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Related Experiment Video

Updated: Aug 25, 2025

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Pathological Features in Paediatric Patients with TK2 Deficiency.

Cristina Jou1,2, Andres Nascimento1,2, Anna Codina1

  • 1Pathology, Biobank, Pediatric Neurology, Neuromuscular Unit and Clinical Biochemistry Departments, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain.

International Journal of Molecular Sciences
|October 14, 2022
PubMed
Summary

Thymidine kinase (TK2) deficiency in children leads to mitochondrial DNA depletion syndrome. Muscle biopsies reveal distinct pathological features that vary with age of onset, impacting disease severity.

Keywords:
TK2 deficiencymitochondrial myopathiesmuscle biopsypaediatric patientsragged red fibresultrastructural studies

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Area of Science:

  • Biochemistry
  • Genetics
  • Neurology

Background:

  • Thymidine kinase (TK2) deficiency is a genetic disorder causing mitochondrial DNA depletion syndrome (MDDS).
  • MDDS affects multiple organs, with severe neurological and muscular manifestations, particularly in pediatric patients.

Purpose of the Study:

  • To comprehensively characterize the clinical, biochemical, genetic, histopathological, and ultrastructural findings in a cohort of pediatric patients with TK2 deficiency.
  • To correlate pathological features with disease onset and severity.

Main Methods:

  • Muscle biopsy analysis including mitochondrial DNA assessment for depletion/deletion.
  • Sanger sequencing of the TK2 gene.
  • Histopathological examination (ragged red fibers, SDH activity, COX staining, MHC I expression) and immunofluorescence.
  • Ultrastructural analysis of muscle mitochondria.

Main Results:

  • Muscle biopsies consistently showed ragged red fibers (RRFs), succinate dehydrogenase (SDH) activity, and cytochrome c oxidase (COX)-negative fibers, with prevalence varying by age.
  • Younger patients exhibited endomysial inflammation and MHC I overexpression.
  • Ultrastructural analysis revealed lamellar cristae, electrodense granules, and intramitochondrial vacuoles.
  • Distinct pathological differences were observed between early- and late-onset disease, with youngest patients showing sarcomeric de-structuration.

Conclusions:

  • TK2 deficiency presents with heterogeneous muscle pathology, differing significantly based on age of onset.
  • Muscle biopsy findings, including ultrastructural alterations and inflammation, are crucial for diagnosing and understanding the pathophysiology of TK2 deficiency in pediatric patients.