A defect in the thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Isolated mitochondrial myopathies (IMM) stem from primary mtDNA defects, nuclear gene mutations affecting mtDNA, or CoQ deficiency.
• Thymidine kinase 2 (TK2) gene defects typically cause mtDNA depletion by depleting mitochondrial dNTP pools in non-dividing cells.

Observation:

• A patient with IMM presented homozygous for the H90N mutation in the TK2 gene.
• Unlike previously reported cases, this patient did not exhibit mtDNA depletion.
• The patient displayed a relatively mild clinical course and ragged red muscle fibers on biopsy, with altered mitochondrial enzyme activities.

Findings:

• The H90N mutation in TK2 can cause IMM without the expected mtDNA depletion.
• Mitochondrial enzyme activity showed a mild decrease in complex I and an increase in complexes IV and II.

Implications:

• This case expands the known phenotypic spectrum of TK2 gene defects.
• Suggests screening for TK2 mutations in all IMM patients, irrespective of mtDNA quantity, is warranted.