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Case Report/Case Series |

Orthostatic Tremor, Progressive External Ophthalmoplegia, and Twinkle

Margherita Milone, MD, PhD1; Bryan T. Klassen, MD1; Megan L. Landsverk, PhD2; Richard H. Haas, MD3; Lee-Jun Wong, PhD2
[+] Author Affiliations
1Department of Neurology, Mayo Clinic, Rochester, Minnesota
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
3Department of Neurosciences and Pediatrics, University of California, San Diego, San Diego, California
JAMA Neurol. 2013;70(11):1429-1431. doi:10.1001/jamaneurol.2013.3521.
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Importance  Orthostatic tremor (OT) is a high-frequency (13-18 Hz) leg tremor occurring in standing position. Orthostatic tremor has an unknown pathophysiologic mechanism. It is thought to be sporadic but siblings with OT from 3 unrelated families were reported. No mutations have been reported in OT. We describe a patient with OT carrying a C10orf2 TWINKLE mutation to highlight the possible association of OT with mitochondrial dysfunction and mutations in the mitochondrial replicative helicase Twinkle.

Observations  A man in his late 60s had ptosis and tremor on standing for 30 years, followed by development of progressive external ophthalmoplegia. Polygraphic recordings revealed an orthostatic synchronic tremor with 17.5-Hz frequency. Electromyography/nerve conduction studies showed evidence for a mild myopathy and associated mild axonal sensorimotor peripheral neuropathy. Muscle biopsy revealed ragged red fibers; mild cerebral atrophy was evident by magnetic resonance imaging. Molecular analysis revealed a novel heterozygous missense mutation at an evolutionarily conserved residue of the C10orf2 TWINKLE gene.

Conclusions and Relevance  Although the incidental association of OT and C10orf2 TWINKLE mutation is possible, the simultaneous onset of OT and eyelid ptosis at a much younger age than usually observed for OT raises the possibility of mitochondrial dysfunction and loss of mitochondrial DNA integrity in the pathogenesis of OT.

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Figure 1.
Tremor Analysis

A, The rectified surface electromyography recordings of tremor discharges from the right triceps (TC), quadriceps (QUAD), and anterior tibialis (AT). The lower extremity tremor is prominent during upright stance. When the patient leans forward with arms resting on the back of a chair, the lower extremity tremor attenuates and a prominent upper extremity tremor of similarly high frequency emerges. B, The power spectra analyses confirm a frequency peak at around 17.5 Hz in all muscles.

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Figure 2.
Brain Magnetic Resonance Imaging

Brain magnetic resonance imaging shows mild generalized cerebral atrophy (T1-weighted image by brain volume imaging).

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