Inherited urea cycle disorder involving ornithine transcarbamylase enzyme resulting in hyperammonemia that causes neurological deficits
- M/C urea cycle disorder (UCD) (M/C, > 50% of all UCDs) (OTC gene located on chromosome Xp21)
- X-linked recessive inheritance (other urea cycle enzyme deficiencies, are autosomal recessive)
Pathophysiology
Urea cycle:
Responsible for metabolism of nitrogen waste from the breakdown of proteins. In doing so, the cycle produces urea from ammonia. The urea cycle is also the only endogenous source of the amino acids arginine, ornithine and citrulline. In humans, this biochemical pathway occurs primarily in the liver, but to a lesser extent in the kidney.
- Ornithine transcarbamylase (OTC) catalyzes the formation of citrulline and inorganic phosphate from carbamyl phosphate and ornithine in the urea cycle.
Other urea cycle disorders:
- Carbamoyl phosphate synthetase (CPS) I deficiency
- ASS1 deficiency (citrullinemia type I)
- ASL deficiency (argininosuccinic aciduria)
- Arginase deficiency
- NAGS deficiency
- Ornithine translocase (ORNT1) deficiency
- Citrin deficiency
Clinical features
The clinical presentation of OTCD is very heterogeneous. Affected hemizygous males usually present in the neonatal period with acute hyperammonemic coma due to a severe enzymatic deficiency, whereas the clinical severity of heterozygous affected females varies considerably, depending partially on the pattern of inactivation of the X chromosome.
Neonatal-onset OTCD:
Males with severe OTC deficiency are typically normal at birth, but become symptomatic on the second to third day of life with poor suck, reduced intake, and hypotonia, followed by lethargy progressing to somnolence and coma. They hyperventilate, and may have seizures. By the time neonates with OTC deficiency come to medical attention they typically are catastrophically ill with low body temperature (hypothermia), severe encephalopathy, and respiratory alkalosis.
- Irritable, lethargic baby, and stops feeding
- Poorly-controlled body temperature and respiratory rates
- May experience seizures
- Without urgent intervention:
- Metabolic encephalopathy → coma & death (within first week of life)
- Hyperammonemia → Preferential brain damage
Late-onset OTCD:
Missense mutations that retain some OTC activity cause late-onset disease in hemizygous males. These symptoms include lethargy, loss of appetite, early morning headaches, and confusion. Unfortunately, delayed diagnosis can lead to more severe complications.
- Headaches, nausea, vomiting, delirium, erratic behaviour, or seizures
- Dietary history of undiagnosed OTC deficiency:
- History of protein avoidance
Diagnosis
Biochemical studies:
- ↑ Orotic acid (blood and urine)
- ↓ BUN
- Hyperammonemia
Molecular analysis:
Management
The principles of OTCD treatment are dietary protein restriction, arginine and citrulline supplementation, and the induction of nitrogen excretion via the administration of sodium phenylbutyrate and/or sodium benzoate
Conservative management:
Avoidance of hyperammonemia
- Strictly-controlled low-protein diet
- Arginine supplementation (bypasses the OTC enzyme in the urea cycle, allowing for urea creation and ammonia elimination)
- Nitrogen scavenging agents (sodium benzoate & sodium phenylbutyrate): Reduces ammonia by using alternative pathways for nitrogen elimination
Haemodialysis
If ammonia rises above 500 micromol/L, the patient should receive urgent hemodialysis. Ammonia levels above 800 micromol/L are associated with severe neuralgic damage, limiting treatment options
Liver transplantation:
Alternative to medical therapy for severe OTCD in the neonatal form, or in the case of frequent episodes of recurrent hyperammonemia or poor metabolic status