Thymidine kinase 2 deficiency
TK2 deficiency

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Description from OMIM

Mitochondrial DNA depletion syndrome-2 is an autosomal recessive disorder characterized primarily by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later childhood onset of a slowly progressive myopathy (Oskoui et al., 2006). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Myopathy skeletal 100 % 11687801 2011-10-19
Myopathy skeletal 100 % 18819985 2011-10-11
Increased blood CK circulatory 100 % 18819985 2011-10-11
Muscle weakness skeletal 100 % 18819985 2011-10-11
Lactate accumulation circulatory 100 % 18819985 2011-10-11
Areflexia nervous 57 % 18819985 2011-10-11
Hypotonia nervous 57 % 18819985 2011-10-11
Seizures nervous 43 % 18819985 2011-10-11
Myopathy skeletal 20 % 12391347 2011-10-04
Cardiomyopathy circulatory 14 % 18819985 2011-10-11

List of references:

Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.
A Saada, A Shaag, H Mandel, Y Nevo, S Eriksson, O Elpeleg,

The mitochondrial deoxyribonucleotide (dNTP) pool is separated from the cytosolic pool because the mitochondria inner membrane is impermeable to charged molecules. The mitochondrial pool is maintained by either import of cytosolic dNTPs through dedicated transporters or by salvaging deoxynucleosides within the mitochondria; apparently, enzymes of the de novo dNTP synthesis pathway are not present in the mitochondria. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on the mitochondrial salvage pathway enzymes, the deoxyribonucleosides kinases. Two of the four human deoxyribonucleoside kinases, deoxyguanosine kinase (dGK) and thymidine kinase-2 (TK2), are expressed in mitochondria. Human dGK efficiently phosphorylates deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates deoxythymidine, deoxycytidine and deoxyuridine. Here we identify two mutations in TK2, histidine 90 to asparagine and isoleucine 181 to asparagine, in four individuals who developed devastating myopathy and depletion of muscular mitochondrial DNA in infancy. In these individuals, the activity of TK2 in muscle mitochondria is reduced to 14-45% of the mean value in healthy control individuals. Mutations in TK2 represent a new etiology for mitochondrial DNA depletion, underscoring the importance of the mitochondrial dNTP pool in the pathogenesis of mitochondrial depletion.

Nature genetics - Nov 2001

Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome.
Alexandra Götz, Pirjo Isohanni, Helena Pihko, Anders Paetau, Riitta Herva, Outi Saarenpää-Heikkilä, Leena Valanne, Sanna Marjavaara, Anu Suomalainen,

Mitochondrial DNA depletion syndrome (MDS) is a severe recessively inherited disease of childhood. It manifests most often in infancy, is rapidly progressive and leads to early death. MDS is caused by an increasing number of nuclear genes leading to multisystemic or tissue-specific decrease in mitochondrial DNA (mtDNA) copy number. Thymidine kinase 2 (TK2) has been reported to cause a myopathic form of MDS. We report here the clinical, autopsy and molecular genetic findings of rapidly progressive fatal infantile mitochondrial syndrome. All of our seven patients had rapidly progressive myopathy/encephalomyopathy, leading to respiratory failure within the first 3 years of life, with high creatine kinase values and dystrophic changes in the muscle with cytochrome c oxidase-negative fibres. In addition, two patients also had terminal-phase seizures, one had epilepsia partialis continua and one had cortical laminar necrosis. We identified two different homozygous or compound heterozygous mutations in the TK2 gene in all the patients: c.739 C s -> T and c.898 C -> T, leading to p.R172W and p.R225W changes at conserved protein sites. R172W mutation led to myopathy or encephalomyopathy with the onset during the first months of life, and was associated with severe mtDNA depletion in the muscle, brain and liver. Homozygosity for R225W mutation manifested during the second year of life as a myopathy, and showed muscle-specific mtDNA depletion. Both mutations originated from single ancient founders, with Finnish origin and enrichment for the new R172W mutation, and possibly Scandinavian ancestral origin for the R225W. We conclude that TK2 mutations may manifest as infantile-onset fatal myopathy with dystrophic features, but should be considered also in infantile progressive encephalomyopathy with wide-spread mtDNA depletion.

Brain : a journal of neurology - Nov 2008

Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.
M Mancuso, L Salviati, S Sacconi, D Otaegui, P Camaño, A Marina, S Bacman, C T Moraes, J R Carlo, M Garcia, M Garcia-Alvarez, L Monzon, A B Naini, M Hirano, E Bonilla, A L Taratuto, S DiMauro, T H Vu,

The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxy-guanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form.

Neurology - Oct 2002