Inborn Errors: Urea Cycle Defects

Question 1

Sx of severe hyperammonemia

Answer 1

• initial symptoms in child are nonspecific: failure to feed, loss of thermoregulation with a low core temperature, and somnolence.
• Symptoms progress from somnolence to lethargy and coma
• ~50% of neonates may have seizures, some without overt clinical manifestations.
• hyperammonemia @ brain stem ==> hyperventilation ==> respiratory alkalosis.
  
  • Hypoventilation and respiratory arrest follow as pressure increases on the brain stem.

Question 2

Sx of mild/patrial hyperammonemia

Answer 2

• Variable with disorder
• In most a hyperammonemic episode is marked by loss of appetite, vomiting, lethargy, and behavioral abnormalities.
• Sleep disorders, delusions, hallucinations, and psychosis may occur.

Question 3

General presentation of severe urea cycle disorders

Answer 3

• Severe deficiency or total absence of activity of any of the first four enzymes (CPS1, OTC, ASS, ASL) or the cofactor producer (NAGS)
• ==> increased ammonia/other precursor metabolites during the first few days of life.
• Infants with a severe urea cycle disorder are normal at birth but rapidly develop cerebral edema and the related signs
  
  • lethargy, anorexia, hyper or hypoventilation, hypothermia, seizures, neurologic posturing, and coma

Question 4

General presentation of mild/partial urea cycle disorders

Answer 4

• milder (or partial) deficiencies of these enzymes and in arginase (ARG) deficiency ==> ammonia accumulation triggered by illness or stress at almost any time of life
• elevations of plasma ammonia concentration and symptoms are often subtle
• first clinical episode may not occur for months or decades
• Can present an any age!

Question 5

Common enzyme deficiencies ==> urea cycle disorders

Answer 5

• NAGS
• CPS1
• OTC
• Arginase
• Arginosuccinate synthetase
• Arginosuccinate lyase

Question 6

Common metabolite increases in urea cycle disorders

Answer 6

• ammonia
• OTC (orinthine trans-carbamoylase) ==> increased carbamoyl phosphate ==> increased orotic acid
• ASS deficiency ==> citrullinemia

Question 7

Common lab findings in urea cycle disorders

Answer 7

• ↑ plasma ammonia
• Plasma amino acids
• ↑ urine amino and orotic acids
• ↑ citrulline
• plasma ammonia concentration of 150 μmol/L or higher associated + normal anion gap + normal plasma glucose indicates UCD

Question 8

MOA of ammonia scavenging meds

Answer 8

• Sodium benzoate binds glycine, creating hippurate, which is excreted in urine.
• Sodium phenylacetate merges phenylacetate with glutamine to make phenylacetylglutamine which is excreted in urine.

Question 9

Approach to tx of urea cycle disorders

Answer 9

• Overall = treatment of manifestations:
• Acute severe hyperammonemia: Dialysis and hemofiltration to reduce plasma ammonia concentration
• IV arginine hydrochloride & nitrogen scavenger drugs
• restriction of protein for 12 to 24 hours
• physiologic stabilization with IV and cardiac pressors while avoiding overhydration.