TK2-Related Mitochondrial DNA Depletion Syndrome via the TK2 Gene

Mitochondrial DNA (mtDNA) Depletion Syndromes (MDSs) are a group of clinically and genetically heterogeneous diseases characterized by a quantitative abnormality of the mitochondrial genome in specific tissues (Suomalainen and Isohanni 2010; El-Hattab et al. 2013). The myopathic form of MDS has a wide clinical spectrum, with a typical age of onset that ranges from infancy to early childhood (Chanprasert et al. 2012).

The most severe presentation of TK2-related MDS is characterized by infantile myopathy with motor regression, resulting in early death from respiratory failure (Oskoui et al. 2006). Clinical features may include hypotonia, proximal muscle weakness, decreased physical stamina, poor feeding, and respiratory difficulties. Other severe phenotypes have been reported, including a spinal muscular atrophy-like presentation, rapidly progressive proximal muscle weakness with encephalopathy and epilepsy, hepatic involvement with elevated transaminases in liver tissue, and progressive myopathy with dystrophic changes (Oskoui et al. 2006; Lesko et al. 2010; Zhang et al. 2010; Collins et al. 2009).

In contrast, milder phenotypes of this disease have also been described, such as late-onset proximal muscle weakness and adult-onset progressive myopathy (Cámara et al. 2015). Although much less frequently reported, TK2 defects may cause autosomal recessive progressive external ophthalmoplegia (arPEO), which is characterized by multiple mtDNA deletions in skeletal muscle (Tyynismaa et al. 2012). This adult-onset disease features ptosis and ophthalmoparesis resulting from progressive weakness of the extraocular eye muscles.

The myopathic form of MDS is an autosomal recessive disorder caused by defects in the TK2 gene (Saada et al. 2001). TK2 has 10 exons that encode thymidine kinase, a mitochondrial deoxyribonucleoside kinase required for mtDNA synthesis. Pathogenic missense, nonsense, and splicing site variants, in addition to small deletion and insertion events, have been found across the whole coding region of TK2. Arg130Trp is a pathogenic Finnish founder variant associated with one of the most severe phenotypes (Götz et al. 2008, referred to as R172W). One large intragenic deletion (encompassing exons 1 and 2 of TK2) and one complex rearrangement have also been documented (Zhang et al. 2010; Stewart et al. 2011). Compound heterozygous TK2 pathogenic variants have also been reported to result in a rare form of adult-onset autosomal recessive progressive external ophthalmoplegia (arPEO), which is more frequently caused by defects in the POLG gene (Tyynismaa et al. 2012). Additionally, pathogenic variants in RNASEH1 or RRM2B have also been reported as a rare cause of arPEO (Reyes et al. 2015; Pitceathly et al. 2012).

In a small cohort of 13 patients, biallelic pathogenic variants in the TK2 gene were found in 46% (6/13) of patients with the myopathic form of MDS (Spinazzola et al. 2009).

Gross deletions or duplications in the TK2 gene appear to be a rare cause of mtDNA depletion syndrome. Only two families have been reported to harbor gross deletions or complex rearrangements in the TK2 gene to date (Zhang et al. 2010; Stewart et al. 2011).

This test provides full coverage of all coding exons of the TK2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).