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In this condition, the USMLE will mention that there are increased levels of the α-ketoacids of leucine, isoleucine and valine in the blood because of deficiency of α-ketoacid dehydrogenase, a thiamine (vitamin B1)-dependent enzyme.
Leucine, isoleucine and valine are all branched-chain amino acids.
The vignette might mention that a mother notices the smell of “burnt sugar” in her infant’s diaper, and then the question will ask you which amino acid has defective metabolism. They’ll literally list all of the amino acids, and you’ll have to know that the disease was MSUD and that the answer is leucine, isoleucine or valine.
| α-ketoacid dehydrogenase is a vitamin B1- dependent enzyme. So are transketolase, α-ketogluterate dehydrogenase and pyruvate dehydrogenase. |
If they ask you for the treatment, the answer is to restrict intake of leucine, isoleucine and valine.
| MSUD is most prevalent in the Ashkenazi Jewish population. |
Since α-ketoacid dehydrogenase is a thiamine-dependent enzyme, if they ask you what could theoretically help mitigate metabolic derangement in the patient, the answer is thiamine.
Symptoms include hypotonia, mental impairment, metabolic acidosis and hypoglycemia.
When broken down:
Leucine → acetyl-CoA → ketogenesis (since we’re in catabolic state)
Isoleucine + valine → propionyl-CoA → succinyl-CoA → gluconeogenesis
That’s why leucine is strictly a ketogenic amino acid. It doesn’t enter the TCA cycle the same way that isoleucine and valine do.
That’s it. Nothing crazy dramatic.
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