Clinical and molecular spectrum of TK2-deficiency: a large Brazilian cohort
Por:
Moreno, CAM, Artilheiro, MC, Fonseca, ATQSM, da Silva, AMS, Fernandes, TR, Camelo, CG, Paiva, MA, di Pace, FT, Pessoa, ALS, Braga, VLL, Mariano, TC, Estephan, ED, Morita, MD, Covaleski, APPM, van der Linden, V, Tomaselli, PJ, Scarpellini, GR, Gurgel-Giannetti, J, Sobrinho, LMF, de Oliveira, TM, Mendonca, RH, Lucas, ELS, Cruzeiro, MM, Junior, CWP, Junior, WM, Sobreira, CFD, Oliveira, ASB, Kok, F, Hirano, M, Nascimento-Osorio A, Schlesinger, D and Zanoteli, E
Publicada:
15 mar 2025
Ahead of Print:
15 mar 2025
Resumen:
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.
Filiaciones:
Moreno, CAM:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Mendelics, Sao Paulo, Brazil
Artilheiro, MC:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Fonseca, ATQSM:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Univ Fed Sao Paulo UNIFESP, Dept Neurol, Fac Med, Sao Paulo, Brazil
da Silva, AMS:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Fernandes, TR:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Camelo, CG:
Univ Fed Juiz de Fora UFJF, Fac Med, Fac Med, Juiz De Fora, MG, Brazil
Paiva, MA:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
di Pace, FT:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Pessoa, ALS:
Hosp Infantil Albert Sabin, Pediat Dept, Fortaleza, CE, Brazil
Braga, VLL:
Hosp Infantil Albert Sabin, Pediat Dept, Fortaleza, CE, Brazil
Mariano, TC:
Hosp Infantil Albert Sabin, Pediat Dept, Fortaleza, CE, Brazil
Estephan, ED:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Fac Med Sao Jose Do Rio Preto, Dept Neurol Sci Psychiat & Psychol, Sao Jose Do Rio Preto, SP, Brazil
Morita, MD:
Fac Med Sao Jose Do Rio Preto, Dept Neurol Sci Psychiat & Psychol, Sao Jose Do Rio Preto, SP, Brazil
Covaleski, APPM:
Univ Fed Pernambuco UFPE, Fac Med, Fac Med, Recife, PE, Brazil
Tomaselli, PJ:
Univ Sao Paulo FMUSP RP, Fac Med Ribeirao Preto, Dept Neurosci, Div Neurol, Sao Paulo, Brazil
Scarpellini, GR:
Univ Sao Paulo FMUSP RP, Fac Med Ribeirao Preto, Dept Neurosci, Div Neurol, Sao Paulo, Brazil
Gurgel-Giannetti, J:
Univ Fed Minas Gerais UFMG, Fac Med, Pediat Dept, Belo Horizonte, MG, Brazil
Sobrinho, LMF:
Univ Fed Minas Gerais UFMG, Fac Med, Pediat Dept, Belo Horizonte, MG, Brazil
de Oliveira, TM:
Univ Fed Goias UFG, Dept Pediat, Fac Med, Goiania, Go, Brazil
Mendonca, RH:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Lucas, ELS:
Hosp Moinhos Vento, Dept Genet, Porto Alegre, Brazil
Cruzeiro, MM:
Univ Fed Juiz de Fora UFJF, Fac Med, Fac Med, Juiz De Fora, MG, Brazil
Junior, CWP:
Univ Fed Minas Gerais UFMG, Fac Med, Pediat Dept, Belo Horizonte, MG, Brazil
Junior, WM:
Univ Sao Paulo FMUSP RP, Fac Med Ribeirao Preto, Dept Neurosci, Div Neurol, Sao Paulo, Brazil
Sobreira, CFD:
Univ Sao Paulo FMUSP RP, Fac Med Ribeirao Preto, Dept Neurosci, Div Neurol, Sao Paulo, Brazil
Oliveira, ASB:
Univ Fed Sao Paulo UNIFESP, Dept Neurol, Fac Med, Sao Paulo, Brazil
Kok, F:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Mendelics, Sao Paulo, Brazil
Hirano, M:
Columbia Univ, Irving Med Ctr, New York, NY USA
Nascimento-Osorio A:
Hosp St Joan de Deu, Pediat Neurol Dept, Neuromuscular & Appl Res Neuromuscular Dis Units, Neurometab Unit,Movement Disorders Unit,Synapt Met, Barcelona, Spain
Schlesinger, D:
Mendelics, Sao Paulo, Brazil
Zanoteli, E:
Fac Med Univ Sao Paulo FMUSP, Dept Neurol, Sao Paulo, Brazil
Green Submitted, gold
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