Interpretative Information

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. PubMed ID: 20444604; El-Hattab and Scaglia. 2013. PubMed ID: 23385875). The myopathic form of MDS has a wide clinical spectrum, with a typical age of onset that ranges from infancy to early childhood (Wang et al. 2012. PubMed ID: 23230576).

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. PubMed ID: 16908738). 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 elevated transaminases in liver tissue, and progressive myopathy with dystrophic changes (Oskoui et al. 2006. PubMed ID: 16908738; Lesko et al. 2010. PubMed ID: 20083405; Zhang et al. 2010. PubMed ID: 19815440; Collins et al. 2009. PubMed ID: 19736010).

TK2d is different from other mitochondrial diseases in that it predominantly, and sometimes exclusively, manifests as myopathy (muscle disease) (Wang et al. 2012. PubMed ID: 23230576). This severe muscle weakness affects different parts of the body and often manifests as respiratory weakness, ptosis, and/or progressive external ophthalmoplegia. Eventually, patients may lose the ability to walk, eat, and breathe independently.

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. PubMed ID: 25948719).