Improving diagnostic yield for primary mitochondrial myopathy: a novel electron microscopy finding


Clinical Management

Poster Number: S77


Vincent Zimmern, MS, MD, MPH, University of Texas Southwestern

Improving diagnostic yield for primary mitochondrial myopathy: a novel electron microscopy finding

Vincent Zimmern, Jose Hinojosa, Prashant Mishra, Chunyu Cai, Salman Bhai


Background: The diagnostic odyssey of primary mitochondrial myopathies (PMM) can be long. These patients often have unexplained exercise intolerance (EI), dyspnea, weakness, or progressive external ophthalmoplegia (PEO) and go long periods of time before their diagnosis. Despite clinical concern for PMM, patients may have negative mitochondrial genome testing from non-muscle samples as well as absence of characteristic histologic findings on muscle biopsy, errantly characterized as a negative work-up for PMM. There is a need for a more reliable diagnostic pipeline for patients presenting with symptoms suggestive of PMM. Here, we suggest a new approach and novel findings to aid in the diagnosis of PMM.

Results: The single-center cohort of 22 patients (ages 20-80, 8/14 M/F) presented to our neuromuscular clinic with symptoms concerning for a possible mitochondrial myopathy. Previous work-up was negative or non-diagnostic for PMM, and variably included muscle biopsy and mitochondrial genome testing from cheek swab or blood. In our center, additional evaluation with cycle exercise testing was performed to confirm an oxidative defect. Further testing with mitochondrial genome testing of the muscle biopsy specimen identified mutations in all these patients. Electron microscopy (EM) evaluation of these muscle biopsy revealed abnormal mitochondria with widened and darkened cristae in 50% (6/12) of the muscle examined, while conventional mitochondria pathology such as ragged red fibers, COX deficient fibers or mitochondria inclusions were only present in 4.5% (1/22). Mitochondrial respiratory analysis on muscle specimens was not sufficiently sensitive to detect PMM.

Summary: PMM patients have non-specific clinical features, potentially with non-diagnostic muscle histology and molecular testing on buccal or blood samples. Mitochondrial respiratory analysis was not clinically helpful in this cohort. However, electron microscopy examination of mitochondria morphology and mitochondria genome analysis improve the diagnosis yield.