非表示:
キーワード:
Adenosine Triphosphate/metabolism
Arginine/genetics
Child
Child, Preschool
DNA Mutational Analysis/methods
DNA, Mitochondrial/*genetics
Female
*Genetic Predisposition to Disease
Humans
Infant
Infant, Newborn
Male
Mitochondria/metabolism
Mitochondria, Muscle/genetics/metabolism
Mitochondrial Diseases/mortality
Mitochondrial Encephalomyopathies/*genetics/pathology
Muscle, Skeletal/metabolism/pathology
Mutagenesis, Site-Directed/methods
Mutation/*genetics
Thymidine Kinase/*genetics
Tryptophan/genetics
要旨:
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.
