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January 14, 2022

Vacuolar Myopathy

Figure 1A and 1B: H&E stained frozen section 100x original magnification

H&E demonstrates myopathic changes consisting of abnormal variability in muscle fiber size, increase in the number of myofibers with internalized nuclei, and frequent scattered basophilic regenerating muscle fibers. In addition scattered muscle fibers contain single to multiple variably sized vacuoles. Some of these contain granular basophilic material (see inset for closer view).

 

This 50-year-old male presented with profound upper and lower extremity proximal muscle weakness. His family history was negative for neuromuscular disorder. Laboratory studies demonstrated elevated CPK (1150), aldolase and sedimentation rate (26), and normal CRP and TSH. A myositis-specific autoantibody panel was negative.  The patient’s home medications did not include a statin, hydroxychloroquine, or colchicine.

Which of the following is the most appropriate pathologic diagnosis based on images #1 through #8?

A. Dermatomyositis

B. Inclusion Body Myositis

C. Statin myopathy

D. Vacuolar myopathy

 

Figure 2: Modified Gomori Trichrome frozen section 200x original magnification

The vacuolar structures are also seen with modified Gomori Trichrome stain.

 

Figure 3: Esterase frozen section 100x original magnification

Note that the vacuoles are nicely highlighted with esterase enzyme histochemical stain.

 

Figure 4: MHC1 immunohistochemical stain 200x original magnification

Immunohistochemical stain for MHC1 (HLA ABC) shows sarcoplasmic and membranous staining of muscle fibers, and also highlights the vacuoles.

 

Figure 5: C5b-9 immunohistochemical stain 200x original magnification

Immunohistochemical stain for C5b-9 (complement membrane attack complex) shows granular staining around the sarcolemmal membrane, and also highlights the vacuoles.

 

Figure 6: DYS1 immunofluorescence stain 400x original magnification

Immunofluorescence stains for proteins that are normally associated with the sarcolemma (DYS1 / dystrophin rod-domain in this case) highlights the sarcolemma as expected, but also nicely lines the vacuoles.

 

Figure 7: Toluidine blue stain thick sections 600x original magnification

The vacuolar structures are visible in toluidine blue stained thick sections prepared from glutaraldehyde-fixed EPON embedded tissue sections.

 

Figure 8: Electron microscopy 1500x magnification

Ultrastructural study shows that the vacuoles contain variable amounts of lysosomal debris and some osmophilic membranous whorled material.  Also, not that the greyish “felt-like” basement membrane-like lining of the vacuole.

Background disorganization of the sarcomeres is present, and would correlate with the presence of regenerating muscle fibers on H&E stained sections with light microscopy.

 

 

Answer: Vacuolar myopathy

The morphologic features seen on H&E and modified Gomori Trichrome stained sections fit under the general umbrella term of “vacuolar myopathy” which has multiple potential causes (including Pompe disease, and toxic myopathies related to colchicine or hydroxychloroquine). The staining of the vacuoles for proteins that are normally associated with the sarcolemma (cell membrane of muscle fibers) such as dystrophin, indicates the presence of “Autophagic Vacuoles with Sarcolemmal Features.” The finding of AVSFs narrows the differential diagnosis for this patient’s vacuolar myopathy:

  • Danon disease LAMP2 Xq24
  • X-linked Myopathy with Excessive Autophagy XMEA VMA21 Xq28
  • Desminopathy DES 2q25
  • CLN3-related autophagic vacuolar myopathy CLN3 16p12.1

These diseases are examples of disordered autophagy (Greek “self-eating”), an evolutionarily conserved homeostatic process for trafficking cytoplasmic material and organelles for degradation and reuse.

 

References/Additional Reading

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Rowland TJ, Sweet ME, Mestroni L, Taylor MR. Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy. J Cell Sci. 2016 Jun 1;129(11):2135-43. doi: 10.1242/jcs.184770. Epub 2016 May 10. PMID: 27165304; PMCID: PMC4920246.

Dowling JJ, Moore SA, Kalimo H, Minassian BA. X-linked myopathy with excessive autophagy: a failure of self-eating. Acta Neuropathol. 2015 Mar;129(3):383-90. doi: 10.1007/s00401-015-1393-4. Epub 2015 Feb 3. PMID: 25644398.

Munteanu I, Ramachandran N, Ruggieri A, Awaya T, Nishino I, Minassian BA. Congenital autophagic vacuolar myopathy is allelic to X-linked myopathy with excessive autophagy. Neurology. 2015 Apr 21;84(16):1714-6. doi: 10.1212/WNL.0000000000001499. Epub 2015 Mar 27. Erratum in: Neurology. 2019 Aug 20;93(8):371. PMID: 25817839; PMCID: PMC4409585.

Weihl CC, Iyadurai S, Baloh RH, Pittman SK, Schmidt RE, Lopate G, Pestronk A, Harms MB. Autophagic vacuolar pathology in desminopathies. Neuromuscul Disord. 2015 Mar;25(3):199-206. doi: 10.1016/j.nmd.2014.12.002. Epub 2014 Dec 12. PMID: 25557463; PMCID: PMC4355324.

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Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. 2014 Jan 20;20(3):460-73. doi: 10.1089/ars.2013.5371. Epub 2013 Aug 2. PMID: 23725295; PMCID: PMC3894687.

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