Multiple mtDNA deletions due to mitochondrion toxicity of anti‐hepadnaviral drugs: Comments to the letter from J. Finsterer

RESPONSE TO LETTER TO THE EDITOR We sincerely appreciate the letter from J. Finsterer commenting on our recently published case report of toxic myopathy with multiple deletions in mitochondrial DNA (mtDNA) associated with long-term use of oral anti-viral drugs for hepatitis B. He argued for a number of additional steps to make this case more meaningful: whole exome sequencing (WES) to exclude a nuclear genetic cause of the mtDNA variants, electron microscopy (ELMI) and biochemical investigations to show which respiratory chain complexes were affected and the degree to which their function was impaired by the deletions, investigation into whether individual and family histories were reviewed for previous muscular complaints or effects on other family members to assess hereditary predisposition to mitochondrial myopathy. He also queried whether the results of prospective investigations for multiorgan involvement were provided to exclude “chronic progressive external ophthalmoplegia (CPEO)-plus”. WES is the state-of-the-art, next generation sequencing technique to identify genetic defects in mitochondrial disorders. Recent studies have shown the effectiveness of WES in patients with suspected mitochondrial disease with a diagnostic yield of 39–60%. However, at the time of our diagnosis, WES was not routinely performed in clinical settings in Japan and we did not prepare the appropriate muscle samples needed for WES. Therefore, we would like to consider using WES in the future if a muscle sample is re-biopsied from the patient. Although ELMI and biochemical investigations also could help us to understand the detailed changes in mitochondria and the mechanisms of mitochondrial dysfunction, unfortunately, we also did not prepare the appropriate muscle tissues for ELMI when the muscle biopsy was performed. As J. Finsterer pointed out, there is a possibility that patients developing drug-induced myopathy have hereditary predispositions to myopathy and subclinical muscle defects before the treatment is initiated because only a portion of the patients receiving the agents develop myopathy. However, the patient in the present case did not have muscle symptoms prior to the initiation of the antiviral treatment. We also agree that genetic investigations of first-degree relatives, particularly the mother, is important. However, the patient in the present case is advanced in age and her parents had already passed away. It is also difficult to biopsy the muscles of her living siblings for genetic investigations because they are also elderly and have no neurological deficits. There is also the possibility that the combination of the two anti-viral drugs (lamivudine and adefovir) enhances mitochondrial toxicity. Although there are no concrete reports referring to increased mitochondrial toxicity with the combination of lamivudine and adefovir treatment, some other nucleoside analog reverse transcriptase inhibitor combinations have been reported to increase mitochondrial toxicity. Further case reports may clarify the association of mitochondrial toxicity with the combination of the two anti-viral drugs. As of the last follow-up of the present case (5 years after the muscle biopsy), the patient had not developed any extraocular muscle weakness, ptosis, higher brain dysfunction, peripheral nervous system involvement, cardiorespiratory dysfunctions, or multiorgan involvement including kidney and liver dysfunction. However, she has developed gonarthrosis in both knees with gradual lower proximal muscle weakness and has difficulty standing up because of pain in her legs. We anticipate that the kind comments from J. Finsterer will contribute to improving our routine clinical care for patients with mitochondrial myopathy.