A comprehensive study investigating thymidine kinase 2 deficiency (TK2d) among Brazilian patients reveals pressing insights on the genetic and clinical spectrum of this severe disease. Published on March 15, 2025, the findings highlight the importance of early diagnosis and the potential for effective treatment with nucleosides replacement therapy.
TK2 deficiency is caused by biallelic pathogenic variants at the TK2 gene, leading to severe and progressive myopathy alongside mitochondrial DNA maintenance defects. This condition manifests with nonspecific clinical features, making early identification challenging yet critically important. Researchers from six tertiary neuromuscular clinics across Brazil conducted the study, focusing on 36 patients from 27 families diagnosed with TK2d.
The study comprised eight patients with the infantile form, 19 with childhood-onset, and five with late-onset TK2d. Notably, extramuscular features were present in approximately 30% of the cohort, complicting both diagnosis and management. Four recurrent variants (p.Thr108Met, p.His121.Asn, p.Arg183Trp, and c.536_538 + 8del) were identified through genotype-phenotype correlation, along with one novel variant (G91D).
According to the researchers, the p.Thr108Met variant was associated with milder disease presentations compared to those with p.His121.Asn. They noted, “Long-term follow-up of five patients harbouring p.Thr108Met showed decreased motor, bulbar, and respiratory function, compared to dramatic improvement in treated patients.” This highlights the potential impact of treatment; three patients receiving nucleosides replacement therapy exhibited significant clinical improvement.
The mean age of the patients involved was 17 years, with the study systematically gathering data from 13 patients who underwent motor and respiratory assessments. Researchers indicated the urgency of obtaining early diagnoses, noting the high mortality particularly among patients with infantile-onset forms—62% died within the first year of life due to complications like ventilatory failure.
Alongside severe muscle weakness, extramuscular manifestations such as neuropathies and encephalopathies were observed, constituting significant diagnostic and therapeutic challenges. The authors emphasized the importance of recognizing extramuscular symptoms, stating, “Extramuscular involvement plays an important role for diagnostic strategies.”
The study incorporated additional genetic assessments through commercial genetic panels and whole-exome sequencing to clarify genetic variants’ roles. Collectively, 12 variants were documented, with three patients being observed who received therapeutic nucleosides. Remarkably, these patients showed significant improvements—gaining motor function and respiratory capability, along with weight increases. For example, patient F6, after 12 months of therapy, recorded improvements such as increased scores on the Chop Intend assessment, moving from 20 to 60 points.
Detailed genetic findings indicated variant frequencies reflective of both the Brazilian and wider population's diversity. For example, the variant p.His121.Asn was found predominantly among families, marking it as significant for clinical correlation analysis.
Despite its rarity, TK2d exhibits severe repercussions on patients’ lives, exacerbated by high variability of clinical presentations based on individual genetic makeups. The study submitted findings bolster the case for more routine screening for TK2d among patients presenting with unexplained muscle weakness, particularly those exhibiting any extramuscular symptoms.
While this study is foundational, the authors acknowledge limitations due to its retrospective nature and the challenges inherent to chart reviews. Comprehensive longitudinal studies will be necessary to continue mapping the natural history of TK2d and to develop targeted strategies for diagnosis and treatment.
By enhancing awareness around TK2d and recognizing its progressive nature, the hope is to facilitate earlier diagnosis and intervention which can fundamentally alter disease trajectories. “This urgency cannot be overstated, particularly where treatment is available,” the authors concluded.