammonemia in inherited metabolic diseases. Cellular and Molecular Neurobiology, 42:2593-2610, Oct 2022. URL: https://doi.org/10.1007/s10571-021-01156-6, doi:10.1007/s10571-021-01156-6. This article has 83 citations and is from a peer-reviewed journal.

  9. (nambiar2022acutefulminantencephalopathy pages 3-4): Vivek K. Nambiar, Aakash Shridharani, Sudheeran Kannoth, Siby Gopinath, and Anand Kumar. Acute fulminant encephalopathy in an adult due to ornithine transcarbamylase deficiency. Annals of Indian Academy of Neurology, 25:722-724, Jul 2022. URL: https://doi.org/10.4103/aian.aian_1028_21, doi:10.4103/aian.aian_1028_21. This article has 1 citations and is from a peer-reviewed journal.

  10. (hu2024indepthanalysisof pages 1-2): Qingyang Hu, Haiming Chen, Tianyi Liu, Xue-Tao Dong, Xuejiao Hu, Wenxin Yan, and Zhong Li. In-depth analysis of otc a208t case induced by otc gene mutation and research on the prediction and simulation of the impact on protein function. Frontiers in Pediatrics, Sep 2024. URL: https://doi.org/10.3389/fped.2024.1450859, doi:10.3389/fped.2024.1450859. This article has 2 citations.

  11. (ribas2022hyperammonemiaininherited pages 1-2): Graziela Schmitt Ribas, Franciele Fátima Lopes, Marion Deon, and Carmen Regla Vargas. Hyperammonemia in inherited metabolic diseases. Cellular and Molecular Neurobiology, 42:2593-2610, Oct 2022. URL: https://doi.org/10.1007/s10571-021-01156-6, doi:10.1007/s10571-021-01156-6. This article has 83 citations and is from a peer-reviewed journal.

  12. (zielinska2022dysregulationofastrocytic pages 1-2): Magdalena Zielińska, Jan Albrecht, and Mariusz Popek. Dysregulation of astrocytic glutamine transport in acute hyperammonemic brain edema. Frontiers in Neuroscience, Jun 2022. URL: https://doi.org/10.3389/fnins.2022.874750, doi:10.3389/fnins.2022.874750. This article has 22 citations and is from a peer-reviewed journal.

  13. (redant2021managementoflate pages 1-3): S. Redant, A. Empain, A. Mugisha, P. Kamgang, R. Attou, P. M. Honoré, and D. De Bels. Management of late onset urea cycle disorders—a remaining challenge for the intensivist? Annals of Intensive Care, Jan 2021. URL: https://doi.org/10.1186/s13613-020-00797-y, doi:10.1186/s13613-020-00797-y. This article has 41 citations and is from a peer-reviewed journal.

  14. (ribas2022hyperammonemiaininherited pages 2-4): Graziela Schmitt Ribas, Franciele Fátima Lopes, Marion Deon, and Carmen Regla Vargas. Hyperammonemia in inherited metabolic diseases. Cellular and Molecular Neurobiology, 42:2593-2610, Oct 2022. URL: https://doi.org/10.1007/s10571-021-01156-6, doi:10.1007/s10571-021-01156-6. This article has 83 citations and is from a peer-reviewed journal.

  15. (matsumoto2019ureacycledisorders—update pages 11-12): Shirou Matsumoto, Johannes Häberle, Jun Kido, Hiroshi Mitsubuchi, Fumio Endo, and Kimitoshi Nakamura. Urea cycle disorders—update. Journal of Human Genetics, 64:833-847, May 2019. URL: https://doi.org/10.1038/s10038-019-0614-4, doi:10.1038/s10038-019-0614-4. This article has 261 citations and is from a peer-reviewed journal.

  16. (takanashi2002distinctlyabnormalbrain pages 1-2): J. Takanashi, A. Kurihara, M. Tomita, M. Kanazawa, S. Yamamoto, F. Morita, H. Ikehira, S. Tanada, and Y. Kohno. Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency. Neurology, 59:210-214, Jul 2002. URL: https://doi.org/10.1212/wnl.59.2.210, doi:10.1212/wnl.59.2.210. This article has 69 citations and is from a highest quality peer-reviewed journal.

  17. (tran2024apreliminaryretrospective pages 2-4): Dien Minh Tran, Trang Thi Thu Tran, Quyen Hue Luong, and Mai Thi Chi Tran. A preliminary retrospective evaluation of screening and diagnosis of ornithine transcarbamylase deficiency in high-risk patients at a referral center in vietnam. Heliyon, 10:e36003, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e36003, doi:10.1016/j.heliyon.2024.e36003. This article has 0 citations.

  18. (yuan2024clinicalcharacteristicsand pages 2-3): Gaopin Yuan, Zhiyong Liu, Zhixu Chen, Xiaohong Zhang, Weifeng Zhang, and Dongmei Chen. Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern china. Italian Journal of Pediatrics, Sep 2024. URL: https://doi.org/10.1186/s13052-024-01740-8, doi:10.1186/s13052-024-01740-8. This article has 0 citations and is from a peer-reviewed journal.

  19. (yilmaz2023genetictherapyapproaches pages 9-10): Berna Seker Yilmaz and Paul Gissen. Genetic therapy approaches for ornithine transcarbamylase deficiency. Biomedicines, 11:2227, Aug 2023. URL: https://doi.org/10.3390/biomedicines11082227, doi:10.3390/biomedicines11082227. This article has 30 citations.

  20. (matsumoto2019ureacycledisorders—update pages 9-10): Shirou Matsumoto, Johannes Häberle, Jun Kido, Hiroshi Mitsubuchi, Fumio Endo, and Kimitoshi Nakamura. Urea cycle disorders—update. Journal of Human Genetics, 64:833-847, May 2019. URL: https://doi.org/10.1038/s10038-019-0614-4, doi:10.1038/s10038-019-0614-4. This article has 261 citations and is from a peer-reviewed journal.

  21. (NCT05345171 chunk 1): Clinical Study of DTX301 AAV-Mediated Gene Transfer for Ornithine Transcarbamylase (OTC) Deficiency. Ultragenyx Pharmaceutical Inc. 2022. ClinicalTrials.gov Identifier: NCT05345171

  22. (NCT06488313 chunk 1): A Study to Evaluate the Pharmacodynamics and Safety of ARCT-810 in Participants With OTCD. Arcturus Therapeutics, Inc.. 2024. ClinicalTrials.gov Identifier: NCT06488313

  23. (NCT05526066 chunk 1): Study for Adolescents and Adults With Ornithine Transcarbamylase Deficiency to Evaluate Safety and Tolerability of ARCT-810. Arcturus Therapeutics, Inc.. 2022. ClinicalTrials.gov Identifier: NCT05526066

  24. (NCT06255782 chunk 1): An Open-label Study to Investigate ECUR-506 in Male Babies Less Than 9 Months of Age With Neonatal Onset OTC Deficiency. iECURE, Inc.. 2024. ClinicalTrials.gov Identifier: NCT06255782