1. Case Study 21
Craig Horbinski, M.D., Ph.D.

2. Question 1
The patient is a 46 year-old woman with bilateral hearing loss, ophthalmoplegia, and dysarthria. Electromyogram (EMG) is consistent with a mild myopathy. A biopsy of the left deltoid is done. Describe the biopsy and histochemical stains. Click the following links to view slides: H&E, NADH, Gomori Trichrome, ATPase 9.4, ATPase 4.3, Esterase

3. Answer
Hematoxylin and eosin stained frozen sections reveal scattered slightly atrophic myofibers with a mild excess of internalized nuclei. A few degenerating and regenerating fibers are seen, but no inflammatory infiltrates. Gomori trichrome reveals only a few ragged red fibers. NADH-TR reacted sections reveal no cores, targetoid or target fibers. Esterase reactivity highlights occasional myophagocytosis. ATPase reacted sections reveal focal loss of the normal checkerboard pattern with a Type 1 to Type 2 fiber ratio of 3:2 and no selective myofiber atrophy.

4. Question 2
In context with the clinical information, what do you think is the most likely diagnosis?  What additional stains should you order to confirm this?

5. Answer
The combination of ophthalmoplegia, hearing loss, and dysarthria is suggestive of a mitochondrial myopathy.  Ragged red fibers are indicative of abnormal subsarcolemmal localization of mitochondria.  There aren’t as many in this biopsy as one might expect, but there are enough to warrant cytochrome oxidase and SDH histochemical stains.  (Of note, ragged red fibers can also be seen in other dystrophies and inflammatory myopathies, so they’re fairly sensitive but not specific.)

6. Question 3
Cytochrome oxidase and SDH stains were done. Describe the findings. Click the following links to view slides: Cytochrome Oxidase, SDH

7. Answer
Approximately 20% of the myofibers have greatly reduced cytochrome oxidase reactivity, a sure sign that the mitochondria are defective. Some of the same fibers are SDH-rich, another sign of mitochondrial dysfunction. It’s important to note the percentage of cytochrome oxidase- negative fibers, because it roughly correlates with the degree of clinical severity. 20% myofiber involvement is quite high. Many elderly people will show occasional myofibers with no cytochrome oxidase, but that is simply age-related changes.

8. Question 4
What’s your diagnosis?  What would your recommendation be to the clinician?

9. Answer
Mitochondrial myopathy.  There are many variants, each with their own unique mutation in either mitochondrial or nuclear DNA.  The only definitive test for the type of mitochondrial disorder is genetic testing; a muscle biopsy cannot tell between the types.