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November 19, 2021

Vacuolar Myopathy

Figure 1: Frozen section hematoxylin and eosin, 400x original magnification

Multiple vacuolar change toward the periphery of the muscle fiber that are variably optically clear to containing finely granular basophilic material (for example see black arrows).

 

This 60-year-old patient noticed slowly progressive difficulty getting into and out of their chair at work over the past year, and increased tripping and falling. Family history was negative for neuromuscular disorder.

 

What is your diagnosis based on Figures 1-5?

A. Inclusion Body Myositis

B. Mitochondrial myopathy

C. Pompe disease

D. Lipid storage myopathy

 

Figure 2: Frozen section modified Gomori Trichrome, 400x original magnification

Multiple vacuolar change toward the periphery of the muscle fiber that are variably optically clear to containing finely granular bluish material (for example see black arrows).

 

Figure 3: Frozen section PAS, 600x original magnification

The vacuolated muscle fibers show increased staining for PAS (for example see black arrows).

 

Figure 4: Frozen section PASd, 600x original magnification

The material within the vacuoles is diastase sensitive as demonstrated with PASd indicating the presence of glycogen (for example see black arrows).  Notice that the basement membrane surrounding individual muscle fibers is PAS positive but not PASd sensitive.

 

Figure 5:Frozen section acid phosphatase, 600x original magnification

The vacuolated areas within muscle fibers show increased lysosomal staining as seen with acid phosphatase enzyme histochemical stain (for example see areas of reddish staining indicated by black arrows).

 

Answer: Pompe disease

Hematoxylin and eosin and modified Gomori Trichrome performed on this patient’s muscle biopsy demonstrate the patchy presence of occasional peripherally vacuolated muscle fibers. The vacuolar areas are strongly highlighted by PAS (periodic acid-Schiff), are diastase (PASd) sensitive, and also stain strongly for lysosomes with acid phosphatase stain. These staining characteristics indicate the presence of glycogen within lysosomes, and in combination with the morphologic features are consistent with the pathologic diagnosis of adult Pompe Disease (also known as acid maltase deficiency and Glycogen Storage Disease type 2 / GSD2).

Genetic testing (Next-Generation sequencing panel) identified two heterozygous pathogenic variants involving the GAA gene which encodes for the enzyme acid alpha-1,4-glucosidase.

 

Why were the other answers wrong?

The vacuoles are not characteristic of rimmed-vacuoles seen in association with Inclusion Body Myositis.

The vacuoles do not show magenta granular staining characteristic of mitochondria on modified Gomori Trichrome.

The lipid droplets accumulating in lipid storage myopathy are typically seen as fine optically clear small vacuoles throughout the muscle fiber on H&E and modified Gomori Trichrome stained sections, and show staining for Oil-Red-O or Sudan Black rather than PAS.

 

Reference(s)/additional reading

https://www.ncbi.nlm.nih.gov/books/NBK1261/

Werneck LC, Lorenzoni PJ, Kay CS, Scola RH. Muscle biopsy in Pompe disease. Arq Neuropsiquiatr. 2013 May;71(5):284-9. doi: 10.1590/0004-282×20130022. PMID: 23689405.

Taverna S, Cammarata G, Colomba P, Sciarrino S, Zizzo C, Francofonte D, Zora M, Scalia S, Brando C, Curto AL, Marsana EM, Olivieri R, Vitale S, Duro G. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging (Albany NY). 2020 Aug 3;12(15):15856-15874. doi: 10.18632/aging.103794. Epub 2020 Aug 3. PMID: 32745073; PMCID: PMC7467391.