P.60A retrospective study of the combination of pyrimidine nucleos(t)ides in patients with thymidine kinase 2 (TK2) deficiency

Abstract

TK2 is a mitochondrial enzyme that phosphorylates thymidine (dT) and deoxycytidine (dC) to generate deoxycytidine and deoxythymidine monophosphates (dCMP/dTMP). TK2 deficiency, an ultra-rare autosomal recessive disorder, results in severe mitochondrial DNA depletion, deletions, or both due to unbalanced nucleotide pools. TK2 deficiency presents as a severe progressive proximal muscle weakness. Clinical presentations are heterogeneous with variable rates of progression, from rapidly progressive weakness in infants and young children leading to hypotonia and death from respiratory failure to a more slowly progressive adult-onset disease manifesting as ptosis, ophthalmoplegia, dysphagia, fatigue, progressive weakness, and respiratory insufficiency. Patients with TK2 deficiency were treated with dCMP/dTMP and dC/dT under compassionate use and investigator INDs. Use of dC/dT was supported by animal studies demonstrating that pyrimidine monophosphates are metabolized to pyrimidine nucleosides. Nucleoside substrate enhancement therapy is believed to act through residual TK2 activity as well as the cytosolic salvage pathways via dCK and TK1. This retrospective medical chart review systematically gathered data on the clinical course of 38 patients at 8 clinical sites in the US, Spain, Italy, and Israel from disease onset and after pyrimidine nucleos(t)ide therapy. Medical records from the time of onset of symptoms were collected to characterize the pretreatment disease course and allow comparison with post treatment disease course. Other analyses compared survival in treated patients with an untreated patient dataset gathered from all published reports of patients with TK2 deficiency. This study provides further knowledge about the safety and efficacy of treatment with pyrimidine nucelos(t)ides and the clinical manifestations and course of disease as well as demonstrates treatment has shifted the natural history of patients with TK2 deficiency.