What causes hyperexcitation of the central nervous system (CNS) in urea cycle disorders (UCDs)?

From the Guidelines

Hyperexcitation of the central nervous system in urea cycle disorders is primarily caused by ammonia toxicity, which disrupts neurological functions and leads to symptoms such as seizures, irritability, and behavioral changes. In urea cycle disorders, the body cannot properly convert ammonia to urea for excretion, resulting in ammonia accumulation in the bloodstream 1. This excess ammonia crosses the blood-brain barrier and is converted to glutamine in astrocytes, causing osmotic stress, cell swelling, and altered neurotransmitter function. Ammonia also directly interferes with glutamate and GABA neurotransmission, creating an imbalance that favors excitation over inhibition 1. Additionally, ammonia disrupts energy metabolism in neurons, impairs mitochondrial function, and triggers oxidative stress, further contributing to neuronal hyperexcitation.

The treatment of hyperammonemia in urea cycle disorders focuses on reducing ammonia levels through:

• Dietary protein restriction
• Medications like sodium phenylbutyrate or sodium benzoate that provide alternative pathways for nitrogen excretion 1
• In emergency situations, hemodialysis to rapidly remove ammonia from circulation 1. The dosage of these medications is crucial, with recommendations including:
• Intravenous sodium benzoate: maximum dose 12 g daily, with body weight <20 kg, 250 mg/kg, and body weight >20 kg, 5.5 g/m2 1
• Intravenous sodium phenylacetate: body weight <20 kg, 250 mg/kg, and body weight >20 kg, 5.5 g/m2 1
• Intravenous l-arginine hydrochloride: body weight <20 kg, 200 mg/kg for otC and CPs deficiencies, and 600 mg/kg for Ass and Asl deficiencies 1

It is essential to note that the choice of dialysis modality, such as intermittent HD or CKRT, depends on institutional preference, local facilities, and the patient's condition 1. The decision to initiate dialysis should be based on the evolving clinical status of the patient, rather than rigid numerical values of ammonia levels 1.

From the FDA Drug Label

In patients with hyperammonemia due to deficiencies in enzymes of the urea cycle, sodium phenylacetate and sodium benzoate injection has been shown to decrease elevated plasma ammonia levels These effects are considered to be the result of reduction in nitrogen overload through glutamine and glycine scavenging by sodium phenylacetate and sodium benzoate injection in combination with appropriate dietary and other supportive measures. Additionally, other signs of intoxication may include obtundation (in the absence of hyperammonemia), hyperventilation, a severe compensated metabolic acidosis, perhaps with a respiratory component, large anion gap, hypernatremia and hyperosmolarity, progressive encephalopathy, cardiovascular collapse, and death

The hyperexcitation of the central nervous system in urea cycle disorder is likely due to hyperammonemia, which can cause progressive encephalopathy. The exact mechanism is not explicitly stated in the label, but it is implied that the reduction of nitrogen overload through glutamine and glycine scavenging can help decrease elevated plasma ammonia levels, which may in turn reduce the risk of hyperexcitation of the central nervous system 2.

• Key points:
  • Hyperammonemia can cause progressive encephalopathy
  • Reduction of nitrogen overload can help decrease elevated plasma ammonia levels
  • Sodium phenylacetate and sodium benzoate injection can help reduce nitrogen overload in patients with urea cycle disorders

From the Research

Urea Cycle Disorder and Hyperexcitation of the Central Nervous System

• The urea cycle disorders (UCDs) are characterized by a defect in ammonium elimination in the liver, leading to hyperammonemia 3.
• This excess of circulating ammonium eventually reaches the central nervous system, where the main toxic effects of ammonium occur, including hyperexcitation 3.
• The brain is much more susceptible to the deleterious effects of ammonium during development than in adulthood, and surviving UCD patients may develop cortical and basal ganglia hypodensities, cortical atrophy, white matter atrophy or hypomyelination and ventricular dilatation 3.
• Ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy, nitric oxide synthesis, axonal and dendritic growth, signal transduction pathways, as well as K(+) and water channels, leading to energy deficit, oxidative stress and cell death 3.

Mechanisms of Hyperexcitation

• The exact mechanisms of hyperexcitation of the central nervous system in UCDs are not fully understood, but it is thought to be related to the toxic effects of ammonium on the brain 3.
• Recent work has proposed that neuroprotective strategies, such as the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine and acetyl-l-carnitine, may counteract the toxic effects of ammonium 3.
• The use of alternative pathway therapy, including oral sodium phenylbutyrate, arginine supplements, or both, may also help to decrease the mortality and morbidity from these disorders, but they remain unacceptably high 4.

Treatment and Management

• Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, can effectively lower plasma ammonium levels and result in survival in the majority of patients 5.
• Liver transplantation may also be considered as a treatment option, especially in patients with severe disease or those who do not respond to medical therapy 6.
• Diet plays a primary therapeutic role in the management of UCDs, but liver transplantation may be considered as a primary intervention to prevent life-threatening acute episodes and chronic mental impairment 6.