Clinical and molecular spectrum of TK2-deficiency: a large Brazilian cohort.

Biallelic pathogenic variants at TK2 lead to a severe and progressive myopathy (TK2d). For a disease with unspecific clinical findings, and the possibility of a supplementation therapy that changes the natural history of the disease, highlighting clinical features that increase suspicion and accelerate diagnosis is essential. Clinical and genetic findings of 36 Brazilian patients with TK2d were identified and presented in this work. Genotype-phenotype correlation was performed for recurrent and novel variants. Motor and respiratory assessments were systematically performed in 13 patients, three of them were receiving the nucleosides replacement therapy. Natural history data was gathered from the follow up of five adult patients. Eight patients with the infantile form, 19 with childhood-onset and five with late-onset form were described. Extramuscular features were present in 30% of the cohort. Neuropathy and encephalopathy were the clinically predominant features for some patients. Four variants were recurrent (p.Thr108M, p.His121Asn, p.Arg183Trp and c.536_538 + 8del) allowing genotype-phenotype correlations, and one was novel (G91D). P.Thr108Met patients presented a milder presentation when compared to the p.His121Asn group. P.Arg183Trp was associated with peripheral nerve involvement and c.536_538 + 8del with encephalomyopathy. Long-term follow-up of 5 patients harbouring p.Thr108Met showed decreased motor, bulbar, and respiratory function, compared to a dramatic improvement in the treated patients. TK2d is a very debilitating and progressive disease among all forms including the childhood-onset as we demonstrated. Early diagnosis is essential since a potential treatment can change the natural history of the disease. Extramuscular involvement plays an important role for diagnostic strategies.