G.P.182: Severe and progressive mitochondrial myopathy in early childhood: novel mutations in TK2 gene

Abstract

The Thymidine kinase 2 (TK2) gene encodes an enzyme of mitochondrial expression involved in the deoxyribonucleotide triphosphates metabolism necessary for replication of mtDNA. Mutations in TK2 are associated with mtDNA depletion syndrome with a well-characterized phenotype, consisting of a severe and progressive generalised muscular weakness and respiratory failure during the first years of life. The aim of this study is to describe the clinical phenotype of 3 Spanish patients and the finding of a novel mutation in TK2 gene. We present 3 unrelated male patients from non-consanguineous families, with normal early development until they showed a progressive hypotonia and muscular weakness with a fast motor regression between 14–24 months of age. Two patients (currently 2 and 3 years of age) lost the gait few months after starting the first clinical symptoms and the other at the age of 7, this patient died at 8,5 years. At present, the other 2 patients are about to start treatment with deoxypyrimidine mono phosphates. All patients presented a mild increase of serum CK and lactate levels. Electromyogram showed a myopathic pattern. Muscle biopsy showed dystrophic features and COX negative fibres. Lipid vacuoles and ragged red fibres (RRF) were observed. The activity of respiratory chain complexes I, III and IV was decreased but there was a normal activity in complex II. Genetic studies showed more than 80 % of depletion in mtDNA in muscle. Sequence analysis of the TK2 gene found two heterozygous pathogenic mutations previously described in 2/3 patients. A novel mutation (c.623A > G; p. Tyr208Cys and c.388C > T p. Arg130Trp) was found in one patient with a significant reduction of TK2 activity studied in fibroblast. Severe and rapidly progressive muscle weakness in early childhood should prompt clinicians to search for evidence of mitochondria dysfunction and alert about a possible diagnosis of TK2 deficiency.