BACKGROUND: TK2-related mitochondrial DNA depletion syndrome (TK2-MDS) is a rare inherited cause of progressive muscle weakness. Respiratory failure is a common cause of morbidity and mortality in this patient population.
OBJECTIVES: To gain awareness of the presentation, prognosis, and management of TK2-MDS.
RESULTS: A 13 year-old girl presents with progressive proximal muscle weakness since she was 4 years old. Before turning 13 years old, she suffered from the flu, requiring prolonged ICU stay, prolonged respiratory recovery, and use of cough assist device. Exam showed thin body habitus, mild ptosis, scapular winging, mild neck flexion weakness, and proximal weakness. Left vastus lateralis muscle biopsy at age 5 showed dystrophic changes. Genetic panel for neuromuscular disorders was negative. Whole exome sequencing revealed a homozygous p.N58S pathogenic variant in the TK2 gene. She is enrolling in clinical trials for treatment with thymidine and deoxycytidine.
A 26-year-old woman presents with progressive proximal muscle weakness since childhood and more recently weak cough and nasal dysarthria. Exam showed thin body habitus, ptosis, orbicularis oculi and buccinator weakness, neck flexion weakness, and proximal weakness. Needle EMG showed myopathic units in all muscles tested. Left vastus lateralis muscle biopsy showed ragged-red fibers. Electron microscopy showed mitochondrial pleomorphism. Whole exome sequencing revealed a homozygous c.323C>T (p.Thr108Met) pathogenic variant in the TK2 gene. She now uses Triology ventilator at night, cough assist, and co-enzyme Q10.
CONCLUSIONS: TK2-MDS should be suspected in patients with progressive proximal muscle and facial weakness, progressive external ophthalmoplegia, and progressive respiratory compromise. If there is strong clinical suspicion for myopathy, and initial genetic screen is unremarkable, whole exome sequencing should be considered. Respiratory monitoring is of utmost importance in patients with TK2-MDS, since respiratory failure is the most common cause of mortality in these patients. Thymidine and deoxycytidine show potential in treating TK2-MDS, and there are currently clinical trials involving treatment with these substances.