Genotypes May Influence When Patients With DMD Have Loss of Ambulation

A single-center study of 555 individuals with Duchenne muscular dystrophy (DMD) treated with corticosteroids revealed that certain genetic mutations are linked to either delaying or accelerating the loss of ambulation.¹

These findings were published in Muscle & Nerve and emphasize the crucial role genotype plays in determining when patients with DMD lose the ability to walk, a key milestone in disease progression.

Loss of ambulation is a key milestone in disease progression | Image credit: LIGHTFIELD STUDIOS – stock.adobe.com

The study included 3948 total medical encounters occurring between 2008 and 2018. It showed that patients with mutations amenable to exon 44 skipping (P = .004), deletions of exons 3 through 7 (P < .001), and duplications of exon 2 (P = .043) experienced a delayed loss of ambulation, often maintaining mobility beyond the age of 14. In contrast, patients with genotypes amenable to exon 51 skipping had a significantly earlier loss of ambulation compared with other groups (P < .001), with just 11.9% of these individuals still able to walk after age 14 compared with 75% of those with deletions of exons 3 through 7.

“This study strengthens previously reported knowledge about genotype-phenotype correlations in DMD and highlights key differences between trends in certain genotypes of interest from the rest of the DMD population,” the study authors said. “This study focused on long term corticosteroid treated individuals and can aid in clinical trial design and clinical management.”

According to the study authors, these findings reinforce past study results on these specific genotypes and their relationship with loss of ambulation. One study compared the age at loss of ambulation between individuals with exon 44 skip amenable variants and those with exon 51 and 53 skip amenable mutations and showed that patients with the exon 44 variants lost the ability to walk about a year later in comparison. Two other studies reported a delay of approximately 2 years in loss of ambulation for those with exon 44 skip amenable mutations when compared with the broader DMD population.

Previous research has associated deletions of exons 3 through 7 with a milder DMD progression, which is hypothesized to be linked to a downstream internal AUG codon in exon 8. Consistent with these findings, the current study also found that individuals with this deletion maintained the ability to walk for longer periods. Among the 13 participants with these deletions who were over 14 years old, only 1 participant had lost the ability to walk before reaching that age.

Duplication of exon 2, the most common exon duplication seen in DMD, is known for its wide range of clinical outcomes often linked to a milder disease course due to a proposed mechanism involving exon 5. Previous studies have shown that a portion of patients with this duplication exhibit intermediate muscular dystrophy, while the majority have a Becker muscular dystrophy phenotype with a later loss of ambulation. In this study, though only 7 individuals had exon 2 duplications, they similarly demonstrated prolonged ambulation, with half still able to walk after age 14.

The study is limited by its retrospective design, making it difficult to guarantee that each participant received equal and consistent care. Many patients also had changes in their medication regimens over time, which hindered accurate subgroup analysis regarding the specific effects of different steroid treatments.

Additionally, the 10-year span of the study and its single-site focus may limit the broader applicability of the findings, as standards of care may have evolved throughout the study period. As the DMD standard of care evolves, addressing disease progression and patient quality of life remains a central focus. While corticosteroids like prednisone and deflazacort have long been the cornerstone of treatment for their anti-inflammatory benefits, their significant long-term side effects have led researchers to explore safer alternatives.² Studies on dissociative steroids, such as vamorolone, show promise in providing similar therapeutic effects with fewer adverse outcomes.

“Although novel dissociative steroids may be superior substitutes to corticosteroids, other potential therapeutics should be explored,” said the authors of a study published in the Orphanet Journal of Rare Diseases. “Repurposing or developing novel pharmacological therapies capable of addressing the many pathogenic features of DMD in addition to anti-inflammation could elicit greater therapeutic advantages.”

References

1. Zygmunt A, Wong B, Moon D, et al. The impact of genotype on age at loss of ambulation in individuals with Duchenne muscular dystrophy treated with corticosteroids: a single-center study of 555 patients. Muscle Nerve. 2024;70(5):1053-1061. doi:10.1002/mus.28255
2. Kourakis S, Timpani CA, Campelj DG, et al. Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better?. Orphanet J Rare Dis. 2021;16(1):117. doi:10.1186/s13023-021-01758-9