Question

A newborn girl appeared normal at birth, but within 24 hours she developed lethargy, hypothermia, and apnea. The attending physician suspects a metabolic disorder and orders a panel of labs. Which diagnostic would be the best to distinguish between a urea cycle disorder and a disorder in β -oxidation? (Please discuss your rationale for this choice) a. Blood glucose b. Urinary acids c. Serum fatty acids d. Plasma glutamine A full blood work up was ordered for this female and the data is presented below. UNE Online _ Case connections The initial blood ammonia level was elevated at 314 ug/dl (normal range = 17–80) and rapidly rose to 600 ug/dl. The urine orotic acid level was markedly elevated at 473 umol/L creatinine (nl = 0–3). The plasma citrulline level was normal at 10 uM/L (nl = 12–55). In this patient where orotic acid levels are elevated, list one urea cycle enzyme that is most likely deficient and one urea cycle enzyme that is least likely to be impaired. (Be sure to justify your answers)

Answer 1

Among given options, Plasma Glutamine will be the best diagnostic tool to differentiate between urea cycle disorder and beta oxidation defect. Glutamine is a non-toxic and non-essential amino acid which takes part in the detoxification and transport of ammonia. In urea cycle disorder along with rise of free ammonia, plasma glutamine levels are also elevated. On the contrary, Glutamine levels are normal in beta oxidation defects.

On the basis of data available from lab reports, the case is a classic example of Ornithine Transcarbamylase (OTC) deficiency. It is a X-linked recessive urea cycle disorder characterized by severe disease in affected boys​​​​ with very high serum ammonia levels whereas affected girls with a disease causing mutation of one of the X chromosomes may develop hyperammonemia, lethargy, apnea like features.

As a result of the deficiency of OTC, Carbamyl phosphate accumulates in mitochondria and then leaks into the cytoplasm from where it is redirected into pyrimidine synthesis resulting in raised levels of Orotic Acid in urine. Raised orotic acid level helps to distinguish OTC deficiency from Carbamyl Phosphatase Synthatase I (CPS I) deficiency. The most likely deficient enzyme in this case will be Ornithine Transcarbamylase (OTC) and the enzyme least likely to be impaired will be Carbamyl Phosphatase Synthatase I (CPS I).