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Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene.
Arch Neurol. 2003 Jul; 60(7):1007-9.AN

Abstract

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.

PATIENTS AND 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.

Authors+Show Affiliations

Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

12873860

Citation

Mancuso, Michelangelo, et al. "Mitochondrial Myopathy of Childhood Associated With Mitochondrial DNA Depletion and a Homozygous Mutation (T77M) in the TK2 Gene." Archives of Neurology, vol. 60, no. 7, 2003, pp. 1007-9.
Mancuso M, Filosto M, Bonilla E, et al. Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene. Arch Neurol. 2003;60(7):1007-9.
Mancuso, M., Filosto, M., Bonilla, E., Hirano, M., Shanske, S., Vu, T. H., & DiMauro, S. (2003). Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene. Archives of Neurology, 60(7), 1007-9.
Mancuso M, et al. Mitochondrial Myopathy of Childhood Associated With Mitochondrial DNA Depletion and a Homozygous Mutation (T77M) in the TK2 Gene. Arch Neurol. 2003;60(7):1007-9. PubMed PMID: 12873860.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene. AU - Mancuso,Michelangelo, AU - Filosto,Massimiliano, AU - Bonilla,Eduardo, AU - Hirano,Michio, AU - Shanske,Sara, AU - Vu,Tuan H, AU - DiMauro,Salvatore, PY - 2003/7/23/pubmed PY - 2003/8/7/medline PY - 2003/7/23/entrez SP - 1007 EP - 9 JF - Archives of neurology JO - Arch Neurol VL - 60 IS - 7 N2 - 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. PATIENTS AND 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. SN - 0003-9942 UR - https://www.unboundmedicine.com/medline/citation/12873860/Mitochondrial_myopathy_of_childhood_associated_with_mitochondrial_DNA_depletion_and_a_homozygous_mutation__T77M__in_the_TK2_gene_ DB - PRIME DP - Unbound Medicine ER -