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 beta-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.