Pathophysiology of Citrullinemia Type 1

Defect in Urea Cycle Enzymes

The American College of Medical Genetics recommends that citrullinemia type 1 is caused by mutations in the ASS1 gene, leading to a deficiency of argininosuccinate synthetase, resulting in toxic accumulation of ammonia and citrulline in the blood 1, 2
The deficiency of argininosuccinate synthetase interrupts the urea cycle, preventing the conversion of citrulline and aspartate to argininosuccinate, and subsequently leading to the accumulation of toxic ammonia 1, 2
The incidence of citrullinemia type 1 is estimated to be 1 in 57,000 births, and it is an autosomal recessive disorder 2

The European Society of Human Genetics states that hyperammonemia causes brain damage through multiple interconnected pathophysiological pathways, including the metabolism of ammonia to glutamine by astrocytes, leading to increased extracellular potassium and intracellular osmolality 1, 2
This process results in cerebral edema and the release of inflammatory cytokines, contributing to neuronal damage 1
Elevated extracellular potassium and glutamate released by astrocytes directly contribute to neuronal damage 1
The final product of ammonia detoxification, glutamine, is a key factor in ammonia-related neurotoxicity 1

The clinical manifestations of citrullinemia type 1 depend on the severity of the enzyme deficiency and the age of presentation, with severe deficiency typically presenting in the neonatal period with symptoms such as lethargy, feeding refusal, and vomiting 1, 2
As ammonia levels increase, symptoms progress to hyperventilation with respiratory alkalosis, hypotonia, ataxia, disorientation, and seizures 1, 2
If left untreated, the progression leads to coma and death 1, 2
Partial enzyme deficiencies may manifest in childhood, adolescence, or adulthood, triggered by metabolic stressors, with symptoms including growth failure, irritability, seizures, vomiting, ataxia, and intellectual disabilities 1, 2

The accumulation of carbamoyl phosphate results in increased production and excretion of orotate 1
Normal ammonia levels are ≤35 μmol/L, while hyperammonemia is defined as >100 μmol/L in neonates or ≥50 μmol/L in infants, children, and adults 2

The duration of hyperammonemic coma is the most important prognostic factor, with coma lasting more than 3 days, increased intracranial pressure, and plasma ammonia levels above 1,000 μmol/L associated with adverse neurological outcomes 2
The duration of coma is inversely correlated with intellectual quotient at 12 months after recovery 2
Ammonia levels >200 μmol/L are associated with poor neurological outcomes 2