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INBORN ERRORS OF
UREA CYCLE
GROUP 5Section 1E E1
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QUESTION #1:
Review the Urea Cycle
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UREA
Major nitrogenous excretory product
Synthesized mostly in the liver
Disposal form of ammonia
Normal Values: 30-60 uM
Detoxified rapidly
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Flow Of Nitrogen From
Amino Acids To Urea
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Two Forms of CPS
1. CPS I
1. CPS II
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Reactions and Intermediates
of Urea Biosynthesis
1. Formation of Carbamoyl Phosphate
2. Formation of Citrulline
3. Formation of Argininosuccinate4. Cleavage of Argininosuccinate Forms Arginine &
Fumarate
5. Cleavage of Arginine Releases Urea & Re-Forms
Ornithine
6. Fate of Urea
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Hyperammonemia
CitrullinemiaArgininosucci
nate AciduriaArginemia
Type I Type II
Enzyme
Deficient
Carbamoyl
PhosphateSynthase I
Ornithine
Transcarbamylase
Argininosuccin
ate Synthase
Argininosuccin
ase
Arginase
Most common Rare
Reaction 1 2 3 4 5
Inheritance Autosomal
recessive
X-linked Autosomal
recessive
Autosomal
recessive
Clinical
Manifestation
s
vomiting,
increasing
lethargy,
hypothermiaand
hyperventilation
Respiratory
alkalosis
Mental
retardation;
episodic
hyperammonemia, vomiting,
lethargy,
ataxia,
siezures,
eventual coma
Hepatomegaly
Kinky hair
(trichorrhexis
nodosa)
Spastic
paraplegia;
mental
retardation
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Hyperammonemia
Citrullinemia Argininosuccinate Aciduria
Arginemia
Type I Type II
Ammonium
(blood)Elevated Elevated Elevated Elevated Elevated
Treatment Nutritional restriction of protein
intake; oral administration of
citrulline or arginine;
Hemodialysis to remove excess
ammonia; oral sodium benzoate
(acute); provide alternate
pathways for nitrogen excretionas hippurate and
phenylacetylglutamine
Nutritional
restriction of
protein intake;
administration
of arginine;
sodium
benzoate forammonia
detoxification
Nutritional
restriction of
protein intake
Nutritional
restriction of
protein intake
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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:
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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
OTHER INBORN ERRORS of UREA CYCLE: