THE USMLE TIMES - #81
Highlights for the week of June 24, 2024
Welcome to issue #81 of The USMLE Times… We’ve now posted a USMLE-specific newsletter eighty-one weeks in a row! Welcome to all the 238 new members of the community 👋
Here’s what’s on tap for issue #81 of the USMLE Times:
Question of the Week (Biochemistry/Pathology)
This week’s video training (HUGE Microbiology Drill Session)
Tweet thread of the week
Links to recent training
Question deep-dive & breakdown
Let’s dive in!
A 2-month-old male infant presents with developmental delay, hypotonia, and seizures. He was born with blond hair, blue eyes, and fair skin. The mother reports that the child has had an eczematous rash and frequent vomiting. Laboratory testing reveals elevated levels of phenylalanine and low levels of neurotransmitters dopamine and serotonin in the cerebrospinal fluid. Despite a phenylalanine-restricted diet, the infant's symptoms persist. What is the most likely enzyme deficiency in this patient?
A. Phenylalanine hydroxylase
B. Cystathionine synthase
C. Dihydrobiopterin reductase
D. Branched-chain alpha-ketoacid dehydrogenase
E. Methylmalonyl-CoA mutase
The answer & question breakdown is at the bottom of the post.
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Building an AI USMLE Study Partner - READ HERE
USMLE Times Issue #80 - READ HERE
Should I Take Step 3 Before Match? - READ HERE
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Suffering From Premature P.O.E.? - READ HERE
ANSWER + QUESTION BREAKDOWN
The Mental Model for this week’s question:
Step 1. Identify the goal of the question (figure out the enzyme deficiency).
Step 2. Determine the problem based on signs & symptoms.
Step 3. Derive your own answer (based on the vignette’s info)
Step 4. Look for your answer in the answer choices.
GENERAL ANALYSIS
This question requires that you understand the biochemical pathways involved in phenylketonuria (PKU) and the potential reasons for the failure of dietary management. The key points to consider are:
Phenylketonuria (PKU): A metabolic disorder characterized by the inability to convert phenylalanine to tyrosine due to enzyme deficiencies.
Dietary Management: Typically involves a low-phenylalanine diet supplemented with tyrosine.
Persistent Symptoms: Despite dietary management, symptoms suggest an alternative or additional metabolic defect.
ANSWER CHOICES:
ANSWER CHOICE A: Phenylalanine hydroxylase
Phenylalanine hydroxylase (PAH) is the enzyme directly responsible for converting phenylalanine to tyrosine. Deficiency in this enzyme is the primary cause of classic PKU. However, if the patient is already on a low-phenylalanine diet and still showing symptoms, it suggests that the issue might be more complex than a simple PAH deficiency.
ANSWER CHOICE B: Cystathionine synthase
Cystathionine synthase deficiency leads to homocystinuria, not PKU. Homocystinuria is characterized by elevated levels of homocysteine and methionine, and symptoms include ectopia lentis, skeletal abnormalities, and thromboembolic events. This condition does not directly affect phenylalanine metabolism.
ANSWER CHOICE C: Dihydrobiopterin reductase
Dihydrobiopterin reductase (DHPR) is involved in the regeneration of tetrahydrobiopterin (BH4), a cofactor for phenylalanine hydroxylase. Deficiency in DHPR can lead to secondary PKU because BH4 is necessary for PAH activity. This condition can cause persistent hyperphenylalaninemia despite dietary management, as the enzyme PAH cannot function without its cofactor.
ANSWER CHOICE D: Branched-chain alpha-ketoacid dehydrogenase
Deficiency in this enzyme leads to maple syrup urine disease (MSUD), characterized by the accumulation of branched-chain amino acids (leucine, isoleucine, and valine). This condition does not affect phenylalanine metabolism and is unrelated to PKU.
ANSWER CHOICE E: Methylmalonyl-CoA mutase
Deficiency in this enzyme causes methylmalonic acidemia, which involves the accumulation of methylmalonic acid. This condition affects the metabolism of certain amino acids and fatty acids but does not directly impact phenylalanine metabolism.
ANSWER CHOICE F: Propionyl-CoA carboxylase
Deficiency in this enzyme leads to propionic acidemia, characterized by the accumulation of propionic acid. This condition affects the metabolism of certain amino acids and fatty acids but does not directly impact phenylalanine metabolism.
FINAL VERDICT…
The infant's persistent symptoms, despite dietary management, suggest a more complex issue than a simple PAH deficiency. Dihydrobiopterin reductase (DHPR) deficiency leads to a lack of tetrahydrobiopterin (BH4), a necessary cofactor for phenylalanine hydroxylase. Without BH4, phenylalanine hydroxylase cannot convert phenylalanine to tyrosine, resulting in elevated phenylalanine levels even with dietary restrictions. This condition is known as malignant or atypical PKU and requires additional treatment with BH4 supplementation and possibly other neurotransmitter precursors.
FINAL ANSWER: C: Dihydrobiopterin reductase
That’s it for issue #81 of The USMLE Times!
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