Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

I will turn it over to Rahul to start with our patient case...

A 2 yo Asian M presents with difficulty feeding. He has a history of epilepsy and recently was switched to Valproic Acid for seizure control as well as OTC deficiency diagnosed at birth. He has had a 3-day history of URI, cough, which now progressed to this difficulty feeding. His parents state he was initially very fussy however in the past few hours he has been more sleepy. He has not had any fevers. They have noticed that while he is sleeping he has been breathing "fast." Prior to arrival at the emergency room, he was noted to have a large non-bloody, non-bilious emesis. Upon transfer to the trauma bay, the patient suddenly has a seizure. A quick POC glucose is normal. His care is escalated & diagnostic workup is initiated.

Pradip, our case had two key elements in his history, namely the h/o OTC deficiency & VPA use, which place him, particularly at high risk to have hyperammonemia. As this is our topic of discussion today, would you mind starting with a general background & definition of hyperammonemia?

Sure, this is a classic case of not only hyperammonemia but also a metabolic crisis in this case related to a urea cycle defect.

As background, the urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body. We get nitrogen sources from a few areas in the body:

from peripheral (muscle)
enteral sources (protein ingestion)

The urea cycle occurs in the liver and once the ammonia is converted to urea in the hepatocyte, it is excreted into the kidney as urea. We will dive into this deeper soon, however, pathologies that impair adequate hepatocyte function, can impair the urea cycle and thus lead to hyperammonemia.

This is a great basic science summary, would you mind commenting about this patient's enzyme defect — the OTC deficiency?

Yes, Ornithine transcarbamylase, or OTC for short, is one of the first few enzymes in the urea cycle.
As a background, the inheritance pattern of majority, all of the urea-cycle-defects (UCD) is autosomal recessive, however, OTC deficiency is different — it is X linked.
In a 21-year, multi-center retrospective study, it was noted that only 34 % of patients with UCD presented during the neonatal period (<30 days of age) — and around 25% of cases present in the 2-12-year-old range. This is why I would like to drive home this clinical point to have a urea cycle defect or any inborn error of metabolism in your differential, especially in a child who presents in a critically ill, undifferentiated state.

Why do you think there are subsets of populations who present later?

This is a great question and the cause may be multi-factorial — it is worth noting that patients may have partial enzyme...

Hyperammonemia

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