Diseases of the urea cycle

Defects in any of these enzymes or associated transporters can lead to urea cycle disorders (UCDs), resulting in hyperammonemia and neurological impairment (reviewed in Waisbren et al, 2019; Matsumoto et al, 2019).

CPS1 deficiency is the most severe UCD, presenting in neonates with lethargy, poor feeding, and seizures due to impaired ammonia detoxification. The clinical presentation of NAGS deficiency is virtually the same as CPS1 deficiency, reflecting the dependence of CPS1 activity on its allosteric activator NAG (reviewed in Waisbren et al, 2019; Matsumoto et al, 2019; Martinez et al, 2010; Caldovic et al, 2010).

The most common UCD is OTC deficiency, an X-linked disorder leading to hyperammonemia and neurological symptoms; males are typically more severely affected.

ASS1 deficiency, also known as Citrullinemia Type I is characterized by elevated citrulline and ammonia levels, presenting with lethargy, vomiting, and seizures in infancy. ASL deficiency, also known as Argininosuccinic Aciduria, presents with elevated argininosuccinate and ammonia levels, leading to neurological symptoms and potential liver involvement. ARG1 deficiency causes elevated arginine levels, leading to progressive spasticity and developmental delay. SLC25A15 deficiency, also known as hyperornithinemia-hyperammonemia-homocitrullinuria or HHH Syndrome), arises due to mutations in the transporter that mediates the exchange of cytosolic ornithine for citrulline from the mitochondrial matrix and is also associated with hyperammonemia and neurological symptoms (reviewed in reviewed in Waisbren et al, 2019; Matsumoto et al, 2019).