Clinical Vignette XVIII

• The clinical picture in conjunction with all of the available test results obtained thus far effectively confirms the presence of an inherited inborn error of metabolism most likely due to an enzyme deficiency. Given the clinical presentation and lab data, the clinician is certain of her working diagnosis and will eventually order additional testing to determine the exact genetic subtype of her leading diagnosis. In the meantime, the newborn will be medically treated intensively and according to the astute clinician’s firmly established diagnosis with an aggressive emphasis on closely monitoring specific dietary restrictions. Which of the following is this newborn male patient’s most likely diagnosis?

A two-day-old full term male neonate born to apparently healthy parents – a G1P1 29-year-old female and a 31-year-old male – begins to exhibit unusual signs of poor feeding, increased vomiting, lethargy and irritability. The male newborn had APGAR scores of 8 and 9, respectively and seemed to be doing well clinically after a routine vaginal delivery without any noted peri-procedural complications. The standard newborn screening panel (the “heel stick” test) was performed approximately 24 hours after birth and the infant’s filter paper card containing the samples of dried blood was sent to the appropriate lab to be tested for a wide assortment of serious medical conditions as part of state-specific newborn screening panel. Depending on the hospital and the state lab performing the newborn screening tests, results from the newborn’s blood spot screening profile can take up to 5 to 7 days to complete and report.

On physical examination, the newborn is afebrile but before the clinician can proceed with the rest of the exam, she notices an unusual sweet smelling odor emanating from the newborn male infant. The clinician quickly tests the newborn’s urine using a standard urine ketone strip and a dinitrophenylhydrazine test. The standard urine ketone test strip is immediately positive for ketonuria. Knowing the urine dinitrophenylhydrazine test result can take up to ten minutes to yield a result, the clinician wastes no time and obtains some additional blood from the newborn male infant and has it sent to the hospital’s inpatient clinical laboratory service for an urgent quantitative plasma concentration amino acid analysis. Several minutes later, the urine dinitrophenylhydrazine test result demonstrates the evidence of a strong precipitate in opaque urine indicating abnormally high urinary concentrations of α-ketoisocaproic acid, α-ketoisovaleric acid, and α-keto-β-methylvaleric acid. Based on the clinical picture, the limited lab testing results, and an intuitive high index of suspicion, the clinician quickly develops a working diagnosis and immediately begins preparing the appropriate medical treatment for the newborn male infant. Shortly thereafter, the test results of the newborn’s quantitative plasma concentration amino acid analysis reveals significantly elevated plasma concentrations of L-Leucine, L-Isoleucine, L-Valine, and L-allo-Isoleucine with decreased concentrations of other essential/non-essential amino acids such as L-Alanine, L-Glutamine, L-Glutamate, etc

• With a firmly established diagnosis based on the two-day-old neonate’s clinical presentation and lab testing results, which of the following cofactors (or coenzymes) is necessary for the proper functioning of the enzyme deficiency associated with this newborn male patient’s newly diagnosed medical condition?