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Becker Muscular Dystrophy (BMD) was first described in 1955 by Peter Emil Becker,1 and has been the subject of recent interest2 including a study by Janneke van den Bergen and colleagues.3 The dystrophin gene and protein were discovered 25 years ago.4 They have been intensively investigated at both the clinical and basic research level since with 6000 publications currently recorded in PubMed. A large number of different mutations (exon deletions, duplications and point mutations) are known to cause either severe Duchenne muscular dystrophy (DMD) or the milder allelic BMD, and more than 10 000 patients are recorded in locus-specific databases and patient registries. Generally, DMD patients show a complete absence of dystrophin protein in skeletal muscle, while BMD patients produce some protein, although with lower abundance or functionality. Frequently, the middle part of the dystrophin protein, the so-called rod domain, is truncated in BMD, but the C-terminal and the N-terminal domains are preserved providing binding to actin and to α-dystroglycan among other proteins. The study by van den Bergen and colleagues3 provides an in-depth clinical characterisation of patients with BMD in the Netherlands.
Despite the level of research activity, several fundamental questions about dystrophin and DMD remain unanswered: why does the clinical severity vary even with the same mutation, and what is the nature of modifier genes. Why is the involvement of other organs such as the brain (intellectual deficits, autism) and the heart (dilated cardiomyopathy, cardiac insufficiency) highly variable? Why do some muscles waste early, while others such as the extraocular muscles remain intact even at late stages of the disease? How can the dramatic clinical differences in mammalian models of dystrophin deficiency be explained? And what are the potential therapies for DMD? Many tailored molecular approaches for therapy of DMD have been explored using cell and animal models, including gene therapy, stem cell therapy and pharmacological approaches such as utrophin upregulation and myostatin blocking. While it is true that there is a general expectation that progress made in DMD research would be of potential use for BMD, the paradigm of an allelic disease with a milder clinical course has also led to the developments of therapeutic approaches based on modifying a DMD phenotype towards a BMD course.
Several of these approaches are now in clinical testing with antisense oligonucleotide (AON)-mediated exon skipping considered to be the most promising. Indeed, different AON chemistries were shown to convert an out-of-frame into an in-frame mRNA, allowing for BMD-type dystrophin protein expression in muscle of DMD patients after local and systemic administration. The proof of clinical efficacy is still awaited with phase 3 clinical studies underway.5
The exon skipping approach to DMD is highly individualised, each mutation requires a specific AON. Even the AON (skipping of exon 51) that is predicted to target the largest proportion of DMD mutations would only be suitable for a maximum of 13% of all DMD patients. Other AONs will target smaller numbers of patients, and some mutations would require two or more AONs to result in an in-frame mRNA. Moreover, depending on the original mutation of the patient, skipping will result in different protein products even with the same AON. For instance, skipping of exon 51 will result in a different protein sequence whether a patient with a deletion of exon 50 or exon 52 is treated. Theoretically, thousands of different protein sequences could be generated using a set of AONs for treating different dystrophin mutations.
While most in-frame dystrophin mRNAs with truncations of the rod domain induced by exon skipping will give rise to a semi-functional BMD protein, some will not, due to protein instability, misfolding, loss of important domains and other mechanisms. The functionality of newly generated dystrophin proteins can be tested in cell and animal model systems to some extent, but would require significant resources and time, while not necessarily predicting efficacy in the human context.6 ,7 Therefore, it is highly logical to investigate the functionality of naturally occurring truncated dystrophin protein, different dystrophin molecules, found in patients with BMD in combination with detailed clinical assessments.
Van den Bergen and colleagues identified 48 BMD patients from the Dutch patient registry carrying dystrophin mutations that would be equivalent to a DMD mutation in combination with a skipped exon, and found generally mild clinical phenotypes with longer preserved ambulation, fewer cardiac complications and normal intellect in most patients.3 This result is reassuring for the prospect of AON-mediated therapy, but has some limitations as the authors correctly point out. Except for two mutations (deletion exons 45–47 and deletion exons 46–48 with 25 and 8 patients, respectively), patient numbers are relatively small. Moreover, there is significant clinical variability even with the same mutation, for example, loss of ambulation between ages 26 and 57 years. A question that can only be answered through clinical trials relates to the influence of the timing of BMD-like protein expression: clearly different in BMD (from birth) to DMD exon skipping (likely after onset of symptoms with significant damage to muscle demonstrably present even in the early stages of the disease). Finally, for some of the mutations found in BMD, there may be only few if any DMD patients with the appropriate skippable DMD mutation. Therefore, larger and multinational studies of BMD may be warranted to gain further insights into BMD-type dystrophin protein function in humans. In addition to dystrophin protein ‘quality’, protein ‘quantity’ in relation to clinical function has been assessed in BMD patients. While the level of dystrophin protein expression may be helpful to predict the clinical severity in BMD, it is also of interest for any therapy in DMD that aims at replacing dystrophin in muscle.2
In summary, the careful clinical and molecular characterisation of BMD patients may inform about new therapeutic approaches for DMD. Therapeutic advances in DMD using some of the other approaches under development may result in benefit for BMD patients and these prospects should be examined in their own right.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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