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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: