Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene

Background: Mitochondrial DNA depletion syndrome is an autosomal recessive disorder characterized by decreased mitochondrial DNA copy numbers in affected tissues. It has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: thymidine kinase 2 (TK2), deoxyguanosine kinase (DGUOK), polymerase gamma (POLG), and SUCLA2, the gene encoding the β-subunit of the adenosine diphosphate-forming succinyl coenzyme A synthetase ligase. Objective: To highlight the variability in the clinical spectrum of TK2-related mitochondrial DNA depletion syndrome. Design: Review of patients and the literature. Setting: Tertiary care university. Patients: Four patients with mitochondrial DNA depletion syndrome and mutations in the TK2 gene. Main Outcome Measures: Definition of clinical variability. Results: Patient 1 had evidence of lower motoneuron disease and was initially diagnosed as having spinal muscular atrophy type 3. Patient 2, who is alive and ambulatory at age 9 years, presented at age 2 years with a slowly progressive mitochondrial myopathy. Patient 3 had a more severe myopathy, with onset in infancy and death at age 6 years of respiratory failure. Patient 4 had a rapidly progressive congenital myopathy with rigid spine syndrome and he died at age 19 months. Conclusion: The clinical spectrum of TK2 mutations is not limited to severe infantile myopathy with motor regression and early death but includes spinal muscular atrophy type 3-like presentation, rigid spine syndrome, and subacute myopathy without motor regression and with longer survival.