The patient is a 50-year-old female who presents with a 5-year history of decreased ability to move her eyes and droopy eyelids. More recently she has noticed some lower extremity muscle weakness (difficulty rising from a chair and climbing stairs).
Figures #1 to #3 demonstrate which of the following abnormalities?
A. Increased lipid
B. Glycogen lakes
C. Tubular aggregates
D. Increased mitochondria
Answer: Increased mitochondria
The images demonstrate increased mitochondria (nicely shown by modified Gomori Trichrome histochemical stain and enzyme histochemical stain for SDH), and frequent blue COX-negative muscle fibers as seen with the combined COX/SDH enzyme histochemical stain. In the context of this patient’s clinical history these findings are consistent with the diagnosis of a mitochondrial disorder: Chronic Progressive External Ophthalmoplegia (CPEO) plus mitochondrial myopathy.
Mitochondrial biology and genetics are pretty amazing:
Eukaryotic cells are required to coordinate two genomes: nuclear (nDNA) and prokaryotic mitochondrial (mtDNA). In humans mitochondria are inherited from one’s mother.
COX is encoded for by mtDNA while SDH is encoded for by nDNA.
In simplistic terms, the clinical complexity of mitochondrial disorders related to energy production (OXPHOS system) is related to dosage (heteroplasmy versus homoplasmy) and cellular threshold (the degree to which an affected cell type is able to tolerate a defect in mitochondrial energy production).
Reference(s) / additional reading:
Kanungo S, Morton J, Neelakantan M, Ching K, Saeedian J, Goldstein A. Mitochondrial disorders. Ann Transl Med. 2018 Dec;6(24):475. doi: 10.21037/atm.2018.12.13. PMID: 30740406; PMCID: PMC6331360.
Fernandez-Vizarra E, Zeviani M. Mitochondrial disorders of the OXPHOS system. FEBS Lett. 2021 Apr;595(8):1062-1106. doi: 10.1002/1873-3468.13995. Epub 2020 Dec 18. PMID: 33159691. Wiese M, Bannister AJ.
Two genomes, one cell: Mitochondrial-nuclear coordination via epigenetic pathways. Mol Metab. 2020 Aug;38:100942. doi: 10.1016/j.molmet.2020.01.006. Epub 2020 Feb 15. PMID: 32217072; PMCID: PMC7300384.
Ma H, Marti Gutierrez N, Morey R, Van Dyken C, Kang E, Hayama T, Lee Y, Li Y, Tippner-Hedges R, Wolf DP, Laurent LC, Mitalipov S. Incompatibility between Nuclear and Mitochondrial Genomes Contributes to an Interspecies Reproductive Barrier. Cell Metab. 2016 Aug 9;24(2):283-94. doi: 10.1016/j.cmet.2016.06.012. Epub 2016 Jul 14. PMID: 27425585; PMCID: PMC4981548.
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