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NBME 25 Answers

Question#18 (reveal difficulty score)
A 35-year-old man comes to the physician ...
Mitochondrial crystalline 🔍 / 📺 / 🌳

Recent comments ...

... drdoom made a comment (nbme25)
 +1  submitted by drdoom(1181)

This question might be tricky because the mutation of interest here is inherited from the dad side (paternal) but affects the mitochondria.

That is, the mutation is not a mutation of the mitochondrial DNA; it is of nuclear DNA which affects mitochondrial function and quality. (Mechanism unknown.)

In their explanation, the NBME says, “Mitochondrial diseases are strictly inherited through the mother” but that is incorrect; it would be more correct for them to have said: Mitochondrial DNA mutations are strictly inherited through the mother.

That is, you can have mitochondrial problems that come from your dad. Mitochondrial DNA mutations, on the other hand, come only from mom.

So, the stem describes a “mitochondrial disease” but it is not a mitochondrial disease dervied from a mitochondrial DNA mutation.

Yes, mitochondria are affected but the mutation is in nuclear DNA that governs the maintenance of "healthy mitochondria".

This explains why dad and dad's brother show the same “proximal muscle weakness of the lower extremities”.

drdoom  Clarifying further: The disease of interest is better described as a "non-mitochondrial DNA–derived" mitochondrial myopathy. It's a mouthful, I know. Yes, mitochondria are affected but the mutation is in somatic (nuclear) genes that govern the maintenance/operation/function of "healthy mitochondria". This is why it is being inherited through the dad and yet manifests in mitochondrial dysfunction. +
... yogurt-dimple made a comment (nbme25)
 +0  submitted by yogurt-dimple(2)

Am I crazy, or does the question stem imply that this was inherited paternally?

raspberry-muffin  In this question sounds like inherited paternally , but this muscle biopsy confirmed Mitochondrial inheritance. Muscle biopsy: Immunohistochemistry typically shows ragged red fibers, which are caused by sub-sarcolemmal and inter-myofibrillar accumulation of defective mitochondria in muscles (mitochondria stain red). Probably Mother has the same condition too. +
yogurt-dimple  Gotcha. Yeah, the red ragged fibers tipped me off to mitochondrial myopathy, but because the stem implied paternal inheritance, I figured there was just another disease I had forgotten about that presents with them. +
drdoom  @raspberry-muffin I'm not convinced. It is highly unlikely the NBME would write this question and expect you to "assume" mom has condition without making any mention of mom. Plus, it is simply highly improbable that myopathy is present in both mom and dad lineage. That seems off to me. +
drdoom  @yogurt-dimple, I think this a key line in the explanation: “However, there are additional mutations that affect mitochondrial RNA translation, trafficking and incorporation of respiratory protein complexes, and maintenance of the inner mitochondrial membrane that can also lead to mitochondrial myopathy.” +
drdoom  Yes, they say, "Mitochondrial diseases are strictly inherited through the mother" but this is not a mitochondrial disease — this is a "non-mitochondrial–derived" mitochondrial myopathy; yes, mitochondria are affected but the mutation is in somatic (nuclear) genes that govern the maintenance of "healthy mitochondria". This is because the mutation affects the function/operation of mitochondria but the mutation itself is in the nuclear DNA (which control something about the "quality" of mitochondria but what exactly is not yet known). +

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