Theragnosis for Duchenne Muscular Dystrophy.

Leonela Luce,Paula I Buonfiglio,Alberto Dubrovsky,Viviana Dalamón,Micaela Carcione,Lilia Mesa,Chiara Mazzanti,Florencia Giliberto,José Corderí

doi:10.3389/fphar.2021.648390

Abstract

Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic 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 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, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, 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 counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Highlights

Muscular Dystrophies (MDs) are hereditary disorders that cause weakness and progressive degeneration of skeletal muscles
In theory dystrophinopathies can be subdivided into three distinctive clinical conditions, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMDassociated dilated cardiomyopathy (DCM), they entail a continuous spectrum of muscle diseases (Darras et al, 2000; Brandsema and Darras, 2015)
Granted that we already had the Whole Exome Sequencing (WES) results of the 29 patients without identified mutation in DMD, we broadened the screening of pathogenic variants to genes associated with other muscular dystrophies (Group 1)

Summary

Introduction

Muscular Dystrophies (MDs) are hereditary disorders that cause weakness and progressive degeneration of skeletal muscles. Dystrophinopathies are the most frequent form of MDs among the pediatric population These are X-linked recessive diseases caused by pathogenic variants in the DMD gene (OMIM ID: 300377) (Hoffman et al, 1987; Koenig et al, 1988). DMD is the most prevalent and severe pediatric form of MD, with an incidence of 1:3500–5000 male births (Mendell et al, 2012). It is characterized by progressive muscle-waste, which leads to disability and premature death (Aartsma-Rus et al, 2017). BMD affects 1:18.000 born males and has a milder symptomatology pattern and/or slower progression rate than DMD

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Conclusion