Urea Cycle

Question 1

Generalized Hyperammonemia

Cause:
Result:
Sx:
Tx: 
Dx:
Keywords:

Answer 1

Cause: High NH3
Result: Hyperammonemia, elevated glutamine, Early: lethargy, irritability and feeding difficulties. Later: CNS conditions
Sx:
Tx: Benzoic Acid or Phenylbutyrate (scaenge NH3 after actiation. Alpha keto acid (prevent a catabolic state). Low prot/high CHo diet Dialysis, live transplant

Question 2

Carbamoyl-Phosphate Synthetase I Deficiency (Hyperammonemia I)

Answer 2

Cause: Deficiency in the CPSI enzyme
Result: Inability to input NH3 into the Urea cycle
Sx: Hyperammonemia, increased Glutamine levels, decreased urea output, severe CNS defects due to dec NT synthesis (due to glutamate deh and glutamine synthase, cerebral oedema
Tx: Supp Arginine > makes NAG > activate CPSI, low prot/high CHO diet, alpha keto acids (lowers BMR), Drugs that conjugae AAs: benzoic acid + (glycine) > Hippuric Acid (1 N out). Phenylbutyrate (prodrug) + glutamine > Phenylacetylglutamine (2N out)
Keywords: Very severe CNS (NO way to excrete NH3)

Question 3

Ornithine Transcarbamoylase Deficiency (Hyperammonemia II)

Answer 3

Cause: Deficiency in OTC enzyme
Result: Buildup of Carbamoyl-Phosphate > Pyrimidine metabolism > produce Orotic Acid (orotic acidurias)
Sx: Hyperammonemia, high blood urea N, high blood glutamine, orotic aciduria, cerebral oedema, lethargy, convulsions, coma > death, metabolic acidosis.
Tx: Arginine > stimulate NAG (N-Acetyl-Glutamate)
Dx:
Keywords: Most common! X-Linked > males

Question 4

Citrullinaemia

Answer 4

Cause: Deficiency in Arginosuccinate Synthase enzyme
Result: Buildup of urine/plasma Citrulline
Sx: Hyperammonemia etc.
Tx: Supplemented Arginine > excretion of Citrulline & inc urea cycle progress (more substrate)
Dx:
Keywords:

Question 5

Arginosuccinic Aciduria

Answer 5

Cause: Deficiency in Arginosuccinate Lyase enzyme
Result: Buildup of Arginosuccinate (urine/plasma), moderately high levels of Citrulline
Sx: Hyperammonemia etc. , Metabolic acidosis, cerebral oedema
Tx: Supp Arginine>excretion of Arginosuccinate
Dx:
Keywords:

Question 6

HyperArgininaemia

Answer 6

Cause: Deficiency in the Arginase enzyme
Result: Buildup of Arginine & NH3 (but not as high NH3 as previous UCD’s)
Sx: Least severe, late-onset (adult/neurological problems) >bc multiple excretable intermediates prior to this step, milder hyperammonemia
Tx: No Arginine, diet w/essential AAs
Dx:
Keywords:

Question 7

Acquired Hyperammonemia

Answer 7

Cause: Liver disease, drug side effects, other diseases
Result: NH3 bypasses liver processing
Sx: Hyperammonemia
Tx: Low Protein/high CHO diet.
Lactulose > gut acidic environment>ammonia is protonated and cannot be absorbed…excreted instead.
Neomycin (antibiotic)> reduce the bacterial load in gut > thus limit Urease activity and promote excretion of urea in the feces.