Theragnosis for Duchenne Muscular Dystrophy

LUCE, LEONELA; CARCIONE, MICAELA; MAZZANTI, CHIARA; BUONFIGLIO, PAULA I.; DALAMÓN, VIVIANA KARINA; MESA, LILIA; CORDERÍ, JOSÉ; GILIBERTO, FLORENCIA

Pharmacogenetics and Pharmacogenomics in Latin America: Ethnic Variability, New Insights in Advances and Perspectives: A RELIVAF-CYTED Initiative

Frontiers Editorial Office

Año: 2022; p. 103 - 116

Dystrophinopathies cover a spectrumof rare progressive X-linked muscle diseases, arisingfrom DMD mutations. They are among the most common pediatric muscular dystrophies,being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact thatthere is still no cure for these serious diseases, unprecedented advances are being madefor the development of therapies for DMD. Some of which are already conditionallyapproved: exon skipping and premature stop codon read-through. The present workaimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identifycandidates for available pharmacogenetic treatments and finally, to conduct a comparativeanalysis of the Latin American (LA) frequencies of mutations amenable for available DMDtherapies. We studied 400 patients with clinical diagnosis of dystrophinopathy,implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exomeand bioinformatics. We also performed a meta-analysis of LA?s metrics for DMDavailable therapies. The employed algorithm resulted effective for the achievement ofdifferential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroidtreatment was correctly indicated and validated in 371 patients with genetic confirmation ofdystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12for exon 45 and another 70 for premature stop codon read-through therapy. Wedetermined that 87.5% of DMD patients will restore the reading frame with theskipping of only one exon. Regarding nonsense variants, UGA turned out to be themost frequent premature stop codon observed (47%). According to the meta-analysis,only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the completemolecular algorithm for dystrophinopathies. We observed different relations among theavailable targets for exon skipping in the analyzed populations, but a more even proportionof nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosiscarried out in Argentinian dystrophinopathy patients. The implemented molecularalgorithm proved to be efficient for the achievement of differential diagnosis, whichplays a crucial role in patient management, determination of the standard of care andgenetic counseling. Finally, this work contributes with the international efforts tocharacterize the frequencies and variants in LA, pillars of drug development andtheragnosis.