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