INBORN ERRORS OF

UREA CYCLE
GROUP 5
Section 1E – E1
QUESTION #1:

Review the Urea Cycle

UREA
 Major nitrogenous excretory product
 Synthesized mostly in the liver
 Disposal form of ammonia
 Normal Values: 30-60 uM
 Detoxified rapidly
Flow Of Nitrogen From
Amino Acids To Urea
Two Forms of CPS
1. CPS I

2. CPS II
 Reactions and Intermediates
of Urea Biosynthesis
1. Formation of Carbamoyl Phosphate
2. Formation of Citrulline
3. Formation of Argininosuccinate
4. Cleavage of Argininosuccinate Forms Arginine &
Fumarate
5. Cleavage of Arginine Releases Urea & Re-Forms
Ornithine
6. Fate of Urea
 Hyperammonemia
Argininosucci
Citrullinemia Arginemia
Type I Type II nate Aciduria

Enzyme Carbamoyl Ornithine Argininosuccin Argininosuccin Arginase

Deficient Phosphate Transcarbamyl ate Synthase ase
Synthase I ase
    Most common     Rare

Reaction 1 2 3 4 5

Inheritance Autosomal X-linked Autosomal Autosomal  

recessive recessive recessive

Clinical vomiting, Respiratory Mental Hepatomegaly Spastic

Manifestation increasing alkalosis retardation; Kinky hair paraplegia;
s lethargy, episodic (trichorrhexis mental
hypothermia hyperammone nodosa) retardation
and mia, vomiting,
hyperventilation lethargy,
ataxia,
siezures,
eventual coma
 Hyperammonemia
Argininosucci
Citrullinemia Arginemia
nate Aciduria
Type I Type II

Ammonium
(blood)
Elevated Elevated Elevated Elevated Elevated

Treatment Nutritional restriction of protein Nutritional Nutritional Nutritional

intake; oral administration of restriction of restriction of restriction of
citrulline or arginine; protein intake; protein intake protein intake
Hemodialysis to remove excess administration
ammonia; oral sodium benzoate of arginine;
(acute); provide alternate sodium
pathways for nitrogen excretion benzoate for
as hippurate and ammonia
phenylacetylglutamine detoxification
OTHER INBORN ERRORS of UREA CYCLE:
1. HHH Syndrome (Hyperornithinemia,
Hyperammonemia, Homocitrullinuria)

• Mutation of the ORNT1 gene  mitochondrial

membrane ornithine transporter
• The failure to import cytosolic ornithine into
the mitochondrial matrix
• Hyperammonemia
• Hyperornithinemia
• Homocitrullinuria
OTHER INBORN ERRORS of UREA CYCLE:
2. N-acetylglutamate Synthetase Deficiency
• Mutations in the N-acetylglutamate synthetase
geneIt is one of the most rare disorders of the
UCDs.
• Manifestations: severe hyperammonemia, mild
hyperammonemia associated with deep coma,
acidosis, recurrent diarrhea, ataxia, hypoglycemia,
and hyperornithinemia.
• Treatments: restriction of protein intake and
administration of arginine or carbamylglutamate