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Diagnosis of mitochondrial DNA depletion syndromes
  1. Shamima Rahman1,2,3,
  2. Joanna Poulton4,5
  1. 1
    Mitochondrial Research Group, UCL Institute of Child Health, London, UK
  2. 2
    MRC Centre for Neuromuscular Diseases, National Hospital for Neurology, Queen Square, London, UK
  3. 3
    Metabolic Unit, Great Ormond Street Hospital, London, UK
  4. 4
    Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK
  5. 5
    Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, UK
  1. Professor Joanna Poulton, Nuffield Department of Obstetrics and Gynaecology, Level 3, The Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; Joanna.Poulton{at}

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Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are a group of clinically heterogeneous autosomal recessive disorders characterised by a severe quantitative reduction of total mtDNA, the genetic material present exclusively within mitochondria. mtDNA is a 16.5 kb circular genome, encoding 13 subunits of the respiratory chain and 24 RNA molecules necessary for the intramitochondrial translation of these 13 proteins. Unlike nuclear DNA, where every cell contains two copies of each gene (one copy from each parent), mtDNA is a multicopy genome, each cell containing thousands of copies. mtDNA depletion has been defined as a residual mtDNA copy number of <30% compared with age-matched controls,1 2 but mtDNA levels are often <10%, and sometimes as little as 1–2%, of controls, particularly in the hepatocerebral form of the disease. Recognised clinical presentations of MDDS include early-onset hepatocerebral disease overlapping with Alpers syndrome, isolated myopathy, encephalomyopathy and the MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) syndrome (table 1).

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Table 1 The mitochondrial DNA (mtDNA) depletion syndromes: genes, phenotypes and pathogenic mechanisms

MDDS may be caused by recessive defects in proteins involved in mtDNA replication (making copies of mtDNA) or in proteins that synthesise deoxyribonucleoside triphosphates (dNTPs) for incorporation into mtDNA (table 1). Both types of defect are likely to cause stalling of the replication complex,3 a mechanism that is also important in the generation of multiple mtDNA deletions, another defect of mtDNA maintenance. Alpers syndrome and related hepatocerebral disorders constitute the most common subgroup of MDDS, caused by mutations in the POLG gene encoding the catalytic subunit of the mitochondrial DNA polymerase γ,4 5 the enzyme responsible for mtDNA replication. Alpers syndrome is characterised by intractable epilepsy and liver dysfunction, but either problem can present in isolation. In patients with POLG mutations and Alpers syndrome, the degree of tissue mtDNA depletion has some correlation with the clinical severity.6 As well as profound tissue depletion of …

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