Inborn Errors: Urea Cycle Defects Flashcards Preview

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Flashcards in Inborn Errors: Urea Cycle Defects Deck (9)
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Sx of severe hyperammonemia

  • 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.



Sx of mild/patrial hyperammonemia

  • 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. 


General presentation of severe urea cycle disorders

  • 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


General presentation of mild/partial urea cycle disorders

  • 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!


Common enzyme deficiencies ==> urea cycle disorders

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


Common metabolite increases in urea cycle disorders 

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


Common lab findings in urea cycle disorders

  • ↑ 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


MOA of ammonia scavenging meds

  • 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.


Approach to tx of urea cycle disorders

  • 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.