Clinical Spectrum of Mitochondrial DNA Depletion Due to Mutations in the Thymidine Kinase 2 Gene

Authors:
  • GDGuido Davidzon
    Guido Davidzon
  • RERicardo Erazo
    Ricardo Erazo
  • JGJuliana Gurgel-Giannetti
    Juliana Gurgel-Giannetti
  • SKSindu Krishna
    Sindu Krishna
  • EBEduardo Bonilla
    Eduardo Bonilla
  • DVDarryl C. De Vivo
    Darryl C. De Vivo
  • SSSara Shanske
    Sara Shanske
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Abstract
Mitochondrial DNA (mtDNA) depletion syndrome is an autosomal recessive disorder first described in 1991.1 It is a quantitative rather than a qualitative defect, characterized by decreased mtDNA copy numbers in affected tissues, which in turn impairs the synthesis of mtDNA-encoded respiratory chain components. The mtDNA depletion syndrome has been linked to 4 genes involved in deoxyribonucleotide triphosphate metabolism: (1) thymidine kinase 2 (TK2), associated with the myopathic form of the disease2,3; (2) deoxyguanosine kinase (DGUOK), associated with the hepatocerebral form of the disease4,5; (3) polymerase gamma (POLG), also associated with the hepatocerebral form of the disease and, more specifically, to Alpers syndrome6,7; and (4) SUCLA2, the gene encoding the β-subunit of the adenosine diphosphate–forming succinyl coenzyme A synthetase ligase, associated with a more generalized encephalomyopathic form of the disease.8 The first described children with TK2 mutations had severe infantile myopathy with motor regression and early death from respiratory insufficiency. However, more recent case reports have expanded the clinical phenotype to include a spinal muscular atrophy–like presentation9 and milder forms with longer survival.10,11 In this article, we describe 4 patients with TK2 mutations, who illustrate the variability in the clinical spectrum of mtDNA depletion syndrome, and review all cases reported to date.

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