534P Clinical and genetic characterization of Brazilian patients with TK2 deficiency

Biallelic pathogenic variants at TK2 lead to a severe and progressive and specific myopathy (TK2d). In a scenario of a potential supplementation therapy that changes the natural history of the disease, it is urgent to increase suspicion and accelerate diagnosis. We described the clinical characterization of 31 TK2d patients from several centers across Brazil. Genotype-phenotype correlation was performed for recurrent and novel variants. Motor and respiratory assessments were systematically performed in 10 patients, three of whom were receiving the nucleosides reposition therapy. Eight patients with the infantile form, 18 with childhood form and 5 with late-onset form were described. Extramuscular features were present in 30% of the cohort. Neuropathy and encephalopathy were clinically predominant for some patients. Four variants were recurrent, and one was novel, allowing genotype-phenotype correlations. T108M patients presented a milder presentation compared to the H121N group. R183T was associated with peripheral nerve involvement and c.536_538+8del with encephalomyopathic involvement. A two-year follow-up of three patients showed decreased motor, bulbar, and respiratory function, compared to a dramatic improvement in treated patients. TK2d is a very debilitating disease. Early diagnosis is essential in order to change the natural history of the disease and reduce the high mortality and morbidity rates. High diagnostic suspicion is imperative, and extramuscular involvement might play an important role for diagnostic strategies, starting with the inclusion of the TK2d in the differential diagnosis for neuropathies and epilepsy. Despite the higher mortality rates among infantile-patients, childhood-onset disease is also a debilitating and progressive disease. And the nucleosides reposition was well tolerated and benefic for the patients presented here.