Remarkable clinical improvement with oral nucleoside treatment in a patient with adult-onset TK2 deficiency: A case report.

OBJECTIVES: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms. We present the response to treatment in a patient with adult-onset TK2d. METHODS: An adult with ptosis, ophthalmoplegia, facial, neck, and proximal muscle weakness, non-invasive nocturnal mechanical ventilation, and dysphagia due to biallelic pathogenic variants in TK2 received treatment with 260 mg/kg/day of deoxycytidine (dC) and deoxythymidine (dT) under a Compassionate Use Program. Prospective motor and respiratory assessments are presented. RESULTS: After 27 months of follow-up, the North Star Ambulatory Assessment improved by 11 points, he walked 195 m more in the 6 Minute-Walking-Test, ran 10 s faster in the 100-meter time velocity test, and the Forced Vital Capacity stabilized. Growth Differentiation Factor-15 (GDF15) levels, a biomarker of respiratory chain dysfunction, normalized. The only reported side effect was dose-dependent diarrhea. DISCUSSION: Treatment with dC and dT can significantly improve motor performance and stabilize respiratory function safely in patients with adult-onset TK2d.

Clinical and Genetic Analysis of Patients With TK2 Deficiency.

Objectives: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive disorder that stems from a perturbation of the mitochondrial DNA maintenance. Nucleoside treatment has recently shown promise as a disease-modifying therapy. TK2d was initially associated with rapidly progressive fatal myopathy in children featuring mitochondrial DNA depletion. Subsequently, less severe variants of the disease were described, with onset of symptoms during adolescence or adulthood and associated with the presence of multiple mtDNA deletions. These less severe phenotypes have been reported in only 15% of the approximately 120 patients described worldwide. However, some reports suggest that these juvenile and adult-onset presentations may be more common. The objective of this study was to describe the clinical phenotype in a sample of patients from Spain. Methods: This study includes 53 patients harboring biallelic TK2 pathogenic variants, compiling data retrospectively from 7 Spanish centers. We analyzed allele frequency, investigated the most recent common ancestor of core haplotypes, and used the Runs of Homozygosity approach to investigate variant coalescence. Results: Symptom onset distribution revealed that 32 patients (60%) experienced symptoms beyond 12 years of age. Approximately 30% of patients died of respiratory insufficiency, while 56% of surviving patients needed mechanical ventilation. Genetic analysis identified 16 distinct variants in TK2. Two variants, p.Lys202del and p.Thr108Met, exhibited significantly higher prevalence in the Spanish population than that reported in gnomAD database (86-fold and 13-fold, respectively). These variants are estimated to have originated approximately 16.8 generations ago for p.Thr108Met and 95.2 generations ago for p.Lys202del within the Spanish population, with the increase in frequency attributed to various forms of inbreeding. In late-onset cases, 46.9% carried the p.Lys202del variant. Discussion: The higher frequency of TK2d in Spain can be partially attributed to the increased prevalence of 2 variants and consanguinity. Notably, in 60% of the cohort, the disease was late-onset, emphasizing the potential underdiagnosis of this subgroup of patients in other regions. Raising awareness of this potentially treatable disorder is of utmost importance because early interventions can significantly affect the quality of life and survival of affected individuals.