Brain Advance Access originally published online on September 26, 2008
Brain 2008 131(11):2841-2850; doi:10.1093/brain/awn236
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Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome
1Research Programme of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, 2Department of Paediatric Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, 3Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, 4Department of Pathology, Oulu University Hospital, Oulu, 5Paediatric Clinics, Tampere University Hospital, Tampere, 6Helsinki Medical Imaging Center, University of Helsinki and 7Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
Correspondence to: Prof. Anu Suomalainen, Research Programme of Molecular Neurology, Biomedicum-Helsinki, room c523a, Haartmaninkatu 8, University of Helsinki, 00290 Helsinki, Finland E-mail: anu.wartiovaara{at}helsinki.fi
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.
Key Words: mitochondrial DNA depletion syndrome; thymidine kinase 2; myopathy; encephalomyopathy; mtDNA
Abbreviations: APP, amyloid beta precursor protein; CK, creatine kinase; COX, cytochrome c oxidase; CytB, cytochrome B; dNTP, deoxy-nucleotidetriphosphate; EEG, electroencephalography; ENMG, electroneuromyography; GT, glutamyl transpeptidase; Mb, mega-basepair; MDS, mitochondrial DNA depletion syndrome; mtDNA, mitochondrial DNA; SDH, succinate dehydrogenase; SMA I, spinal muscular atrophy type I; TK2, thymidine kinase 2.
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Received May 23, 2008. Revised August 21, 2008. Accepted September 3, 2008.
*These authors contributed equally to this work.
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