title: Two novel mutations in thymidine kinase-2 cause early onset fatal encephalomyopathy and severe mtDNA depletion.
abstract: Deficiency of thymidine kinase-2 (TK2) has been described in children with early onset fatal skeletal myopathy. TK2 is a mitochondrial deoxyribonucleoside kinase required for the phosphorylation of deoxycytidine and deoxythymidine and hence is vital for the maintenance of a balanced mitochondrial dNTP pool in post-mitotic tissues. We describe a patient with two novel TK2 mutations, which caused disease onset shortly after birth and death at the age of three months. One mutation (219insCG) generated an early stop codon, thus preventing the synthesis of a functional protein. The second mutation (R130W) resulted in an amino acid substitution, which caused a severe reduction (<3%) of TK2 enzyme activity. These two novel TK2 mutations cause an extremely severe phenotype with overwhelming central nervous system symptoms not commonly seen in patients with TK2-deficiency. We conclude that the severe clinical presentation in this patient was due to a virtual lack of mitochondrial TK2 activity.
authors.affiliation: Department of Laboratory Medicine, Division of Metabolic Diseases, Karolinska Institutet, Stockholm, Sweden. Nicole.Lesko@karolinska.se
authors.forename: Nicole
authors.initials: N
authors.lastname: Lesko
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Nicola
authors.initials: N
authors.lastname: Solaroli
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001120:Arginine / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000401:mortality; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009154:Mutation / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014364:Tryptophan / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D014364:Tryptophan; D000255:Adenosine Triphosphate; D001120:Arginine; C105339:thymidine kinase 2; D013937:Thymidine Kinase