A 5-month-old boy is brought to the office by his parents who are concerned that he has developmental delay. He has 3 older siblings, and the parents report that his siblings were much more active and interactive at the boy's age. The family has just moved to the United States from South America and did not have consistent primary care previously. Physical examination shows that the boy is unable to roll from front to back or back to front and does not seem to recognize his parents. Comprehensive laboratory evaluation reveals impaired tetrahydrobiopterin synthesis. Which of the following is most likely deficient in this patient?

Question

A 5-month-old boy is brought to the office by his parents who are concerned that he has developmental delay.  He has 3 older siblings, and the parents report that his siblings were much more active and interactive at the boy's age.  The family has just moved to the United States from South America and did not have consistent primary care previously.  Physical examination shows that the boy is unable to roll from front to back or back to front and does not seem to recognize his parents.  Comprehensive laboratory evaluation reveals impaired tetrahydrobiopterin synthesis.  Which of the following is most likely deficient in this patient?

Quizplus · Accepted Answer

11ec160b_36f0_6bf6_9249_490be2c03609_MD0001_00 Tetrahydrobiopterin (BH₄) is a cofactor in the synthesis of serotonin (a major neurotransmitter), tyrosine (a precursor of DOPA), and DOPA (the antecedent of the neurotransmitters dopamine, norepinephrine and epinephrine). Dihydropteridine reductase enzymatically reduces dihydrobiopterin (BH₂) to tetrahydrobiopterin (BH₄). Serotonin (5-hydroxytryptamine, or 5HT) is formed through hydroxylation and decarboxylation of the amino acid tryptophan. Most cases of phenylketonuria are due to phenylalanine hydroxylase deficiency. Less commonly, the etiology is due to BH₄ deficiency secondary to dihydropteridine reductase deficiency. The consequences of defective phenylalanine and tryptophan metabolism are phenylalanine accumulation (Choice D) and low levels of serotonin and other neurotransmitters, respectively. The combination of high phenylalanine levels, which may disrupt neuronal and glial development, and low serotonin and other neurotransmitters results in progressive neurologic deterioration in untreated patients. Manifestations include developmental delay, hypotonia, dystonia, and seizures. Treatment includes both a low phenylalanine diet and BH₄ supplementation. (Choice A) Acetylcholine is a neuromuscular junction neurotransmitter synthesized from choline and acetyl-CoA by choline acetyltransferase. In myasthenia gravis, production of antibodies against acetylcholine receptors leads to muscle weakness. (Choice B) Gamma-aminobutyric acid (GABA) is an inhibitor of presynaptic transmission in the central nervous system that is formed by glutamate decarboxylation, a reaction catalyzed by glutamate decarboxylase. Phenobarbital, an antiepileptic medication, potentiates GABA activity to decrease or cease seizure activity. (Choice C) Glutamate is an excitatory neurotransmitter that is synthesized from glutamine by the enzyme glutaminase. Ketamine is an N-methyl-D-aspartate (NMDA) receptor noncompetitive antagonist that blocks glutamate, which can result in anesthesia, sedation, and memory loss. Educational objective: Tetrahydrobiopterin (BH₄) is a cofactor used by hydroxylase enzymes in the synthesis of tyrosine, dopamine, and serotonin. Phenylketonuria can result from BH₄ deficiency due to dihydropteridine reductase deficiency. Intellectual disability is the hallmark of this condition and results in neurotransmitter (eg, serotonin) deficiency and hyperphenylalanemia. Treatment involves a low phenylalanine diet and BH₄ supplementation. __________ References: Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. (http://www.ncbi.nlm.nih.gov/pubmed/21937252) Disorders of Tetrahydrobiopterin Metabolism and their Treatment (http://www.ncbi.nlm.nih.gov/pubmed/12003346)

A 5-Month-Old Boy Is Brought to the Office by His