Background TK2 is a nuclear gene encoding the mitochondrial matrix protein thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial nucleotide salvage pathway. Deficiency of TK2 activity causes mitochondrial DNA (mtDNA) depletion, which in humans manifests predominantly as a mitochondrial myopathy with onset typically in infancy and childhood. We previously showed that oral treatment of the Tk2 H126N knock-in mouse model (Tk2 −/− ) with the TK2 substrates, deoxycytidine (dCtd) and thymidine (dThd), delayed disease onset and prolonged median survival by 3-fold. Nevertheless, dCtd + dThd treated Tk2 −/− mice showed mtDNA depletion in brain as early as postnatal day 13 and in virtually all other tissues at age 29 days. Methods To enhance mechanistic understanding and efficacy of dCtd + dThd therapy, we studied the bioavailability of dCtd and dThd in various tissues as well as levels of the cytosolic enzymes, TK1 and dCK that convert the deoxynucleosides into dCMP and dTMP. Findings Parenteral treatment relative to oral treatment produced higher levels of dCtd and dThd and improved mtDNA levels in liver and heart, but did not ameliorate molecular defects in brain or prolong survival. Down-regulation of TK1 correlated with temporal- and tissue-specificity of response to dCtd + dThd. Finally, we observed in human infant and adult muscle expression of TK1 and dCK, which account for the long-term efficacy to dCtd + dThd therapy in TK2 deficient patients. Interpretations These data indicate that the cytosolic pyrimidine salvage pathway enzymes TK1 and dCK are critical for therapeutic efficacy of deoxynucleoside therapy for Tk2 deficiency. Fund National Institutes of Health P01HD32062.

In late 2019, the novel coronavirus, SARS-CoV-2, and the disease it causes, COVID-19, was identified. Since then many different neurological manifestations of COVID-19 have been well reported. Movement abnormalities have been rarely described. We report here a critically ill patient with COVID-19 who developed generalized myoclonus during the recovery phase of the infection. Myoclonus was associated with cyclical fevers and decreased alertness. Movements were refractory to conventional anti-epileptic therapies. There was concern that myoclonus could be part of a post-infectious immune-mediated syndrome. The patient improved fully with a 4-day course of high-dose steroids. Our experience highlights a rare, generalized myoclonus syndrome associated with COVID-19 that may be immune-mediated and is responsive to treatment.

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