RRM2B Associated Autosomal Dominant Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions in a 68-year-old Female Patient with Dysphagia and Musculoskeletal Weakness: A Case Report

Case Diagnosis: RRM2B Associated Autosomal Dominant Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions and Autosomal Recessive Mitochondrial DNA Depletion Syndrome

Case Description or Program Description: A 68-year-old female with HLD, GERD, stable angina, long-standing ophthalmoplegia and ptosis, and recent hospitalization for 1-2 months of dysphagia with weight loss and associated change in vocal quality now s/p PEG tube placement presented to neuromuscular clinic for worsening mobility. She endorsed life-long ophthalmoplegia and ptosis and reported that her father could not move his eyes. Over the past few months, she reported muscle weakness and fatigue that affected her mobility. She was prescribed prednisone previously which did not improve her symptoms. Prior testing for myasthenia gravis was negative.
Her physical exam was significant for complete ophthalmoplegia with no other cranial nerve deficits. Strength was 5/5 in bilateral upper and lower extremities. Sensation, coordination and reflexes were normal. She had no UMN signs.

Setting: Neuromuscular Clinic

Assessment/Results: Genetic testing was significant for pathogenic mutation of RRM2B (p.Arg327*) associated with autosomal dominant progressive external ophthalmoplegia (PEO) with mitochondrial DNA deletions and autosomal recessive mitochondrial DNA depletion syndrome.

Discussion (relevance): RRM2B mitochondrial DNA maintenance defects (RRM2B-MDMDs) have four common phenotypes based on under 100 confirmed cases. This patient’s symptoms most closely match the autosomal dominant phenotype (adPEO) which generally manifests in one’s late teens to early forties with ophthalmoplegia and may include ptosis, bulbar dysfunction, fatigue, and muscle weakness. However, her early childhood onset of ophthalmoplegia and ptosis is more consistent with other phenotypes that generally present with an earlier and more severe onset of musculoskeletal weakness and bulbar dysfunction. PEO+ syndromes also exist and may include hearing loss, gait ataxia, parkinsonism, neuropathy, and/or depression.

Conclusions: As genetic testing for myopathies and neuropathies becomes more common, it is likely that older patients with milder forms of genetic disorders will reveal a broader spectrum of disease than currently described.