A 4-day-old infant is brought to the emergency department with abnormal movements. The patient has had intermittent episodes of tonic posturing over the past 3 hours as well as poor feeding, vomiting, and irritability for the past 2 days. The mother also reports that his diapers smell like "caramelizing sugar." There are no known medical problems in the family, but the child's maternal aunt died "sometime in the first year" of life from unknown causes. Examination shows a lethargic infant with intermittent posturing episodes and increased generalized muscle tone. Laboratory studies of plasma and urine confirm the diagnosis. In addition to appropriate dietary restriction, supplementation with which of the following may improve this infant's condition?

Question

A 4-day-old infant is brought to the emergency department with abnormal movements.  The patient has had intermittent episodes of tonic posturing over the past 3 hours as well as poor feeding, vomiting, and irritability for the past 2 days.  The mother also reports that his diapers smell like "caramelizing sugar."  There are no known medical problems in the family, but the child's maternal aunt died "sometime in the first year" of life from unknown causes.  Examination shows a lethargic infant with intermittent posturing episodes and increased generalized muscle tone.  Laboratory studies of plasma and urine confirm the diagnosis.  In addition to appropriate dietary restriction, supplementation with which of the following may improve this infant's condition?

Quizplus · Accepted Answer

11ec160b_36cb_f4ca_9249_c536558b5fdb_MD0001_00 This infant has symptoms typical of maple syrup urine disease (MSUD), an autosomal recessive disorder characterized by the defective breakdown of branched-chain amino acids (leucine, isoleucine, and valine). Degradation of these 3 amino acids first involves transamination to their respective α-ketoacids, which are subsequently metabolized by several enzymes referred to as the branched-chain α-ketoacid dehydrogenase complex (BCKDC). Mutations in BCKDC result in accumulation of the branched-chain amino acids in serum and peripheral tissues, resulting in neurotoxicity that includes seizures, irritability, lethargy, and poor feeding. A metabolite of isoleucine gives the urine a distinctive sweet odor. MSUD can be life-threatening if untreated, as brain swelling may lead to death. Branched-chain α-ketoacid dehydrogenase (in addition to pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) requires 5 cofactors: Thiamine, Lipoate, Coenzyme A, FAD, NAD (mnemonic: Tender Loving Care For Nancy). Some patients with MSUD improve with high-dose thiamine treatment, but most still require lifelong dietary restrictions. (Choice A) Most disorders of the urea cycle require arginine as an essential amino acid. When patients with urea cycle disorders develop hyperammonemia, arginine is administered for production of downstream water-soluble intermediates (eg, ornithine, citrulline) that lead to nitrogen disposal and decreased plasma ammonia levels. (Choice B) Cobalamin (vitamin B₁₂) deficiency leads to megaloblastic anemia, neurologic changes including peripheral neuropathy, and elevated plasma levels of homocysteine (a prothrombotic substance). Supplementation of cobalamin is recommended to lower homocysteine levels in patients with hyperhomocysteinemia. (Choice C) Pyridoxine (vitamin B₆) is involved in the transamination and decarboxylation steps in amino acid metabolism, as well as heme and neurotransmitter synthesis. Pyridoxine supplementation is also used in the treatment of hyperhomocysteinemia. (Choice D) Tetrahydrobiopterin deficiency results in phenylketonuria, as tetrahydrobiopterin is a cofactor for phenylalanine hydroxylase. Phenylalanine levels can be reduced by tetrahydrobiopterin supplementation in patients with tetrahydrobiopterin deficiency. Educational objective: Branched-chain α-ketoacid dehydrogenase requires several coenzymes: Thiamine, Lipoate, Coenzyme A, FAD, NAD (mnemonic: Tender Loving Care For Nancy). Some patients with maple syrup urine disease improve with high-dose thiamine treatment, but most require lifelong restriction of leucine, isoleucine, and valine. __________ References: Branched-chain amino acid metabolism: From rare Mendelian diseases to more common disorders. (http://www.ncbi.nlm.nih.gov/pubmed/24651065) Maple syrup urine disease. (http://www.ncbi.nlm.nih.gov/pubmed/20301495)

A 4-Day-Old Infant Is Brought to the Emergency Department with Abnormal