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Urea Cycle Disorders Overview

Urea cycle disorders (UCDs) overview

What are UCDs?

Urea cycle disorders (UCDs) are genetic diseases characterized by potentially toxic elevations of ammonia levels in the blood and brain (hyperammonemia).1,2 UCDs leave patients without a physiological safeguard against elevated ammonia levels because the liver is unable to convert ammonia so it can be eliminated from the body in the urine.1-6 In the bloodstream this leads to an accumulation of ammonia, which can cross the blood-brain barrier and act as a neurotoxin in the brain.3,4,7 Left untreated, hyperammonemia can result in coma, brain damage, and, in some cases, even death.3,5,8-11

What causes UCDs?

UCDs are caused by a deficiency of one of the enzymes or transporters that play a role in the urea cycle, a metabolic process that is responsible for removing excess nitrogen from the system by converting ammonia into urea.3-6

The urea cycle is composed of 6 enzymes and 2 transporter proteins6,12

Urea cycle enzymes and transporters diagram
The urea cycle is a process that occurs in the liver, clearing ammonia from the blood by converting it into urea. A defect in any one of the enzymes or transporters shown in the diagram may result in a specific type of urea cycle disorder (UCD), leaving patients at constant risk of hyperammonemia.6,13 Ornithine transcarbamylase deficiency is the most common UCD.8,14

UCDs are inherited from a flaw in a gene passed down from one or both parents. The majority of UCDs result from inheriting a mutation on an autosomal chromosome. However, the most common UCD, ornithine transcarbamylase deficiency (OTC), is inherited through a mutation on the X chromosome.8,13,14

There are 8 subtypes of UCDs, depending on the enzyme or transporter that is defective.6,13 OTC represents up to 60% of all UCDs.8,14

What are the UCD subtypes?

Each specific UCD is referred to by the initials of the missing enzyme.12,13

  • OTC – ornithine translocase
  • CPS1 – carbamyl phosphate synthetase 1
  • NAGS – N-acetylglutamate synthase
  • ASS – argininosuccinate synthetase (citrullinemia)
  • ASL – argininosuccinate lyase (argininosuccinic aciduria)
  • ARG – arginase

Additionally, there are 2 mitochondrial transporter defects.12,13

  • Mitochondrial ornithine carrier (hyperornithinemia-hyperammonemia-homocitrullinuria, or HHH syndrome)
  • Mitochondrial aspartate/glutamate carrier (citrullinemia type II)

Regardless of their UCD subtype, patients remain vulnerable to experiencing neurological damage throughout the course of their disease.3,8,9

Who do UCDs affect?

The incidence of UCDs has been estimated to occur between 1 in 20,0003 and 1 in 35,000 live births, but the unrecorded incidence of partial defects may mean the actual incidence is much higher.10,13-15 UCDs occur in both children and adults.13 Newborns with severe disease become extremely ill within several hours of birth.3,4 However, acute or chronic symptoms can present at any age.3,12

Patients with UCDs may even appear “asymptomatic,” which may cause diagnosis to be missed or delayed into adulthood.3,4 Most patients with UCDs present with symptoms later in life.15

There are 3 main types of patients with UCDs15:

  • 26% present with hyperammonemia in the neonatal period (symptomatic early-onset)
  • 69% present with symptoms later in life (symptomatic late-onset)
  • 5% remain “asymptomatic”

UCD management and monitoring

Without proper management, UCDs can lead to serious disease-related consequences,12 including hyperammonemic episodes, and physical and mental disabilities.1,10 Because prompt diagnosis and treatment of hyperammonemia associated with UCDs can improve patient outcomes, it is important to continuously manage patients’ ammonia levels.12,16,17

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References:  1. Allen SN. Urea cycle disorder. Ment Health Clin. 2013;2(12):398-401. doi:10.9740/mhc.n155467.  2. Maloney W. Urea cycle disorders. WebMed Central website.   https://www.webmedcentral.com/wmcpdf/Article_WMC00507.pdf. Published September 3, 2010. Accessed August 8, 2017.  3. Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). 2004;43(8):683-689. doi:10.1177/000992280404300801.  4. 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.  5. McGuire PJ, Lee HS, Summar ML; Urea Cycle Disorders Consortium. Infectious precipitants of acute hyperammonemia are associated with indicators of increased morbidity in patients with urea cycle disorders. J Pediatr. 2013;163(6):1705-1710. doi:10.1016/j.jpeds.2013.08.029.  6. The Physician’s Guide to Urea Cycle Disorders. National Organization for Rare Disorders website. 2012. http://nordphysicianguides.org/urea-cycle-disorders/. Accessed August 8, 2017.  7. Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol. 2002;67(4):259-279. doi:10.1016/S0301-0082(02)00019-9.  8. 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.  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. 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.  11. Mokhtarani M, Diaz GA, Rhead W, et al. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mol Genet Metab. 2012;107(3):308-314. doi:10.1016/j.ymgme.2012.08.006.  12. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. doi:10.1186/1750-1172-7-32.  13. Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M; for Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. J Pediatr. 2013;162(2):324-329.e1. doi:10.1016/j.jpeds.2012.06.065.  14. Summar ML, Koelker S, Freedenberg D, et al; European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD) and Members of the Urea Cycle Disorders Consortium (UCDC). The incidence of urea cycle disorders. Mol Genet Metab. 2013;110(1-2):179-180. doi:10.1016/j.ymgme.2013.07.008.  15. 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(0):127-130. doi:10.1016/j.ymgme.2014.08.001.   16. Lee B, Diaz GA, Rhead W, et al. Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. Genet Med. 2015;17(7):561-568. doi:10.1038/gim.2014.148.  17. Smith W, Kishnani PS, Lee B, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005;21(4)(suppl):S9-S17. doi:10.1016/j.ccc.2005.05.007.