Theragnosis for Duchenne Muscular Dystrophy

LEONELA LUCE; CARCIONE, MICAELA;; MAZZANTI, CHIARA; LILIA MESA; ALBERTO DUBROVSKY; JOSÉ CORDERI; FLORENCIA GILIBERTO

Congreso; World Muscle Sociaty (WMS2021) Virtual Congress; 2021

Theragnosis for Duchenne Muscular DystrophyLuce, Leonela1,2; Carcione, Micaela1,2; Mazzanti, Chiara1,2; Mesa, Lilia4; Dubrovsky, Alberto4; José Corderí4; Giliberto, Florencia1,2*.1Laboratorio de Distrofinopatías, Cátedra de Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.2 Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina.4Instituto de Neurociencias, Fundación Favaloro, Buenos Aires, Argentina.* Correspondence: Florencia Gilibertogilibertoflor@gmail.com Keywords: Dystrophinopathies, Duchenne Muscular Dystrophy, Meta-analysis, Latin America, Theragnosis, Mutagenic spectrum, Nonsense, Exon skipping. AbstractDystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common neuromuscular diseases, being Duchenne Muscular Dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, advances are being made for the development of therapies for DMD. Some of which are already approved: exon skipping and premature stop codon read-through (Ataluren). The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of Dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome/in-silico panels and bioinformatics. We also performed a meta-analysis of LA’s metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, 371 patients with genetic confirmation of Dystrophinopathy resulted candidates for corticosteroid treatment, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for Ataluren. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Respecting nonsense variants, UGA resulted the most frequent premature stop codon observed (47%) and transitions were 2.2 times more frequent than transversions. According to the meta-analysis, only 4 LA countries (Argentina, Brazil, Colombia and Mexico) complete the molecular algorithm for Dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed countries, but a more even proportion of nonsense variants (~40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian Dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counselling. Finally, this work contributes with the international efforts to characterize the frequencies and variants of LA, pillars of drug development and theragnosis.