Severe TK2 enzyme activity deficiency in patients with mild forms of myopathy

Abstract

Thymidine kinase 2 (TK2) is a mitochondrial enzyme participating in the salvage of deoxyribonucleotides needed for mitochondrial DNA (mtDNA) replication. TK2 catalyzes the first and rate-limiting step of the deoxypyrimidine salvage pathway. Mutations in TK2 were typically associated with a severe myopathic form of mtDNA depletion syndrome (MDS) characterized by a dramatic decrease in mtDNA copy number in muscle that manifests during infancy and leads to the early death of most patients.1 Recently, several patients have been diagnosed with a late-onset or slow-progressing form of the disease manifesting as a milder myopathy with mtDNA multiple deletions.2–5 Here we describe 7 adult cases presenting with a mild myopathy compatible with a relatively normal life for decades and associated with multiple mtDNA deletions and no marked depletion in skeletal muscle. TK2 activity was drastically reduced in cultured fibroblasts of 2 of these patients, suggesting that redundant or complementary biochemical mechanisms could bypass the defect in some individuals, in contrast with severely affected infantile patients.