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