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Mitochondrial DNA depletion syndrome

Synonym(s) mtDNA depletion syndrome
Prevalence Unknown
Inheritance Autosomal recessive
Age of onset All ages
  • G71.3
  • C0342782
MeSH -
  • 10059396


The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mtDNA copy number in affected tissues without mutations or rearrangements in the mtDNA. MDS may be a relatively common neurogenetic disorder of infancy and childhood. In one report, 11% of young children (<2 years old) referred for weakness, hypotonia, and developmental delay had mtDNA depletion. MDS is phenotypically heterogeneous, manifesting either as a hepatocerebral form, a myopathic form, a benign 'later-onset' myopathic form or a cardiomyopathic form. Children usually present in infancy with hypotonia, lactic acidosis, and elevated serum creatin kinase (CK). Some of them also have severe, often fatal hepatopathy or renal involvement mimicking the de Toni-Fanconi syndrome. A reduced activity of the respiratory chain, and, more importantly, a low mtDNA/nDNA ratio in affected tissues confirm clinical diagnosis. MDS is thought to be a primary process. Depletion of mtDNA can also be secondary (as seen in inclusion body myositis) or iatrogenic (as seen in patients treated with nucleoside analogs). MDS often strikes recurrently in families with a possible autosomal recessive inheritance, suggesting a genetic defect in the nuclear DNA. Actually, mutations in the nuclear-encoded mitochondrial deoxyguanosine kinase (DGUOK) and deoxythymidine kinase (TK2) genes have been associated with the hepatocerebral and myopathic forms of MDS, respectively. These two genes encode mitochondrial salvage pathway enzymes, which are involved in mtDNA synthesis via supply of deoxyribonucleotides (dNTPs). Muscle weakness and exercise intolerance may be responsive to coenzyme Q supplementation.

Expert reviewer(s)

  • Dr Rosalba CARROZZO
  • Dr Simona LUCIOLI

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Detailed information

Clinical practice guidelines
  • DE (2012)
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