METABOLIC DISORDERS

ARE ASSOCIATED WITH

EACH REACTION OF
THE UREA CYCLE
 Disorders of the Urea Cycle
• The main function of Urea cycle is to remove
toxic ammonia from blood as urea.

• Defects in the metabolism of conversion of

ammonia to urea.
• That leads to hyperammonemia or NH3
intoxication .
Signs, symptoms & treatment
Treatments

• Low-protein diet
• Amino acid supplements 
• Ammonia-controlling medicines
• Liver transplant
Enzymes of Inherited Metabolic
Disorders of the Urea Cycle

• five major metabolic disorders in urea cycle and

the disorders are:
• 1. Hyperammonemia Type I
• 2. Hyperammonemia Type II
• 3. Citrullinemia
• 4. Arginosuccinic Aciduria
• 5. Hyperargininaemia.

• These are caused by the deficiency of these

enzymes
Carbamoyl Phosphate Synthetase I

• is type of urea cycle disorder .

• It causes toxic levels of ammonia to

accumulate in the blood.

• Hyperammonemia due to carbamoyl

phosphate synthetase 1 deficiency

• N-acetylglutamate is essential for the

activity of carbamoyl phosphate
synthetase I
N-acetylglutamate Synthetase
• Deficiency of this enzyme has been described in a number of
affected individuals.
• Symptoms mimic those of CPSI deficiency
• N-Acetyl glutamate is essential for Carbamoyl phosphate
synthase I activity
• The NAGS gene encodes N-acetyl glutamate synthase, which
catalyzes the condensation of acetyl-CoA with glutamate.
• Defects in the NAGS gene result in severe hyperammonemia,
which in this specific instance may respond to administered N
acetyl glutamate
Ornithine Permease
• also called  HHH syndrome.
• syndrome results from mutation of the ORNT1 gene that encodes the mitochondrial membrane
ornithine permease.
• The failure to import cytosolic ornithine into the mitochondrial matrix renders the urea cycle
inoperable.
• In the absence of its normal acceptor (ornithine), mitochondrial carbamoyl phosphate
carbamoylates lysine to homocitrulline, resulting in homocitrullinuria.
Ornithine Transcarbamoylase
• The X-chromosome–linked deficiency termed
“hyperammonemia type 2”
• Ornithine transcarbamylase (OTC) deficiency is a
genetic disease that causes too much ammonia to
accumulate in the blood .
• Ammonia is toxic when levels are too high and
especially affects the nervous system.
• Severe OTC deficiency the early-onset form typically
affects males and rarely females.
Argininosuccinate Synthetase
• is an autosomal recessive disorder of the urea cycle that
also affects the synthesis of arginine.
•  commonly referred to as citrullinemia type I (CTLN1)
• There are at least 22 known mutations in the AS gene that
result in argininosuccinate synthetase deficiency (ASD).
• Mutations include missense, nonsense and exon deletions.
• The frequency of ASD is approximately 1 per 57,000 live
births.