Urea Cycle Defects

hyperammonemia

• direct neurotoxicity → encephalopathy

• stimulation of brainstem breathing centers → respiratory alkalosis

  • low CO2, high pH on a blood gas

• small molecule, rapidly diffuses across the blood-brain barrier

• exerts osmotic force → cerebral edema → herniation

general principles of the urea cycle

• sources of protein

  • diet (most Americans consume well over the RDA)

  • endogenous recycling: proteins are constantly degraded back to amino acids and used to reconstitute proteins

• urea cycle is the only major metabolic pathway for detoxifying waste nitrogen formed during protein metabolism

• occurs in the liver

• 5-step pathway which results in conversion of 2 molecules of ammonia and 1 of bicarbonate to urea

neonatal onset of symptoms

• often within 24 hours of life

• irritability

• poor feeding, vomiting

• lethargy 

• hypotonia, seizures

• respiratory distress, apnea

• liver dysfunction 

  • albumin → edema

  • coagulation proteins → bleeding

  • bilirubin → jaundice, icterus

• declining mental status

• coma, death

later onset of symptoms

• neuropsychiatric symptoms: hyperactivity, self-injurious behavior, hallucinations

• protein avoidance

• developmental delay

• seizures, stroke, ataxia, vision loss

• episodic hyperammonemia

  • precipitated by viral illness

  • misdiagnosed as Reyes syndrome

  • vomiting

  • poor growth

• severe cases result in lethargy, delirium, coma, and death

carbamoyl phosphate synthetase deficiency 

• Overview: deficiency of rate-limiting enzyme in urea cycle, most severe urea cycle defect 

• Gene(s): CPS1

• Inheritance Pattern: autosomal recessive 

• Features:

  • testing shows low orotic acid, low citrulline, and low arginine

  • liver enzyme analysis and molecular testing can be used for diagnosis

ornithine transcarbamylase deficiency 

• Overview: hyperammonemia, respiratory alkalosis, elevated orotic acid in urine

• Gene(s): OTC

• Inheritance Pattern: X-linked dominant

  • Males: neonatal severe, some later onset forms

  • Females: >15% experience symptoms; worse with menstruation and pregnancy; aversion to protein/alcohol, migraines, cyclic vomiting

• Features:

  • seizures

  • vomiting

  • poor feeding

  • hyperventilation

  • hepatomegaly

• Later-Onset Forms: high incidence of neuropsychiatric illness

  • crises are precipitated by alcohol use, trauma, Atkins-type diet or bariatric surgery, etc.

arginosuccinate synthetase deficiency

(citrullinemia type I)

• Overview: citrullinemia

• Gene(s): ASS1

• Inheritance Pattern: autosomal recessive

• Features: 

  • lethargy 

  • coma

  • seizures

  • vomiting

  • poor feeding

  • hepatomegaly 

arginosuccinate lyase deficiency

(argininosuccinic aciduria)

• Overview: elevated arginosuccinic acid in urine

• Gene(s): ASL

• Inheritance Pattern: autosomal recessive 

• Features:

  • lethargy 

  • seizures

  • vomiting

  • poor feeding

  • hyperventilation

  • hepatomegaly 

• Other: unique disease manifestations unrelated to degree of hyperammonemia

  • neurocognitive deficiencies

  • liver disease

  • trichorrhexis nodosa

  • hypertension 

trichorrhexis nodosa 

• coarse, brittle hair

• Fun Fact: hair is 10.5% arginine by weight

arginase deficiency

• Overview: markedly elevated plasma arginine, lactate, and CSF glutamine, and modestly elevated blood ammonia

• Gene(s): ARG1

• Inheritance Pattern: autosomal recessive

• Features:

  • delayed development

  • protein intolerance

  • spasticity

  • loss of muscle control

  • seizures

  • irritability

• Other: hyperammonemic crises less severe and less commen; unique presentation with spastic paraplegia around 2-3 years, progressive ID, seizures

treatments for urea cycle defects

• limit ammonia accumulation

  • limitation of protein intake: balancing with growth and potential for catabolism (metabolic formulas)

  • avoid catabolism (starvation, fever, illness, stress) thus avoid increased protein breakdown

  • avoid hypoglycemia/enhance anabolism

• replacement of urea cycle intermediates

  • citrulline or arginine

• increase ammonia removal 

  • ammonia scavenging drugs (sodium benzoate, glycerol, or sodium phenylbutyrate)

  • hemodialysis

  • liver transplantation