G.P.3.08 Atypical myofiber changes of a childhood mitochondrial DNA depletion syndrome with a novel thymidine kinase 2 gene mutation

Background: The mitochondrial DNA depletion syndromes (MDS) are autosomal recessive disorders characterized by a decreased mitochondrial DNA copy number. Mutations in thymidine kinase 2 (TK2) have been associated with the myopathic form of MDS. Objective: To characterize a child with MDS that had atypical, histopathologic myofiber changes and novel mutations in the TK2 gene. Patient and methods: The child is a cognitively normal male with severe progressive muscle weakness that started at two years of age. Clinical features include failure-to-thrive, ventilator-dependence since age three, and prolonged QT syndrome. Histo-pathological and biochemical analysis were performed in muscle biopsy specimens. Results: MRI and MR spectroscopy of the brain were normal. MRI of the chest showed near complete fatty replacement of virtually all thoracic muscles. Creatine kinase at initial presentation was 570. A muscle biopsy at age two showed “ragged red fibers”, atrophic fibers and some central nuclei. Decreased cytochrome oxidase staining was noted. A muscle biopsy obtained eight years later showed severe fibrofatty displacement. Portions of the muscle fibers appeared “dystrophic”. Myofibers showed a strong membranous staining pattern for dystrophin epitopes, sarcoglycogens and merosin. However, the laminin reaction was weak. No “ragged-red fibers” were seen. Electron transport chain enzymatic analysis was suggestive of a Complex I deficiency. Total mitochondrial DNA content in muscle was 24% of age – and tissue – matched mean. TK2 gene sequence analysis showed a heterozygous missense variant, c.515G>A (p.R172Q) and a heterozygous frame shift mutation, c.255_c.258delAGAA. The p.R172Q mutation occurs at an evolutionary conserved residue. Conclusions: This report extends the phenotype and genotype of TK2 defects. Therefore, in children with progressive myopathic and dystrophic changes, mitochondrial DNA depletion defects should be considered.