A 2-year-old boy is brought to the emergency department with fever, vomiting, and sleepiness. He had several episodes of emesis this morning, and his mother was unable to wake him from his afternoon nap. The boy has had mild rhinorrhea and fever for the past 3 days. Since the newborn period, the parents say that the patient has had multiple illnesses characterized by vomiting and sleepiness. Prior laboratory testing revealed increased blood ammonia levels during these episodes and markedly increased orotic acid excretion in the urine. Physical examination shows a tachypneic boy who is unresponsive to all stimuli. Which of the following enzymes is most likely to be deficient in this patient?

Question

A 2-year-old boy is brought to the emergency department with fever, vomiting, and sleepiness.  He had several episodes of emesis this morning, and his mother was unable to wake him from his afternoon nap.  The boy has had mild rhinorrhea and fever for the past 3 days.  Since the newborn period, the parents say that the patient has had multiple illnesses characterized by vomiting and sleepiness.  Prior laboratory testing revealed increased blood ammonia levels during these episodes and markedly increased orotic acid excretion in the urine.  Physical examination shows a tachypneic boy who is unresponsive to all stimuli.  Which of the following enzymes is most likely to be deficient in this patient?

Quizplus · Accepted Answer

11ec160b_36c0_f82f_9249_fb97e6bd2856_MD0001_00 Ammonia generated from the metabolism of amino acids is converted into urea by the urea cycle. The combination of bicarbonate (HCO₃-), ammonia, and ATP is catalyzed by carbamoyl phosphate synthetase (rate-limiting enzyme in the urea cycle) to yield carbamoyl phosphate. Carbamoyl phosphate combines with ornithine to form citrulline in a reaction catalyzed by ornithine transcarbamylase. Citrulline enters the cytosol and is converted to argininosuccinate, which is then converted to arginine. The conversion of arginine to ornithine by arginase completes the urea cycle by releasing a urea molecule. N-acetylglutamate serves as a regulator of the urea cycle through activation of carbamoyl phosphate synthetase I. This patient most likely has ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder. OTC deficiency results in excess carbamoyl phosphate, which stimulates pyrimidine synthesis. As an intermediate product in this pathway, orotic acid accumulates and results in increased urinary orotic acid. Patients also have hyperammonemia due to impaired ammonia excretion, which is a metabolic emergency. Ammonia is neurotoxic and causes episodes of vomiting and confusion/coma. Tachypnea also occurs due to cerebral edema from ammonia buildup, resulting in central hyperventilation and respiratory alkalosis. Metabolic decompensation is often triggered by illness (eg, viral upper respiratory infection, acute otitis media), fasting, or increased protein intake. (Choices A and C) Although defects in carbamoyl phosphate synthetase I and N-Acetylglutamate synthetase also result in hyperammonemia, levels of carbamoyl phosphate are low and orotic acid is not elevated in the urine. (Choice B) Hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome) results in hyperuricemia because purines cannot be salvaged from degraded DNA. Urate kidney stones and self-mutilation are classic clinical manifestations. (Choice E) Uridine monophosphate synthetase (UMPS) is part of the pyrimidine synthesis pathway. UMPS deficiency leads to orotic acid buildup (similar to OTC deficiency) but not hyperammonemia. Characteristic findings include megaloblastic anemia and delayed growth. Educational objective: Patients with urea cycle disorders typically have discrete episodes of vomiting, tachypnea, and confusion/coma secondary to hyperammonemia (a metabolic emergency). Ornithine transcarbamylase deficiency is the most common disorder of the urea cycle and is characterized by hyperammonemia and elevated urinary orotic acid. __________ References: Ornithine Transcarbamylase Deficiency. (http://www.ncbi.nlm.nih.gov/pubmed/24006547) Urea Cycle Disorders Overview. (http://www.ncbi.nlm.nih.gov/pubmed/20301396)

A 2-Year-Old Boy Is Brought to the Emergency Department with Fever