Urea Cycle Disorders (UCDs) – Underlying cause and clinical presentation1
- UCDs are very rare, serious and life threatening disorders comprising a group of inherited deficiencies of one of the enzymes or transporters involved in the urea cycle, which converts ammonia to urea
- Absence or severe dysfunction of the enzymes or transporters result in the accumulation of toxic levels of ammonia in the blood and brain of affected patients
- There are six different types of UCDs, one for each enzyme in the urea cycle:
- NAGS – N-acetylglutamate synthase deficiency*
- CPS 1 – carbamoyl phosphate synthase 1 deficiency
- OTC – ornithine transcarbamylase deficiency
- ASS – argininosuccinate synthetase deficiency, also called citrullinemia type 1
- ASL – argininosuccinate lyase deficiency, also called arginosuccinic aciduria
- ARG – arginase deficiency
- There are also two enzyme transporter deficiencies, which are also considered UCDs:
- HHH – ornithine translocase deficiency, also called hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome
- CTLN2 – citrin or citrullinaemia type 2 deficiency*
- Although genetically distinct, the UCDs share important features and are therefore typically considered as a group
- UCDs affect about 1 in 35.000 people and symptoms vary from individual to individual and may present at different ages
* Please note that RAVICTI is not licensed for NAGS and CTLN2
Urea cycle
6 Enzymes
NAGS = N-Acetylglutamate synthetase
CPS1 = Carbamoylphosphate-Synthetase 1
OTC = Ornithine transcarbamylase
ASS = Argininosuccinate synthetase
ASL = Argininosuccinate lyase
ARG = Arginase
1 Carrier
ORNT1 = Ornithine/Citrulline antiporter
Correlation between ammonia levels and clinical symptoms
- Increasing levels of ammonia will lead to development of characteristic symptoms and, if untreated, eventually to a hyperammonaemic crisis.1,2
- Early symptoms in affected neonates are nonspecific but can quickly progress to coma and death.3,4
- The effects of chronic hyperammonaemia can appear subtle and nonspecific, which can conceal the progressive risks of UCDs.3,5,6
- Regardless of age of presentation, all patients with UCDs face the risk of severe neurological consequences and premature death.4,6
Ammonia
(µmol/l)
>250
Above ULN
ULN
Potential symptom(s)
Hyperammonaemic coma
Coma
Cerebral oedema
Psychiatric symptoms (hallucination, paranoia, mania)
Somnolence
Lethargy
Vomiting
Progressive poor appetite
Subtle symptoms
Normal
ULN = Upper Limit of Normal. ULN is individually defined for each hospital laboratory.
In the Ravicti clinical trials the ULN was defined as 35 μmol/l.7
Ammonia (NH3)
(umol/l)
>250
61-200
36-60
≤35
(ug/dl)
>450
110-360
65-108
≤63
>450
Potential symptom(s)
Hyperammonaemic coma
Coma
Cerebral oedema
Vomiting
Disorientation
Somnolence
Lethargy
Irritability
Anorexia
Subclinical hyperammonaemia
Normal
Consequences of ammonia elevation are unpredictable
- Ammonia levels can vary 10-fold over the course of a day.8
- Hyperammonaemia can be triggered by normal life events such as illness, alcohol use, pregnancy, surgery and accidents.9-10
Treatment of Urea Cycle Disorders
The aims with chronic treatment of UCDs are to keep the level of ammonia in the blood down at safe levels, maintain stable metabolic control, eliminate chronic complications and to achieve normal development and growth.11 Long-term treatment consists of reduction of dietary protein along with pharmaceuticals (e.g. nitrogen scavengers) and supplementation of essential amino acids, vitamins and trace elements. Additional treatment options for some patients are dialysis or liver transplantation.11 RAVICTI® (glycerol phenylbutyrate) is a nitrogen scavenger treatment used to treat patients of all ages with UCDs and designed to facilitate easy administration and adherence to treatment.7,12 Learn more about RAVICTI
References: 1. Summar M, Tuchman M. J Pediatr. 2001;138(1):6–10. 2. Häberle J et al. J Inherit Metab Dis. 2019;1–39. 3. Ah Mew N et al. In: Pagon RA, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 2015. http://www.ncbi.nlm.nih.gov/books/NBK1217/. Last visited 2020-10-21. 4. Cohn RM et al. Clin Pediatr (Phila). 2004;43:683-689. 5. Gropman AL et al. Metab Brain Dis. 2013;28:269–275. 6. Häberle J et al. Orphanet J Rare Dis. 2012;7:32. 7. Diaz GA et al. Hepatology. 2013;57(6):2171–2179. 8. Mokhtarani M et al. Mol Genet Metab. 2012;107:308–314. 9. Summar ML et al. Acta Paediatr. 2008;97:1420–1425. 10. McGuire PJ et al. J Pediatr. 2013;163:1705–1710. 11. Häberle Jz, McCandless S. Orphan drugs in development for UCDs, Orphan Drugs Research and Reviews 2014. 12. Summary of Product Characteristics RAVICTI.
