UREA CYCLE

GROUP 3
DISORDER
NIÑA CHARISE EVANGELISTA
MARIEL JOY FRANCISCO
JOAQUIN GALICIA JR.
AURELIA GARCIA
IDOWU OMONIYI JULIUS
EKWE DAVID ANTHONY
UREA CYCLE DISORDER LEARNING OUTCOME

After this activity, the students are able to:

 recognize and explain the clinical manifestations of Urea Cycle
Disorders,
 determine the different types, differentiate it from other organic
acidemia such as MSUD and
 discuss the principle of treatment.
UREA CYCLE DISORDER SPECIFIC LEARNING
OBJECTIVES

1. To be able to explain the Urea Cycle.

2. To determine the different types.
3. To be able to explain the molecular basis of Urea Cycle Disorders.
4. To determine the pathophysiologic mechanism of signs and
symptoms.
5. Discuss proper diagnosis and management.
UREA CYCLE DISORDER SIGNIFICANCE

What is the significance of Urea Cycle?

 It eliminates toxic ammonia from the body, especially from the brain, via
its conversion into a nontoxic urea which can be excreted in the urine
 A major source of arginine, ornithine and citrulline
 Urea cycle clears waste nitrogen products from protein turnover e.g.
creatinine
 Knowledge of the urea cycle helps in the in-depth understanding of its
disorders and how to properly manage them.
 UREA CYCLE DISORDER ENZYMES AND
CATALYSIS
Enzymes in the pathway and the reactions that they catalyze:
Urea Cycle enzymes Reactions catalyzed
Condensation of CO2, ammonia, and ATP to form
Carbamoyl Phosphate Synthetase I (CPS1) carbamoyl phosphate

Catalyzes transfer of the carbamoyl group of

Ornithine transcarbamylase (OTC) carbamoyl phosphate to ornithine, forming citrulline
  and orthophosphate
 
Links aspartate and citrulline via the amino group of
Argininosuccinic acid synthetase (ASS1) aspartate and provides the second nitrogen of urea
   
 UREA CYCLE DISORDER ENZYMES AND
CATALYSIS

Cleav argininosuccinate; proceeds with retention

of all three nitrogens in arginine and release of
Argininosuccinic acid lyase (ASL) the aspartate skeleton as fumarate
   
Hydrolytic cleavage of the guanidino group of
Arginase (ARG1) arginine releases urea
   
UREA CYCLE DISORDER DEFINITIONS AND
TYPES

What are Urea Cycle Disorders? What is the most common type?
Urea Cycle disorders - defects in the biosynthesis of enzymes of
the urea cycle

 N-acetylglutamate synthase deficiency (NAGS deficiency)

 described in a number of affected individuals.
 Symptoms mimic those of CPS1 deficiency (CPS1 is rendered inactive in the
absence of N-acetylglutamate)
 UREA CYCLE DISORDER DEFINITIONS AND
TYPES
 Carbamoylphosphate synthetase I deficiency (CPS1 deficiency)
 most severe of the urea cycle disorders
 Complete CPS1 deficiency rapidly develop hyperammonemia in newborn period
 Children successfully rescued from crisis are chronically at risk for repeated bouts of
hyperammonemia
 Ornithine transcarbamylase deficiency (OTC deficiency)
 Absence of OTC activity in males is as severe as CPS1 deficiency.
 Approx. 15% of carrier females develop hyperammonemia during lifetime and many
require chronic medical management
 Recently been recognized that carrier females who never had symptoms of overt
hyperammonemia have deficiencies in executive function
 UREA CYCLE DISORDER DEFINITIONS AND
TYPES

 Citrullinemia type I (ASS1 deficiency)

 hyperammonemia can also be quite severe
 Affected individuals are able to incorporate some waste nitrogen into urea
cycle intermediates, which makes treatment slightly easier than in the other
UCDs.
 UREA CYCLE DISORDER DEFINITIONS AND
TYPES
 Argininosuccinic aciduria (ASL deficiency)
 also present with rapid-onset hyperammonemia in newborn
 past the point in metabolic pathway at which all the waste nitrogen has been incorporated
into the cycle
 Some affected individuals develop chronic hepatic enlargement and elevation of
transaminases
 Liver biopsy -> enlarged hepatocytes, may progress to fibrosis. Etiology: unclear
 Affected individuals can develop trichorrhexis nodosa, a node-like appearance of fragile
hair usually responds to arginine supplementation.
 Affected individuals who never had prolonged coma nevertheless been reported to have
significant developmental disabilities.
 UREA CYCLE DISORDER DEFINITIONS AND
TYPES

 Arginase deficiency (hyperargininemia, ARG1 deficiency)

 not typically characterized by rapid-onset hyperammonemia, however, some individuals
present earlier with more severe symptoms.
 Affected individuals develop progressive spasticity and can also develop tremor, ataxia,
and choreoathetosis.
 Growth is affected.
 UREA CYCLE DISORDER DEFINITIONS AND
TYPES

 Ornithine translocase deficiency (ORNT1 deficiency,

hyperornithinemia- hyperammonemia-homocitrullinuria syndrome,
HHH syndrome)
 has a variable age of onset ranging from infancy to adulthood.
 Clinical presentation can be with chronic neurocognitive deficits, hyperammonemic crisis,
or chronic liver dysfunction.
 UREA CYCLE DISORDER DEFINITIONS AND
TYPES

 Citrin deficiency
 can manifest in newborns as neonatal intrahepatic cholestasis caused by citrin deficiency
(NICCD)
 older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD)
 adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia
type II (CTLN2).
 UREA CYCLE DISORDER ETIOLOGY
ETIOLOGY
The etiology of UCDs is complex since multiple proteins and 2 subcellular compartments are involved,
for example, the mitochondrial matrix and cytoplasm. The first 2 enzymatic steps in the urea cycle take
place in the mitochondrial matrix.
 Step 1: carbamoyl phosphate synthetase I (CPS1) ligates ammonia with bicarbonate forming carbamoyl
phosphate which enters the urea cycle.
 Step 2: the liver enzyme, ornithine transcarbamylase (OTC) catalyzes the reaction of carbamoyl phosphate
with ornithine to form citrulline.
 Step 3: this and all remaining enzymatic steps take place in the cytoplasm. Argininosuccinate synthase 1
(ASS1) catalyzes the formation of argininosuccinate from citrulline and aspartic acid. 
 Step 4: cleavage of argininosuccinate to form fumaric acid and arginine, and this reaction is catalyzed by
argininosuccinate lyase (ASL).
 Step 5: In the last step of the urea cycle, the arginine from step 4 is cleaved into urea and ornithine by the
arginase enzyme which is coded for by the ARG1 gene. Defects in arginase can result in both argininemia and
hyperammonemia.
 UREA CYCLE DISORDER EPIDIMIOLOGY

Overall, the incidence of UCDs has recently been determined to be 1 in 35,000 births. Most
State Screening Laboratories currently detect only 2 of all the conditions that cause UCDs.
About two-thirds of all USDs are due to mutations in OTC, one-fifth due to ASS1, and one-
tenth due to ASL.
UREA CYCLE DISORDER PATHOPHYSIOLOGY
There has been considerable progress in understanding the pathophysiology of UCDs which may
ultimately promote better medical interventions. Hyperammonemia is a key etiological factor in
UCDs and plays a key role in CNS toxicity. Although complex, some important concepts are
emerging.  The toxic effects of ammonia on the CNS are more severe in the developing brain than in
the adult brain.  Whether the toxic effects of hyperammonemia are reversible or not depends upon the
exposure time, the dose of hyperammonemia and the stage of neurological development. In the
neonatal brain, hyperammonemia results in edema caused by swelling of astrocytes. The subsequent
frequency and degree of swelling are key factors in determining the severity of CNS neurological
disorders such as seizures, coma, and cognitive/motor deficits.
While OTC deficiency (OTCD) is inherited in an X-linked manner, all other UCDs follow an
autosomal recessive pattern. Moreover, there is evidence that even asymptomatic female carriers of
OTCD can develop cognitive defects as a result of episodic hyperammonemia.
UREA CYCLE DISORDER HISTORY AND PHYSICAL
EXAMINATION

 Family history. A three-generation family history with attention to other relatives (particularly
children) with neurologic signs and symptoms suggestive of UCD should be obtained.
Documentation of relevant findings in relatives can be accomplished either through direct examination
of those individuals or review of their medical records including the results of biochemical testing,
molecular genetic testing, and autopsy examination. A family history consistent with X-linked
inheritance suggests OTC deficiency.
 Physical examination. No findings on physical examination distinguish among the eight types of urea
cycle defect; however, trichorrhexis nodosa can be suggestive of ASL deficiency and progressive
spasticity of the lower extremities suggestive of arginase deficiency.
UREA CYCLE DISORDER EVALUATION AND MEDICAL
MANAGEMENT
 UCD can be evaluated through:

 Biochemical testing
 Plasma ammonia concentration
 Quantitative plasma amino acid analysis
 For concentrations of citrulline, arginine, ornithine
 Urinary orotic acid
 Urine amino acid analysis
 Molecular Genetic Testing
 Serial single-gene testing 
 multigene panel
 More comprehensive genomic testing (including exome and genome sequencing)
 Enzymatic activity
 Newborn screening
UREA CYCLE DISORDER EVALUATION AND MEDICAL
MANAGEMENT
 UCD can be medically managed through:

 Dialysis - to remove ammonia from the blood

 Supplementation - of sugars, fats, and amino acids
 Medicines - to remove extra nitrogen

 Long term management includes –

 A low protein, high-calorie diet
 Medications to remove nitrogen
 Supplements of amino acids
 Drinking plenty of water
 Liver transplant - can reverse symptoms of a urea cycle disorder
UREA CYCLE DISORDER HEALTH COMPLICATIONS

WHAT POSSIBLE COMPLICATIONS CAN ARISE IF UCDIS NOT RECOGNISED AND TREATED
EARLY?

The liver in a person with urea cycle disorder is missing an enzyme necessary to convert nitrogen
into urea. As a result, ammonia, a highly toxic substance, builds up in the bloodstream and is not removed
from the body. Untreated, the high amounts of ammonia can cause brain damage, coma and eventually
death.
UREA CYCLE DISORDER HEALTH CARE OUTCOME
 What will you suggest to improve the healthcare outcome of patients with UCD?

  for advancing care: improved means of identifying and managing asymptomatic (i.e., mild, chronic)
HA, updated guidance on UCD treatment decisions, including consideration of adherence challenges
(e.g., difficulties with side effects, tolerability, and drug administration), and additional resources to
assess and support attention/focus and emotional/social difficulties among UCD patients and their
families.
UREA CYCLE DISORDER REFERENCES
Rodwell, W.; Bender, D.; Botham, K.; Kennelly, P. & Weil, A. (2018). Harper’s Illustrated
Biochemistry (31st ed.) [E-book]. McGraw-Hill Education. https://www.mhprofessional.com
Ah Mew N, Simpson KL, Gropman AL, et al. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated
2017 Jun 22]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle
(WA): University of Washington, Seattle; 1993-2021.
https://www.ncbi.nlm.nih.gov/books/NBK1217/ Urea Cycle Disorders Overview
https://www.ncbi.nlm.nih.gov/books/NBK482363/

https://www.webmd.com/children/urea-cycle-disorders#3
https://www.sciencedirect.com/science/article/pii/S1096719219302896