Abstract Details

Title Twinkle, Progressive External Ophthalmoplegia and Orthostatic Tremor

Topic Movement Disorders

Presentation(s) P07 - (-)

Poster/Presentation
Number 201

Objective

Background BACKGROUND: Autosomal dominant PEO can result from mutations in genes controlling mitochondrial DNA replication and maintenance (POLG, POLG2, TWINKLE-PEO1 and ANT1). In addition, mutations in POLG and TWINKLE have been associated with Parkinsonism. OT is characterized by high frequency (13-18Hz) tremor occurring in standing position. Its pathophysiologic mechanism is unknown. Although OT is thought to be sporadic, siblings with OT from 3 unrelated families have been reported.

Design/Methods DESIGN/METHODS: Clinical examination, EMG/nerve conduction and multichannel surface EMG recordings, muscle biopsy, brain MRI and MR spectroscopy (MRS), sequencing of all coding exons and flanking introns of POLG, TWINKLE and ANT1.

Results RESULTS: A 69-year-old man manifested progressive bilateral ptosis and "shaking spells" upon standing at age 37 years. Six years ago, he developed PEO and limb fatigue. His father had bilateral ptosis; a sister and a son have bilateral ptosis and ophthalmoparesis. He had clinical and electrophysiological evidence for a mild myopathy and sensorimotor axonal peripheral neuropathy. Polygraphic recordings showed an orthostatic synchronic 17.5Hz tremor in the leg muscles spreading to the lumbar paraspinal and arm muscles. There was no rest tremor and no clinical evidence for parkinsonism. Brain MRI showed mild diffuse atrophy; MRS was normal. Scattered ragged-red fibers were present on muscle biopsy. Gene analysis revealed a novel heterozygous missense mutation at an evolutionarily conserved residue of the TWINKLE gene and no pathogenic mutations in POLG or ANT1. The affected sister and son carry the same variant.

Conclusions CONCLUSIONS: Although one cannot exclude the incidental association of OT and Twinkle mutation, the onset of OT at the same time of the ptosis and at a much younger age than usually observed raises the possibility of mitochondrial dysfunction in the pathogenesis of OT.

Authors/Disclosures
Margherita Milone, MD, FAAN (Mayo Clinic) PRESENTER	Dr. Milone has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cartesian Therapeutics. Dr. Milone has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics, AAN. The institution of Dr. Milone has received research support from Mayo Clinic, CCaTS-CBD. The institution of Dr. Milone has received research support from Mayo Clinic, SGP Award. The institution of Dr. Milone has received research support from MDA for Care Center grant. The institution of Dr. Milone has received research support from Regenerative medicine Minnesota.
Bryan T. Klassen, MD (Mayo Clinic)	The institution of Dr. Klassen has received research support from Insightec.
	No disclosure on file
Lee-jun C. Wong, PhD (Baylor College of Medicine)	No disclosure on file
Edward Fox, MD, PhD, FAAN	Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW Pharmaceuticals. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Genentech. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Bristol Myers Squibb. The institution of Dr. Fox has received research support from Biogen. The institution of Dr. Fox has received research support from Genentech. The institution of Dr. Fox has received research support from Celgene - BMS. The institution of Dr. Fox has received research support from Chugai. The institution of Dr. Fox has received research support from Novartis. The institution of Dr. Fox has received research support from EMD-Serono. The institution of Dr. Fox has received research support from TG Therapeutics. The institution of Dr. Fox has received research support from AbbVie. The institution of Dr. Fox has received research support from Sanofi Genzyme. The institution of Dr. Fox has received research support from AbbVie.

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