Defects in the replication, maintenance, and repair of
mitochondrial DNA (
mtDNA) constitute a growing and genetically heterogeneous group of
mitochondrial disorders. Multiple genes participate in these processes, including
thymidine kinase 2 (TK2) encoding the mitochondrial matrix
protein TK2, a critical component of the mitochondrial
nucleotide salvage pathway. TK2 deficiency (TK2d) causes
mtDNA depletion, multiple deletions, or both, which manifest predominantly as
mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: < 2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb
myopathy with ptosis,
ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the
TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program,
growth differentiation factor 15 (GDF-15) appears to be a useful
biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.