Objective The aim of this study is to describe the phenotype of 4 Spanish patients and the finding of a novel mutation in TK2 gene. Methods We report 4 unrelated male patients from non-consanguineous families. Details of the clinically features, biochemical, anatomy pathology and genetic findings are presented. Results 3/4 showed a similar phenotype with normal early development until a progressive hypotonia and muscular weakness with a fast motor regression started between 14 and 24 months old. The other patient showed a mild late onset phenotype, starting the clinical symptoms at 4 years old with facial and hand-feet distal muscle weakness. Currently he is able to walk independently with severe hyperlordosis, facial and scapular muscle weakness. All patients presented a mild increase of serum CK and lactate levels. Electromyography showed a myopathy pattern. Muscle biopsy showed dystrophic features and COX negative fibres, lipid vacuoles and ragged red fibres (RRF) in 4/4 patients, but the patient with the mild-late onset phenotype had a less severe pattern. Genetic studies showed more than 80% of depletion in mtDNA in the muscles of all of them. The one with late-onset mild phenotype showed a less reduced percentage of depletion in mtDNA in muscle (50–60%). Sequence analysis of the TK2 gene found two heterozygous pathogenic mutations as previously described in the literature. A novel mutation (c.623A>G; p.Tyr208Cys) was found in one patient with a significant reduction of TK2 activity studied in fibroblast. Conclusion Severe and fast progressive muscle weakness in early childhood should lead the clinicians to search for evidence of mitochondria dysfunction and alert about a possible TK2 deficiency diagnosis. The new approach with dTMP–dCMP in early stages of this disorder should be considered.
