Abstract Details

Title Novel DNA2 Mutation Leading to Mitochondrial DNA Deletions with MELAS-like Phenotype

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P2 - Poster Session 2 (8:00 AM-9:00 AM)

Poster/Presentation
Number 11-031

Objective

To describe a patient with adult-onset encephalomyopathy who was found to have a novel nonsense DNA replicase helicase/nuclease 2 (DNA2) mutation, with reduced mitochondrial-DNA (mtDNA) content and multiple mtDNA deletions.

Background DNA2 is a nuclear-DNA (nDNA) encoded helicase/nuclease involved in mtDNA repair and stability. Mutations in DNA2 are associated with multiple mtDNA deletions in skeletal muscle, classically causing limb-girdle weakness and progressive external ophthalmoplegia (PEO). Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) have not been reported.

Design/Methods NA

Results 71-year-old male with asymmetric sensorineural hearing loss and short stature experienced episodic confusion, headaches, and speech difficulties, worsening over 3 years. Brain MRI revealed progressive T2 hyperintensities, with enhancement and diffusion restriction starting in the right temporoparietal cortex and later involving right frontal and insular lobes, without intracranial atherosclerosis. Examination showed normal muscle strength without ptosis/ophthalmoparesis. However, vastus lateralis muscle biopsy showed fiber size variation, increased internal nuclei, ragged red and blue fibers, and COX-deficient fibers. CK and lactate levels were normal. Next-generation sequencing of blood identified a heterozygous nonsense variant in DNA2 c.1215T>G, p.(Y405*). Muscle tissue analysis found no pathogenic variants in genes associated with MELAS but revealed two large mtDNA deletions (m.6342_14004del and m.8649_16084del). Muscle mtDNA content was 56% of age- and tissue-matched controls.

Conclusions

Missense DNA2 mutations can cause multiple mtDNA deletions but only myopathy and PEO phenotypes have been reported. We hypothesized that this novel nonsense mutation results in DNA2 truncation, with loss of helicase function affecting mtDNA stability, and leading to decreased mtDNA copy number and deletions. Like POLG mutations (which also affect mtDNA maintenance), DNA2 mutations may affect the brain, presenting as encephalomyopathy with stroke-like episodes, mimicking MELAS. Our findings broaden the phenotypic spectrum of DNA2-associated disorder to include adult-onset encephalomyopathy, along with myopathy and PEO.

Authors/Disclosures
Abhigyan Datta, MD (University of Minnesota) PRESENTER	Dr. Datta has nothing to disclose.
Georgios Manousakis, MD, FAAN (University of Minnesota)	Dr. Manousakis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stealth Biotherapeutics. Dr. Manousakis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Manousakis has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. The institution of Dr. Manousakis has received research support from Marzolf foundation.
Pitcha Chompoopong, MD (University of Minnesota)	Dr. Chompoopong has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astrazeneca. Dr. Chompoopong has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alnylam.

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