Clinical Spectrum of Mitochondrial DNA Depletion Due to Mutations in the Thymidine Kinase 2 Gene

Abstract

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 ␤-subunit of the adenosine diphosphateforming 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.

TK2 mutation presenting as indolent myopathy

“…[1][2][3] However, the progression of weakness may vary, 4 as shown by recently described adult patients with late-onset myopathy. 5,6 To date, only 5 adult patients with TK2-related MDS have been reported.…”

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

“…Other, less common, presentations include spinal muscular atrophylike presentation [13] and chronic progressive external ophthalmoplegia with proximal muscle weakness [23]. Milder presentations have been reported and include late onset proximal muscle weakness [15], adult-onset progressive myopathy [22], and sensorineural hearing loss [21].…”

“…mtDNA content is typically severely reduced in muscle tissue. Electron transport chain (ETC) activity assays in skeletal muscle typically show decreased activity of multiple complexes with complex I, I + III, and IV being the most affected [13][14][15][16][17][18][19][20][21][22][23].…”

Oxidative Stress Induced S-glutathionylation and Proteolytic Degradation of Mitochondrial Thymidine Kinase 2

“…Deficiency in TK2 activity is associated with the devastating mitochondrial DNA depletion syndrome, and the disease phenotype extends to the involvement of multiple organs beside skeletal muscle, as described in initial reports (1)(2)(3)(4)(5). TK2 is expressed in all tissues at low levels; however, little is known regarding TK2 regulation at the transcriptional, translational, and post-translational levels.…”