About UCDs
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of UCD Subtypes

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Urea Cycle Disorder Pathophysiology and Prevalence

A UCD affects the process of protein degradation in the body.1,2 When protein is broken down into amino acids, any excess nitrogen is converted into ammonia, which is then converted by the urea cycle into urea for safe removal from the body.2,3

An enzyme or transporter that is missing or defective in the urea cycle may cause a UCD.4 The urea cycle is, therefore, unable to excrete toxic ammonia resulting in a buildup of ammonia in the blood.3

The elevated levels of ammonia in the body can cause fatigue, confusion, headaches, vomiting, behavioral changes, learning difficulties, brain damage, or coma.2,5 Presentation of these symptoms can range from asymptomatic to severe depending on the affected enzyme and the extent of the enzyme deficiency.4,6

Graphic of Urea Cycle Disorder pathophysiology showing how high ammonia levels accumulateGraphic of Urea Cycle Disorder pathophysiology showing how high ammonia levels accumulate

Click chart to enlarge

UCD is a rare disease affecting an estimated 1 in 35,000 live births in the United States, though actual incidence may be greater.4,5,7-9

Urea Cycle Disorder Inheritance

Eight UCD subtypes are identified based on the affected enzyme or transporter3,10:

  • Ornithine transcarbamylase (OTC) deficiency
  • Carbamoyl phosphate synthetase 1 (CPS1) deficiency
  • Argininosuccinate synthetase (ASS) deficiency or citrullinemia type 1 (CTLN1)
  • Argininosuccinate lyase (ASL) deficiency
  • Arginase-1 (ARG) deficiency
  • N-acetylglutamate synthase (NAGS) deficiency
  • Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome
  • Citrin deficiency or citrullinemia type II (CTLN2)

OTC deficiency is the only X-linked UCD subtype. A mother may pass the affected OTC gene to her sons or daughters, while a father may pass the affected OTC gene to his daughters.4 Individuals with OTC deficiency may experience symptoms and require treatment.4,5,11

All other UCD subtypes are inherited in an autosomal recessive manner.4 The presentation and severity of symptoms in individuals with an autosomal recessive UCD may vary based on the specific UCD subtype.4

Rarely, a UCD is the result of a new—or de novo—mutation.4 These mutations, similar to inherited mutations, may be passed on to children.4

Inheriting X-linked
UCD from father

Graphic of the Urea Cycle Disorder inheritance pattern for X-linked UCDs from fathersGraphic of the Urea Cycle Disorder inheritance pattern for X-linked UCDs from fathers

Inheriting autosomal
recessive UCD

Graphic of the Urea Cycle Disorder inheritance pattern for autosomal recessive UCDGraphic of the Urea Cycle Disorder inheritance pattern for autosomal recessive UCD

Urea Cycle Disorder Signs & Symptoms

Signs and symptoms of UCD can vary person to person.

Physical symptoms5:

  • Fatigue
  • Headaches
  • Seizures
  • Vomiting
  • Poor appetite/protein aversion
  • Slow growth
  • Vision loss
  • Ataxia
  • Muscle weakness
  • Tremor

Cognitive/behavioral symptoms5,13,14:

  • Mood swings
  • Attention problems
  • Learning disabilities
  • Hallucinations
  • Personality changes
  • Aggression

The wide range of nonspecific symptoms makes identifying a UCD challenging. If a UCD is suspected, a specialist may be able to help make a diagnosis.

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Other clinical signs of UCD include high ammonia levels and elevated glutamine, urinary orotic acid, citrulline, and alanine aminotransferase biomarkers. High ammonia levels can result in a wide range of effects including hyperammonemic encephalopathy, which can lead to coma and death.

Effects of High Ammonia Levels

Infographic showing how high ammonia levels can increase risk of hyperammonemic encephalopathyInfographic showing how high ammonia levels can increase risk of hyperammonemic encephalopathy

High Ammonia Levels Can Cause Neurological Deficits

Elevated ammonia levels, whether acute or chronic, may be toxic and have significant neurological consequences.16

With acute or peak ammonia elevations, increases in blood ammonia concentration may result in cerebral edema, coma, and eventual death.1,8 These risks of mortality and neurological damage are influenced by the number, extent, and duration of acute episodes of a hyperammonemic crisis.17-25

Similarly, chronic or moderate ammonia elevations over time may result in negative neurological and cognitive effects.4,8,16,27 The risk of irreversible brain damage is not predicted by the presence or absence of symptoms related to elevated ammonia levels.4,8,16,27 Even moderate increases in blood ammonia concentration may also lead to coma or death if left untreated.8

Pie chart showing triggers of hyperammonemic encephalopathy for urea cycle disorder patients, including illness, poor diet, missed medication, and stressful life eventsPie chart showing triggers of hyperammonemic encephalopathy for urea cycle disorder patients, including illness, poor diet, missed medication, and stressful life events

Potential triggers of hyperammonemic crises include illness, poor diet, medication noncompliance, and stressful life events.9

The first hyperammonemic crisis may have severe neurological outcomes of disability or death when ammonia levels are particularly elevated. Neurocognitive function further declines with subsequent hyperammonemic events.

The Specific Enzyme Deficiency Determines the UCD Type

Learn More About UCD Subtypes

References: 1. Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. 2009;24(1):95-102.doi:10.1007/s11011-008-9112-7 2. Stone WL, Basit H, Jaishankar GB. Urea Cycle Disorders. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 9, 2022. 3. Matsumoto S, Häberle J, Kido J, Mitsubuchi H, Endo F, Nakamura K. Urea cycle disorders-update.J Hum Genet.2019;64(9):833-847. doi:10.1038/s10038-019-0614-4 4. Ah Mew N, Simpson KL, Gropman AL, Lanpher BC, Chapman KA, Summar ML. Urea Cycle Disorders Overview. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; April 29, 2003. 5. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42(6):1192-1230. doi:10.1002/jimd.12100 6. Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr. 2001;138(1 Suppl):S6-S10. doi:10.1067/mpd.2001.111831 7. Batshaw ML, Tuchman M, Summar M, Seminara J; Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113(1-2):127-130. doi:10.1016/j.ymgme.2014.08.001 8. Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). 2004;43(8):683-689. doi:10.1177/000992280404300801 9. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008;97(10):1420-1425. doi:10.1111/j.1651-2227.2008.00952.x 10. Urea Cycle Disorders Consortium. UCDC Update. Spring 2013. https://www.rarediseasesnetwork.org/cms/Portals/UCDC/Docs/UCDCNewsletter42213Final.pdf. Accessed January 23, 2019. 11. National Organization for Rare Disorders (NORD). The Physician’s Guide to Urea Cycle Disorders. Accessed March 23, 2020. https://rarediseases.org/physician-guide/urea-cycle-disorders/ 12. Johnson NA, Lachance J. The genetics of sex chromosomes: evolution and implications for hybrid incompatibility. Ann N Y Acad Sci. 2012;1256:E1-E22. doi:10.1111/j.1749-6632.2012.06748.x 13. Gardeitchik T, Humphrey M, Nation J, Boneh A. Early clinical manifestations and eating patterns in patients with urea cycle disorders. J Pediatr. 2012;161(2):328-332. doi:10.1016/j.jpeds.2012.02.006 14. Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res. 2009;66(1):96-101. doi:10.1203/PDR.0b013e3181a27a16 15. Lee B, Diaz GA, Rhead W, et al. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder [published correction appears in Genet Med. 2015 May;17(5):427. Genet Med. 2015;17(7):561-568. doi:10.1038/gim.2014.148 16. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis. 2007;30(6):865-879. doi:10.1007/s10545-007-0709-5 17. Gropman AL, Prust M, Breeden A, Fricke S, VanMeter J. Urea cycle defects and hyperammonemia: effects on functional imaging. Metab Brain Dis. 2013;28(2):269-275. doi:10.1007/s11011-012-9348-0 18. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003;162(6):410-416. doi:10.1007/s00431-003-1188-9 19. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med. 2007;356(22):2282-2292. doi:10.1056/NEJMoa066596 20. Hediger N, Landolt MA, Diez-Fernandez C, Huemer M, Häberle J. The impact of ammonia levels and dialysis on outcome in 202 patients with neonatal onset urea cycle disorders. J Inherit Metab Dis. 2018;41(4):689-698. doi:10.1007/s10545-018-0157-4 21. Kido J, Nakamura K, Mitsubuchi H, et al. Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis. 2012;35(5):777-785. doi:10.1007/s10545-011-9427-0 22. Martín-Hernández E, Aldámiz-Echevarría L, Castejón-Ponce E, et al. Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. Orphanet J Rare Dis. 2014;9:187. Published 2014 Nov 30. doi:10.1186/s13023-014-0187-4 23. Nettesheim S, Kölker S, Karall D, et al. Incidence, disease onset and short-term outcome in urea cycle disorders -cross-border surveillance in Germany, Austria and Switzerland. Orphanet J Rare Dis. 2017;12(1):111. Published 2017 Jun 15. doi:10.1186/s13023-017-0661-x 24. Posset R, Garcia-Cazorla A, Valayannopoulos V, et al. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders [published correction appears in J Inherit Metab Dis. 2018 Jan 12;:]. J Inherit Metab Dis. 2016;39(5):661-672. doi:10.1007/s10545-016-9938-9 25. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998;21 Suppl 1:151-159. doi:10.1023/a:1005374027693 26. Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol. 2004;55(1):80-86. doi:10.1002/ana.10794 27. Maestri NE, Lord C, Glynn M, Bale A, Brusilow SW. The phenotype of ostensibly healthy women who are carriers for ornithine transcarbamylase deficiency. Medicine (Baltimore). 1998;77(6):389-397.