This document discusses urea cycle disorders including carbamoyl phosphate synthetase deficiency, ornithine transcarbamoylase deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, arginase deficiency, and N-acetyl glutamate synthase deficiency. The disorders are inherited in an autosomal recessive manner and cause hyperammonemia. Symptoms range from mild to severe and include vomiting, seizures, developmental delays, and coma. Treatment involves reducing protein intake, supplementing with essential amino acids, and medications to help alternative pathways for nitrogen excretion like sodium benzoate, sodium phenylbutyrate, and phenylacetate. Newer treatments discussed are gly

1. Urea Cycle
Disorders

2. Ornithine
transcarbamoylase
deficiency
Carbamoyl phosphate
synthetase deficiency
Argininosuccinate
synthetase deficiency or
citrullinemia
Argininosuccinate lyase
deficiency
Arginase deficiency

3. Urea cycle
defects
Incidence : approx. 1 in
30 000 newborns
Autosomal recessive
Hyperammonemia is the
common presentation

4. Carbamoyl
Phosphate
Synthetase I
Deficiency
• Autosomal recessive
disorder
•CPS 1 catalyze formation
of carbamoyl phosphate
from ammonium and
bicarbonate
•Causes
hyperammonemia

5. Clinical
Features
• characterized by moderate to sever
cerebral damage and hyperammonemic
coma in neonatal
• CPS enzyme is totally absent
Early onset form
• Due to the partial deficiency of CPS
enzyme
• Intermediate seizure may be present
with episode of vomiting, mild
abdominal pain and muscle weakness
Delayed onset form

6. Ornithine
Transcarbamoylase
Deficiency
Worldwide prevalence 1/56,500 to 1/113,000 live births.
X-linked inborn error of metabolism of the urea cycle
It catalyze transfer of carbamoyl from CP to ornithine
Causes hyperammonemia, encephalopathy and
respiratory alkalosis
It characterized by high orotic acid level following high
protein diet

7. Clinical Features
Chronic ammonia intoxication and mental retardation are
the major features
 Milder form
Activity of enzyme is upto 25%
 Sever form
Activity of enzyme is 5-7%
 Skin lesions

8. N – acetyl Glutamate
Synthase Deficiency
• NAGS catalyze formation of
NAG from glutamine and acetyl
CoA
• N-acetyl glutamate is an
activator of CPS 1
• NAGS deficiency causes high
concentration of ammonia and
glutamine
• Patients have vomiting,
uncontrollable movement,
developmental delay, visual
impairment....
• It characterized by
hyperammonemia without
increased excretion of orotic acid

9. Arginosuccinate Aciduria
• Called argininosuccinase defeciency, argininosuccinate lyase deficiency
• Autosomal recessive disorder
• Argininosuccinase cleave argininosuccinate to yield arginine and fumarate
• It characterized by low arginine as well as hyperammonemia
• Clinical features include mental and physical retardation, convulsion,
episodic unconsciousness, liver enlargement and skin lesions
• It has two type, early onset type which is fatal and late onset type

10. Citrullinemia
• Also called citrullinuria and argininosuccinate synthetase deficiency
• Argininosuccinate synthetase combines citrulline with aspartate to
form
• argininosuccinate
• It is characterized by orotic acid urea and hyperammonemia
• Clinical features are sever vomiting which begin at the age of 9 months
and mental retardation
• Symptoms included delayed menarche, insomnia, nocturnal sweats,
recurrent vomiting, tremors, lethargy, convulsions and hallucination

11. It has 3 type
Type 1 which is duo to the
changes in the kinetic
properties of enzyme
Type 2 or late onset form
Type 3 which is
characterized by no
detectable enzyme activity
and no translation activity
for ASS mRNA

12. • Also called Arginase deficiency and hyperargininemia
• Autosomal recessive disorder
• Arginase hydrolyzes arginine to ornithine and urea and is virtually
exclusive to the liver
• The patients present with psychomotor retardation, epileptic seizures
and spastic paraplegia
• Children may have vomiting, hypotonia, irritability and ataxia
• Arginase deficiency dose not commonly have the sever
hyperammonemia

13. Diagnosis
• Inherited hyperammonaemias: urea cycle
defects and organic acid disorders.
• urea cycle defects: alkalosis and normal
anion gap
• organic acid disorders: acidosis and
increased anion gap
• Plasma amino acid analysis, GC/MS
analysis of urinary organic acids, or HPLC
analysis of orotic acids and orotidine.
• Confirmation by enzyme analysis in liver
tissue or mutation analysis.

16. Treatment
Reduction of natural protein to decrease ammonia production
Supplementation with essential amino acids
Replacement of arginine
Utilization of alternative pathways for nitrogen excretion. (sodium benzoate and sodium
phenylbutyrate or phenylacetate)
In N-acetylglutamate synthetase deficiency, N-carbamylglutamate can be used as an
alternative allosteric activator of carbamoyl-phosphate synthase

17. New treatment
strategies

18. Glycerol phenylbutyrate
• Glycerol phenylbutyrate (GPB) consists of three molecules of phenylbutyrate linked to a
glycerol backbone.
• Pancreatic lipases hydrolyze GPB in the small intestine to release phenylbutyrate, and
then to phenylacetate.
• Phenylacetate is released more slowly than sodium phenylbutyrate, resulting in superior
overnight ammonia control
• In clinical trials, GPB provides effective ammonia control in adult and pediatric UCD
patients

19. Carglumic acid
• Carglumic acid: synthetic analog of Nacetylglutamate that reactivates CPS-1,
restoring normal urea cycle function
• Given the rarity of NAGS deficiency, trials to determine the optimal dose for
therapeutic efficacy remain difficult.
• Carglumic acid also seems to be effective for hyperammonemia due to NAGS
inhibition caused by valproic acid and organic acidurias