Types of Urea Cycle Disorders (UCDs)
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Urea Cycle Disorder Subtypes

There are 8 UCD subtypes identified based on the affected enzyme or transporter1-3:

  • 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
  • Citrulline deficiency or citrullinemia type II (CTLN2)

All UCD deficiencies except OTC are inherited in an autosomal recessive manner. OTC deficiency is inherited in an X-linked manner.3

Variable Severity

The severity of UCDs varies based on the position and extent of the enzyme deficiency. Proximal defects typically present earlier in life and are more severe than distal defects.3 Variability exists even within each subtype.3,4

Graphic showing Urea Cycle Disorder severity by subtype, starting by the most severe, and including CPS1 Deficiency, NAGS Deficiency, OTC Deficiency, ASS Deficiency, ASL Deficiency, and ARG1 DeficiencyGraphic showing Urea Cycle Disorder severity by subtype, starting by the most severe, and including CPS1 Deficiency, NAGS Deficiency, OTC Deficiency, ASS Deficiency, ASL Deficiency, and ARG1 Deficiency

Complete deficiencies are characteristic of hyperammonemic crises shortly after birth and are associated with higher rates of mortality, cognitive impairment, and recurrent crises.3,5

Partial deficiencies are associated with more variable presentations at any age. However, risk of cognitive effects and premature death is still present.3,5

Urea Cycle Disorders in Newborns

UCDs present differently in newborns versus adults.

Symptomatic early-onset UCDs present in the neonatal period and account for 26% of UCD cases.5,6 Early symptoms include lethargy, vomiting, and somnolence but may progress quickly to coma and death.3,7

Symptoms of high ammonia levels in newborns may be misdiagnosed as neonatal sepsis.5 However, initial symptoms often appear after discharge which can delay diagnosis.8

Urea Cycle Disorders in Adults

Symptomatic late-onset UCDs can present at any age and account for 69% of UCD cases.5-7 Symptoms of elevated ammonia are subtle and may include headaches, lethargy, confusion, vomiting, and loss of appetite. These nonspecific symptoms can result in delayed diagnosis or misdiagnosis.5,8

As the UCD remains undiagnosed, patients may experience repeat hyperammonemic attacks causing cognitive damage or dysfunction.3,5,9

The remaining 5% of UCD cases are asymptomatic with only nonspecific symptoms.5,6 With the absence of clinical symptoms, the UCD may continue to be undiagnosed or misdiagnosed until a hyperammonemic crisis occurs.5,8,10,11

Regardless of presentation and onset of symptoms or patient age, UCDs remain challenging to diagnose.

Genetic Testing May Help Identify a Defective Gene

Learn About Testing for UCDs

References: 1. 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 2. Urea Cycle Disorders Consortium. UCDC Update. Spring 2013. Accessed January 23, 2019. https://www.rarediseasesnetwork.org/cms/Portals/UCDC/Docs/UCDCNewsletter42213Final.pdf 3. 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. 4. 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/ 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. 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 7. Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). 2004;43(8):683-689. doi:10.1177/000992280404300801 8. 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 9. 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 10. 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 11. Legras A, Labarthe F, Maillot F, Garrigue MA, Kouatchet A, Ogier de Baulny H. Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations. Crit Care Med. 2002;30(1):241-244. doi:10.1097/00003246-200201000-00035