EP.63Clinical, pathological, and molecular findings in Argentine patients with nonsense mutations in the DMD gene

Abstract

Nonsense mutations in the DMD gene are described in around 15% of patients with dystrophinopathies. Most nonsense mutations result in a non-functional protein due to the presence of a premature stop codon in the transcribed mRNA and are associated with Duchenne muscular dystrophy. However, some patients with nonsense mutations located in in-frame exons present with a milder phenotype. The aim of this study is to describe the clinical, pathological, and molecular findings in 26 patients with nonsense mutations followed-up by our interdisciplinary team over the last 10 years. The mean age of the patients at the time of this study was 14.2 years (r: 4-20 years). Symptom onset ranged from 1 to 6 years of age. Overall, 69% of the patients received corticosteroid therapy. Nonsense mutations were located in in-frame exons in 10 cases and in out-of-frame exons in 16 cases. In the available muscle biopsies (n=18), immunostaining showed complete dystrophin deficiency in 6 cases while revertant fibers and/or dystrophin traces were observed in the remaining 12 cases. Complete dystrophin deficiency was most frequent in patients with mutations in out-of-frame exons (83.3%). Eighteen patients lost ambulation at an age ranging from 8 to 15.5 years. No significant difference was observed in the age at loss of ambulation between patients with mutations in in-frame exons and out-of-frame exons. It is noteworthy than one patient, in whom the mutation was located in exon 37, has preserved gait at 20 years of age. In-frame deletions in this dystrophin region have been observed in asymptomatic individuals. This study shows the phenotypic variation in patients with nonsense mutations in our cohort that pose a challenge regarding patient outcome in the emerging mutation-specific treatments. mRNA analysis on muscle biopsy will allow us to achieve a comprehensive genotype-phenotype correlation in these patients.