A 4-day-old girl is brought to the office for a routine newborn visit. She was born at 39 weeks gestation via normal spontaneous vaginal delivery to a gravida 5 para 4 woman. The patient has been breastfed exclusively but has had increasing difficulty feeding over the past 24 hours. Her parents say that she is "too sleepy to feed" and has been vomiting. The infant has 3 healthy, living siblings and a brother who died in infancy from "low sugar in his blood." Physical examination shows tachypnea and signs of dehydration. The patient is responsive to painful stimuli only. After acute treatment and stabilization, urine testing reveals significantly elevated levels of methylmalonic acid. Which of the following sets of laboratory values would most likely result from this patient's condition?

Question

Quizplus · Accepted Answer

11ec160b_36ee_9732_9249_937f31607a16_MD0001_00 This patient's presentation is consistent with methylmalonic acidemia, an autosomal recessive organic acidemia resulting from complete or partial deficiency of the enzyme methylmalonyl-CoA mutase. Catabolism of isoleucine, valine, threonine, methionine, and odd-chain fatty acids normally leads to formation of propionyl CoA, which is then converted to methylmalonyl CoA by biotin-dependent carboxylation. Isomerization of methylmalonyl CoA through a vitamin B12-dependent reaction forms succinyl CoA, which subsequently enters the TCA cycle. Mutations in methylmalonyl-CoA mutase result in buildup of methylmalonic acid and propionic acid, leading to a metabolic acidosis. Hypoglycemia results from overall increased metabolic rate leading to increased glucose utilization and direct toxic inhibition of gluconeogenesis by the organic acids. The presence of hypoglycemia leads to increased free fatty acid metabolism that produces ketones, resulting in a further anion gap metabolic acidosis. Finally, organic acids also directly inhibit the urea cycle, leading to hyperammonemia. Complete deficiency of methylmalonyl-CoA mutase results in an anion gap metabolic acidosis, hypoglycemia, ketosis, and hyperammonemia. These metabolic derangements manifest as hypotonia, lethargy, vomiting, and respiratory distress (tachypnea due to acidosis) in the neonatal period. Diagnosis is confirmed by the presence of elevated urine methylmalonic acid and propionic acid. Propionic acidemia, a deficiency in propionyl-CoA carboxylase, also results in hyperammonemia, hypoglycemia, and metabolic acidosis, although it does not display elevated levels of urine methylmalonic acid. (Choice A) Production of ketones in the presence of hypoglycemia is an appropriate response in the fasting state, as ketones provide fuel for the brain. In this patient, the notable family history and elevated serum methylmalonic acid level make methylmalonic acidemia more likely than simple fasting or dehydration. (Choice C) Fatty acid oxidation disorders, such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, can present with hypoglycemia, hyperammonemia, and metabolic acidosis, but these disorders lack an appropriate ketosis. (Choice D) Urea cycle defects typically present with hyperammonemia without hypoglycemia or ketosis. (Choice E) Propionic acid levels are elevated in patients with methylmalonic acidemia due to downstream enzymatic deficiency of methylmalonyl-CoA mutase. Educational objective: Methylmalonic acidemia is an organic acidemia due to complete or partial deficiency of methylmalonyl-CoA mutase. Complete deficiency classically presents with lethargy, vomiting, and tachypnea in a newborn. Laboratory testing shows hyperammonemia, ketotic hypoglycemia, and metabolic acidosis. The diagnosis is confirmed by elevated urine methylmalonic acid and propionic acid. __________ References: Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. (http://www.ncbi.nlm.nih.gov/pubmed/25205257)

A 4-Day-Old Girl Is Brought to the Office for a Routine