Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.
BACKGROUND
The mitochondrial DNA depletion syndrome is an autosomal recessive disorder of infancy or childhood characterized by decreased mitochondrial DNA copy number in affected tissues. Mutations in 2 genes involved in deoxyribonucleotide metabolism, the deoxyguanosine kinase gene (DGK) and the thymidine kinase 2 gene (TK2), have been related to this syndrome.


OBJECTIVE
To describe 3 siblings with the myopathic form of mitochondrial DNA depletion syndrome and a homozygous mutation in the TK2 gene.


METHODS
These children developed normally until 12 to 16 months of age, when they started showing difficulty walking, which rapidly progressed to severe limb weakness. They died of respiratory failure between the ages of 23 and 40 months. Histochemical and biochemical studies of respiratory chain complexes were performed in muscle biopsy specimens. The whole coding region of the TK2 gene was sequenced.


RESULTS
Muscle biopsy showed ragged-red cytochrome-c oxidase-negative fibers. All affected siblings had markedly decreased activities of respiratory chain complexes. Southern blot analysis showed severe reduction of the mitochondrial DNA-nuclear DNA ratio in muscle biopsy specimens from all patients, indicating 80% to 90% mitochondrial DNA depletion. Sequencing of the TK2 gene showed a homozygous C-->T transition at nucleotide 228 in exon 5, which changes a threonine to a methionine at position 77 (T77M).


CONCLUSIONS
These results document the importance of screening the TK2 gene in patients with myopathic mitochondrial DNA depletion syndrome and confirm that exon 5 is a "hot spot" for TK2 mutations.
Mancuso
Michelangelo
M
Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Filosto
Massimiliano
M
Bonilla
Eduardo
E
Hirano
Michio
M
Shanske
Sara
S
Vu
Tuan H
TH
DiMauro
Salvatore
S
D015139:Blotting, Southern; D002675:Child, Preschool; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics*; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D017809:Fatal Outcome; D005260:Female; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D017354:Point Mutation; D013937:Thymidine Kinase / Q000235:genetics*
D004272:DNA, Mitochondrial; D009247:NADH, NADPH Oxidoreductases; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; C105339:thymidine kinase 2; D013937:Thymidine Kinase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III