Clinical spectrum and molecular features of asymptomatic and paucisymptomatic DMD mutations


Clinical Management

Poster Number: T301


Stefan Nicolau, MD, Abigail Wexner Research Institute at Nationwide Children's Hospital

Background: In-frame variants in the DMD gene generally cause Becker muscular dystrophy, which ranges in severity from loss of ambulation in the late teenage years to preserved ambulation into the 80s. In recent years, the widespread availability of genetic testing has led to an increased recognition of asymptomatic individuals with DMD variants.
Objective: We sought to characterize the clinical and molecular features of individuals forming the mildest end of the dystrophinopathy spectrum.
Results: Only patients with deletions, duplications, splice site, or nonsense variants were included. We identified 21 patients aged ≥10 years who had 5/5 power on the MRC scale in all muscles. In addition to these patients, we found 9 patients aged <10 who had a CK level <3-fold the ULN. The median age of the overall cohort was 13. Incidental laboratory findings or family history led to the diagnosis in 83%. Cramps or myalgias were present in 77% of patients aged ≥3. Among those aged ≥5, 83% had a North Star Ambulatory Assessment score ≥32, while 56% had the maximum score of 34. Cardiomyopathy was present in 17% of patients ≥12. Sixteen variants were represented, the most common being exon 49-51 deletion (23%), exon 48-51 deletion, exon 45-55 duplication, and p.Trp3X (10% each). In total, 53% had deletions beginning or ending at exons 45 or 51. Four patients had undergone muscle biopsy. Automated immunofluorescence analysis showed nearly 100% dystrophin-positive fibers in each case, with dystrophin expression by western blot between 51% and 100% of normal. Conclusions: These findings provide valuable prognostic information for the growing number of patients with incidentally detected DMD variants. In addition, the representation of multiple “skip-equivalent” variants demonstrates the therapeutic potential of these dystrophin isoforms, if expressed in sufficient amounts, as is the goal with next-generation exon skipping and gene editing approaches.